Jayesh Desai

Translation of clinical trial outcomes to metastatic colorectal cancer patients in community practice

Publisher: Wiley

Date: 17-08-2014

DOI: 10.1111/AJCO.12260

Abstract: As multiple new agents have been added to the treatment options for patients with metastatic colorectal cancer, survival outcomes in clinical trials have continued to improve. Similarly, improved outcomes in routine clinical care would be anticipated, but have yet to be demonstrated. Here, we aim to explore whether survival gains demonstrated in clinical trials are reproducible in routine practice, and whether factors beyond new therapies may be contributing to improved outcomes. Comparison of comprehensive treatment and outcome data for consecutive patients diagnosed in 2003-2006 versus 2007-2010 at four specialist hospitals in Australia. Data were available on 965 patients median age 66.1 years (range 19-93), 572 (59%) were male. For the latter time period, there was an increase in patients receiving any treatment (74% vs 66%, P = 0.014), initial combination chemotherapy (57% vs 44%, P < 0.001) and bevacizumab (15% vs 2%, P < 0.001). There was no change in the percentage undergoing resection of distant metastatic disease. For the latter time period, overall survival was improved (median 24.8 vs 17.4 months, P < 0.001), including patients not receiving any active treatment (11.9 vs 6.4 months, P = 0.014). Survival outcomes in routine clinical care for patients with metastatic colorectal cancer have markedly improved in recent years following the introduction of multiple new active therapies. The improved outcome of untreated patients suggests earlier diagnosis and improved supportive care may also be contributing to survival gains.

First-in-Man Dose-Escalation Study of the Selective BRAF Inhibitor RG7256 in Patients with BRAF V600-Mutated Advanced Solid Tumors

Publisher: Springer Science and Business Media LLC

Date: 27-08-2015

DOI: 10.1007/S11523-015-0381-X

Abstract: BRAF mutations are a validated target for cancer therapy. A second-generation BRAF inhibitor with an improved preclinical safety profile (RG7256) was evaluated in a first-in-man study in order to determine the safety, efficacy, pharmacokinetics and pharmacodynamics in patients with BRAF V600-mutated advanced solid tumors. Patients received RG7256 orally over 8 dose levels from 200 mg once a day (QD) to 2400 mg twice a day (BID) (50-, 100- and 150-mg tablets) using a classic 3 + 3 dose escalation design. In total, 45 patients were enrolled most (87 %) had advanced melanoma (94 % BRAF V600E). RG7256 was rapidly absorbed, with limited accumulation and dose-proportional increase in exposure up to 1950 mg BID. The maximal tolerated dose (MTD) was not reached. The most common drug-related adverse events (AEs) were dyspepsia (20 %), dry skin (18 %), rash (18 %), fatigue (16 %) and nausea (13 %), mainly grade 1. Three patients (7 %) developed cutaneous squamous cell carcinoma. Photosensitivity, arthralgia and increased liver enzyme levels were each observed in only one patient each. Of 44 evaluable patients, 14 (32 %) had a partial response (melanoma and thyroid cancer). At high dose levels (>1200 mg BID), 10 of 16 (63 %) patients had a partial response. A decrease in maximum standardized uptake value (SUVmax) on FDG-PET of ≥25 % was observed in 19 of 37 patients. On-treatment reductions in pERK were documented in eight of ten paired tumor s les. RG7256 has a favorable safety profile compared to other BRAF inhibitors while maintaining clinical activity, and MTD was not reached. The excessive pill burden needed to provide the desired exposure, and thus concerns about patient compliance, limited further development of this agent. Study Identifier: ClinicalTrials.gov (NCT01143753).

First-in-human phase I clinical trial of a combined immune modulatory approach using TetMYB vaccine and Anti-PD-1 antibody in patients with advanced solid cancer including colorectal or adenoid cystic carcinoma: The MYPHISMO study protocol (NCT03287427).

Publisher: Elsevier BV

Date: 12-2019

DOI: 10.1016/J.CONCTC.2019.100409

Mesenchymal chondrosarcoma: An Australian multi-centre cohort study.

Publisher: Wiley

Date: 23-05-2022

DOI: 10.1002/CAM4.4849

Abstract: Mesenchymal chondrosarcoma (MCS) is an ultra-rare sarcoma that follows a more aggressive course than conventional chondrosarcoma. This study evaluates prognostic factors, treatments (surgery, chemotherapy, and radiation), and outcomes in an Australian setting. We collected demographics, clinicopathological variables, treatment characteristics, and survival status from patients with MCS registered on the national ACCORD sarcoma database. Outcomes include overall survival (OS) and progression-free survival (PFS). We identified 22 patients with MCS between 2001-2022. Median age was 28 (range 10-59) years, 19 (86%) had localised disease at diagnosis of whom 16 had surgery (84%), 11 received radiation (58%), and 10 chemotherapy (53%). Ten (52%) developed recurrence and/or metastases on follow-up and three patients with initial metastatic disease received surgery, radiation, and chemotherapy. At a median follow-up of 50.9 (range 0.4-210) months nine patients had died. The median OS was 104.1 months (95% CI 25.8-182.3). There was improved OS for patients with localised disease who had surgical resection of the primary (p = 0.003) and those with ECOG 0-1 compared to 2-3 (p = 0.023) on univariate analysis. This study demonstrates contemporary Australian treatment patterns of MCS. The role of chemotherapy for localised disease remains uncertain. Understanding treatment patterns and outcomes help support treatment decisions and design of trials for novel therapeutic strategies.

Co-enrichment of CD8-positive T cells and macrophages is associated with clinical benefit of tislelizumab in solid tumors

Publisher: Springer Science and Business Media LLC

Date: 07-03-2023

DOI: 10.1186/S40364-023-00465-W

Abstract: Activated immune cells (IC) in the tumor microenvironment (TME) are critical for anti-tumor efficacy. Greater understanding of the dynamic ersity and crosstalk between IC is needed to clarify their association with immune checkpoint inhibitor efficacy. Patients from three tislelizumab monotherapy trials in solid tumors (NCT02407990, NCT04068519, NCT04004221) were retrospectively ided into subgroups by CD8 + T-cell and macrophage (Mφ) levels, assessed via multiplex immunohistochemistry (mIHC n = 67) or gene expression profiling (GEP n = 629). A trend of longer survival was observed in patients with both high CD8 + T-cell and Mφ levels versus other subgroups in the mIHC analysis ( P = 0.11), which was confirmed with greater statistical significance in the GEP analysis ( P = 0.0001). Co-existence of CD8 + T cells and Mφ was coupled with elevated CD8 + T-cell cytotoxicity, T-cell trafficking, MHC class I antigen presentation signatures/genes, and enrichment of the pro-inflammatory Mφ polarization pathway. Additionally, a high level of pro-inflammatory CD64 + Mφ density was associated with an immune-activated TME and survival benefit with tislelizumab (15.2 vs. 5.9 months for low density P = 0.042). Spatial proximity analysis revealed that closer proximity between CD8 + T cells and CD64 + Mφ was associated with a survival benefit with tislelizumab (15.2 vs. 5.3 months for low proximity P = 0.024). These findings support the potential role of crosstalk between pro-inflammatory Mφ and cytotoxic T cells in the clinical benefit of tislelizumab. NCT02407990, NCT04068519, NCT04004221.

Long‐term outcomes of pexidartinib in tenosynovial giant cell tumors

Publisher: Wiley

Date: 16-11-2020

DOI: 10.1002/CNCR.33312

Abstract CT029: Phase Ib study of GDC-6036 in combination with cetuximab in patients with colorectal cancer (CRC) with KRAS G12C mutation

Publisher: American Association for Cancer Research (AACR)

Date: 14-04-2023

DOI: 10.1158/1538-7445.AM2023-CT029

Abstract: Background: GDC-6036 is an oral, highly potent and selective KRAS G12C inhibitor that demonstrated anti-tumor activity in patients with KRAS G12C-positive advanced solid tumors, including CRC. In a previously reported single-agent cohort, GDC-6036 achieved a best response of partial response or complete response in 35% (19/55) of patients, with a confirmed overall response rate (ORR) of 24% (13/55 patients) in KRAS G12C-positive CRC patients (Desai et. al., ESMO 2022). EGFR blockade may sensitize tumors to KRAS G12C inhibition and the combination of an anti-EGFR antibody (cetuximab) with a KRAS G12C inhibitor showed greater anti-tumor activity than single-agent KRAS G12C inhibition in preclinical models (Amodio et. al., 2020). Methods: In an ongoing Phase I study (NCT04449874), patients with advanced or metastatic KRAS G12C-positive CRC were administered GDC-6036 (200-400 mg orally once a day) with cetuximab (400 mg/m2 intravenously initially, then 250 mg/m2 weekly) until intolerable toxicity or disease progression. Endpoints included safety (NCI-CTCAE v5), pharmacokinetics (PK), and preliminary anti-tumor activity (RECIST v1.1). Results: As of the clinical data cut-off date of 21 Nov 2022, 29 patients (enrolled by 07 Oct 2022) had received GDC-6036 and cetuximab. The median lines of prior metastatic therapy was 2 (range 1-8) and the median time on study treatment was 5.2 (range 1.4-11.2) months. All patients experienced at least one treatment-related adverse event (TRAE) the most common TRAEs (≥15%) were rash (grouped terms), diarrhea, nausea, vomiting, dry skin, and paronychia. Grade 3-4 TRAEs occurred in 11 patients (38%). Five patients (17%) experienced at least one serious AE, none of which were treatment-related (including 2 patients who died of CRC progression during the safety follow-up). AEs led to GDC-6036 modifications (interruptions and/or reductions) in 13 (45%) patients, dose reduction in 3 (10%) patients, and no patients discontinued due to AEs. Eleven patients discontinued from study treatment (10 due to disease progression and 1 due to physician’s discretion). The PK profile of GDC-6036 (400 mg once a day) was similar in combination with cetuximab when compared with single-agent. A partial response was achieved in 66% (19/29) of patients, with a confirmed ORR of 62% (18/29 patients). Conclusions: GDC-6036 in combination with cetuximab demonstrated a manageable safety profile and promising clinical activity. These data support that the addition of anti-EGFR therapy to GDC-6036 may lead to robust clinical benefit in patients with KRAS G12C-positive CRC. Citation Format: Jayesh Desai, Sae-Won Han, Jong-Seok Lee, Einat Shacham-Shmueli, Erminia Massarelli, Andrés Cervantes, Elena Garralda, Alejandro Falcon, Wilson H. Miller, Eelke Gort, Thomas Karasic, Salvatore Siena, Rafal Stec, Laura Medina, Luis Paz-Arez, Angelo Delmonte, Adrian Sacher, Hans Prenen, Martin Forster, Tae Won Kim, Matthew G. Krebs, Rasha Cosman, Yoonha Choi, Sandhya Mandlekar, Mark T. Lin, Kenneth K. Yau, Julie Chang, Stephanie Royer-Joo, Neekesh V. Dharia, Jennifer L. Schutzman, Manish Patel. Phase Ib study of GDC-6036 in combination with cetuximab in patients with colorectal cancer (CRC) with KRAS G12C mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023 Part 2 (Clinical Trials and Late-Breaking Research) 2023 Apr 14-19 Orlando, FL. Philadelphia (PA): AACR Cancer Res 2023 (8_Suppl):Abstract nr CT029.

Impact of Primary Tumor Site on Bevacizumab Efficacy in Metastatic Colorectal Cancer

Publisher: Elsevier BV

Date: 06-2016

DOI: 10.1016/J.CLCC.2016.02.007

Abstract: With an ever-increasing focus on personalized medicine, all factors known to affect treatment response need to be considered when defining optimal therapy for in idual patients. While the prognostic impact of primary tumor site on colorectal cancer (CRC) outcomes is established, emerging data suggest potential differences in response to biologic therapies. We studied the impact of tumor site on bevacizumab efficacy in patients with metastatic CRC. We analyzed data of patients in an Australian prospective multicenter metastatic CRC (mCRC) registry who received first-line chemotherapy. Tumor site was defined as right colon, cecum to transverse left colon, splenic flexure to rectosigmoid and rectum. Kaplan-Meier and Cox models were used for survival analyses. Of 926 patients, 297 had right colon, 354 left colon, and 275 rectum primary disease. Median age was 68.6, 65.9, and 63.3 years, respectively (P = .001). Right colon disease was significantly associated with intraperitoneal spread (P < .0001), while left colon and rectum disease preferentially metastasized to the liver and lungs, respectively (P < .0001 in both settings). A total of 636 patients (68.7%) received bevacizumab. Progression-free survival was superior for bevacizumab-treated patients in all groups but appeared greatest in right colon disease (hazard ratio, 0.46 95% confidence interval, 0.36-0.60 P ≤ .001). Overall survival was longest in patients with disease of the rectum, followed by left colon and right colon (median, 26.2, 23.6, and 18.2 months, respectively P = .0004). Tumor site appears to be prognostic in mCRC, with rectum and right colon disease associated with the best and worst outcomes, respectively. Patients who received bevacizumab in addition to chemotherapy had superior outcomes, with the effect appearing greatest in patients with right colon disease.

Safety, efficacy and pharmacodynamics (PD) of MEDI9447 (oleclumab) alone or in combination with durvalumab in advanced colorectal cancer (CRC) or pancreatic cancer (panc).

Publisher: American Society of Clinical Oncology (ASCO)

Date: 20-05-2018

DOI: 10.1200/JCO.2018.36.15_SUPPL.4123

An Update on Immunotherapy for Solid Tumors: A Review

Publisher: Springer Science and Business Media LLC

Date: 23-07-2018

DOI: 10.1245/S10434-018-6658-4

Abstract: In recent years, it has been demonstrated that immunotherapy is an effective strategy for the management of solid tumors. The origins of immunotherapy can be traced back to the work of William Coley, who elicited an immune response against sarcoma by injecting patients with a mixture of dead bacteria. Significant progress has been made since, with immune markers within the tumor now being used as predictors of cancer prognosis and manipulated to improve patient survival. While surgery remains central to the management of most patients with solid malignancies, it is important that surgeons consider the different immunotherapy strategies that can be employed to manage disease. Here, we highlight how the immune system influences tumorigenesis and bring attention to how current and future immunotherapies can serve as an adjunct to surgery.

Phase IA/IB study of single-agent tislelizumab, an investigational anti-PD-1 antibody, in solid tumors

Publisher: BMJ

Date: 06-2020

DOI: 10.1136/JITC-2019-000453

Abstract: The programmed cell death-1 rogrammed cell death ligand-1 (PD-1/PD-L1) axis plays a central role in suppressing antitumor immunity axis dysregulation can be used by cancer cells to evade the immune system. Tislelizumab, an investigational monoclonal antibody with high affinity and binding specificity for PD-1, was engineered to minimize binding to FcγR on macrophages to limit antibody-dependent phagocytosis, a potential mechanism of resistance to anti-PD-1 therapy. The aim of this phase IA/IB study was to investigate the safety/tolerability, antitumor effects and optimal dose and schedule of tislelizumab in patients with advanced solid tumors. Patients (aged ≥18 years) enrolled in phase IA received intravenous tislelizumab 0.5, 2, 5 or 10 mg/kg every 2 weeks 2 or 5 mg/kg administered every 2 weeks or every 3 weeks or 200 mg every 3 weeks patients in phase IB received 5 mg/kg every 3 weeks. Primary objectives were to assess tislelizumab’s safety/tolerability profile by adverse event (AE) monitoring and antitumor activity using RECIST V.1.1. PD-L1 expression was assessed retrospectively with the VENTANA PD-L1 (SP263) Assay. Between May 2015 and October 2017, 451 patients (n=116, IA n=335, IB) were enrolled. Fatigue (28%), nausea (25%) and decreased appetite (20%) were the most commonly reported AEs. Most AEs were grade 1–2 severity anemia (4.9%) was the most common grade 3–4 AE. Treatment-related AEs led to discontinuation in 5.3% of patients. Grade 5 AEs were reported in 14 patients 2 were considered related to tislelizumab. Pneumonitis (2%) and colitis (1%) were the most common serious tislelizumab-related AEs. As of May 2019, 18% of patients achieved a confirmed objective response in phase IA and 12% in phase IB median follow-up duration was 13.6 and 7.6 months, respectively. Pharmacokinetics, safety and antitumor activity obtained from both phase IA and IB determined the tislelizumab recommended dose ultimately, tislelizumab 200 mg intravenous every 3 weeks was the dose and schedule recommended to be taken into subsequent clinical trials. Tislelizumab monotherapy demonstrated an acceptable safety/tolerability profile. Durable responses were observed in heavily pretreated patients with advanced solid tumors, supporting the evaluation of tislelizumab 200 mg every 3 weeks, as monotherapy and in combination therapy, for the treatment of solid tumors and hematological malignancies. NCT02407990 .

Immunomodulation by MYB is associated with tumor relapse in patients with early stage colorectal cancer

Publisher: Informa UK Limited

Date: 29-06-2016

DOI: 10.1080/2162402X.2016.1149667

PIK3CA and PTEN gene and exon mutation-specific clinicopathologic and molecular associations in Colorectal cancer

Publisher: American Association for Cancer Research (AACR)

Date: 13-06-2013

DOI: 10.1158/1078-0432.CCR-12-3614

Abstract: Purpose: PIK3CA and PTEN mutations are prevalent in colorectal cancer and potential markers of response to mitogen-activated protein/extracellular signal–regulated kinase inhibitors and anti-EGF receptor antibody therapy. Relationships between phosphoinositide 3-kinase (PI3K) pathway mutation, clinicopathologic characteristics, molecular features, and prognosis remain controversial. Experimental Design: A total of 1,093 stage I–IV colorectal cancers were screened for PIK3CA (exons 9 and 20), KRAS (codons 12–13), BRAF (codon 600) mutations, and microsatellite instability (MSI). PTEN (exons 3–8) and CpG island methylator phenotype (CIMP) status were determined in 744 and 489 cases. PIK3CA data were integrated with 17 previous reports (n = 5,594). Results: PIK3CA and PTEN mutations were identified in 11.9% and 5.8% of colorectal cancers. PTEN mutation was associated with proximal tumors, mucinous histology, MSI-high (MSI-H), CIMP-high (CIMP-H), and BRAF mutation (P & 0.02). PIK3CA mutation was related to older age, proximal tumors, mucinous histology, and KRAS mutation (P & 0.04). In integrated cohort analysis, PIK3CA exon 9 and 20 mutations were overrepresented in proximal, CIMP-low (CIMP-L), and KRAS-mutated cancers (P ≤ 0.011). Comparing PIK3CA exonic mutants, exon 20 mutation was associated with MSI-H, CIMP-H, and BRAF mutation, and exon 9 mutation was associated with KRAS mutation (P ≤ 0.027). Disease-free survival for stage II/III colorectal cancers did not differ by PI3K pathway status. Conclusion: PI3K pathway mutation is prominent in proximal colon cancers, with PIK3CA exon 20 and PTEN mutations associated with features of the sessile-serrated pathway (MSI-H/CIMP-H/BRAFmut), and PIK3CA exon 9 (and to a lesser extent exon 20) mutation associated with features of the traditional serrated pathway (CIMP-L/KRASmut) of tumorigenesis. Our data highlight the PI3K pathway as a therapeutic target in distinct colorectal cancer subtypes. Clin Cancer Res 19(12) 3285–96. ©2013 AACR.

A phase 1, first-in-human study of AMG 900, an orally administered pan-Aurora kinase inhibitor, in adult patients with advanced solid tumors

Publisher: Springer Science and Business Media LLC

Date: 07-07-2018

DOI: 10.1007/S10637-018-0625-6

Abstract CT302: Phase Ia/Ib dose-escalation study of the anti-TIGIT antibody tiragolumab as a single agent and in combination with atezolizumab in patients with advanced solid tumors

Publisher: American Association for Cancer Research (AACR)

Date: 15-08-2020

DOI: 10.1158/1538-7445.AM2020-CT302

Abstract: Background: The immunomodulatory receptor TIGIT (T-cell Immunoreceptor with Ig and ITIM domains) is a novel inhibitory immune checkpoint present on activated T cells and NK cells in multiple cancers. In preclinical models, co-inhibition of the TIGIT and PD-L1/PD-1 pathways improved anti-tumor activity compared to either agent alone. Tiragolumab (tira or MTIG7192A) is a humanized IgG1/kappa monoclonal antibody (mAb) that binds TIGIT to prevent its interaction with its ligand PVR (CD155). In this first-in-human dose-escalation study, we report the preliminary safety and anti-tumor activity of tira as a single agent and in combination with atezolizumab (atezo) in patients with advanced solid tumors. Methods: Enrolled patients, ECOG PS 0-1, had advanced tumors for whom standard therapy did not exist or was ineffective. Patients received escalating doses of tira alone IV Q3W alone (Phase Ia) or in combination with atezo 1200 mg IV Q3W (Phase Ib) to determine the maximum tolerated dose (MTD) and continued until disease progression, intolerable toxicity, or patient/investigator decision. Study objectives included evaluation of safety and tolerability, pharmacokinetics (PK), pharmacodynamics, and anti-tumor activity of tira alone or tira + atezo. Data cut-off date was April 2019. Results: 73 patients with multiple tumor types were treated in dose-escalation (24 in Phase Ia, 49 in Ib with tira + atezo). In Phase Ia and Phase Ib, median age was 60 and 54 years, ECOG 0 for 29% and 27% of patients, and those who received ≥ 3 prior therapies were 67% and 57%, respectively. No DLTs were observed. Across doses, treatment-related AEs occurred in 67% in Phase Ia and 59% in Phase Ib (Grade ≥ 3: 4% and 4%, respectively), and most common AEs were fatigue (38%) in Phase Ia and anemia (31%) in Phase Ib. Exposure of tira increased with increasing dose, and saturation of nonlinear PK occurred at tira doses ≥ 100 mg Q3W. Complete and sustained occupancy of peripheral TIGIT receptors was observed at tira doses ≥ 30 mg Q3W. In Phase Ia, there were no objective responses, but SD of & 4 months duration was observed (n=4). In Phase Ib, there were 3 responses, which all occurred in PD-L1 positive tumors (2 non-small cell lung cancer [NSCLC]: 1 CR, 1 PR and 1 head/neck squamous cell carcinoma: PR) with two patients not receiving prior immunotherapy (CIT-naïve). Therefore, expansion cohorts were initiated in PD-L1-positive CIT-naïve indications in Phase Ib. In the metastatic NSCLC expansion cohort (n=14) ORR was 50%, with 1 CR and 6 PRs DCR was 79%, and the safety profile was similar. Conclusions: Tira monotherapy or combined with atezo was well-tolerated and had an acceptable safety profile across all dose levels. Preliminary anti-tumor activity was observed in Phase Ib with tira + atezo in CIT-naïve PD-L1-positive tumors, including NSCLC, and enrollment is ongoing in these expansion cohorts. Citation Format: Johanna C. Bendell, Philippe Bedard, Yung-Jue Bang, Patricia LoRusso, Stephen Hodi, Michael Gordon, Sandra D'Angelo, Sandra D'Angelo, Jayesh Desai, Elena Garralda, Antoine Italiano, Myung-Ju Ahn, Andres Cervantes, Zev Wainberg, Emiliano Calvo, Marta Gil-Martin, Maria Martinez-Garcia, Rastilav Bahleda, Philippe Cassier, Jean-Pierre Delord, Amy Prawira, Ignacio Melero, Leisha Emens, Emanuela Romano, Karen Miller, Robert W. Hsieh, Cloris Xue, Kari Morrissey, Patrick Twomey, Kelly Gash, Namrata S. Patil, Jane Grogan, Raymond Meng, Byoung Cho, Tae Won Kim. Phase Ia/Ib dose-escalation study of the anti-TIGIT antibody tiragolumab as a single agent and in combination with atezolizumab in patients with advanced solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR Cancer Res 2020 (16 Suppl):Abstract nr CT302.

Histone deacetylase inhibitors in cancer: What have we learned?

Publisher: Wiley

Date: 23-12-2015

DOI: 10.1002/CNCR.29177

Metastasis-Associated Gene Expression Changes Predict Poor Outcomes in Patients with Dukes Stage B and C Colorectal Cancer

Publisher: American Association for Cancer Research (AACR)

Date: 14-12-2009

DOI: 10.1158/1078-0432.CCR-09-1431

Abstract: Purpose: Colorectal cancer prognosis is currently predicted from pathologic staging, providing limited discrimination for Dukes stage B and C disease. Additional markers for outcome are required to help guide therapy selection for in idual patients. Experimental Design: A multisite single-platform microarray study was done on 553 colorectal cancers. Gene expression changes were identified between stage A and D tumors (three training sets) and assessed as a prognosis signature in stage B and C tumors (independent test and external validation sets). Results: One hundred twenty-eight genes showed reproducible expression changes between three sets of stage A and D cancers. Using consistent genes, stage B and C cancers clustered into two groups resembling early-stage and metastatic tumors. A Prediction Analysis of Microarray algorithm was developed to classify in idual intermediate-stage cancers into stage A–like/good prognosis or stage D–like oor prognosis types. For stage B patients, the treatment adjusted hazard ratio for 6-year recurrence in in iduals with stage D–like cancers was 10.3 (95% confidence interval, 1.3-80.0 P = 0.011). For stage C patients, the adjusted hazard ratio was 2.9 (95% confidence interval, 1.1-7.6 P = 0.016). Similar results were obtained for an external set of stage B and C patients. The prognosis signature was enriched for downregulated immune response genes and upregulated cell signaling and extracellular matrix genes. Accordingly, sparse tumor infiltration with mononuclear chronic inflammatory cells was associated with poor outcome in independent patients. Conclusions: Metastasis-associated gene expression changes can be used to refine traditional outcome prediction, providing a rational approach for tailoring treatments to subsets of patients. (Clin Cancer Res 2009 (24):7642–51)

Recurrent SPECC1L–NTRK fusions in pediatric sarcoma and brain tumors

Publisher: Cold Spring Harbor Laboratory

Date: 03-11-2020

DOI: 10.1101/MCS.A005710

Abstract: The identification of rearrangements driving expression of neurotrophic receptor tyrosine kinase ( NTRK ) family kinases in tumors has become critically important because of the availability of effective, specific inhibitor drugs. Whole-genome sequencing (WGS) combined with RNA sequencing (RNA-seq) can identify novel and recurrent expressed fusions. Here we describe three SPECC1L–NTRK fusions identified in two pediatric central nervous system cancers and an extracranial solid tumor using WGS and RNA-seq. These fusions arose either through a simple balanced rearrangement or in the context of a complex chromoplexy event. We cloned the SPECC1L–NTRK2 fusion directly from a patient s le and showed that enforced expression of this fusion is sufficient to promote cytokine-independent survival and proliferation. Cells transformed by SPECC1L–NTRK2 expression are sensitive to a TRK inhibitor drug. We report here that SPECC1L–NTRK fusions can arise in a range of pediatric cancers. Although WGS and RNA-seq are not required to detect NTRK fusions, these techniques may be of benefit when NTRK fusions are not suspected on clinical grounds or not identified by other methods.

A first-in-human, phase 1a/1b, open-label, dose-escalation and expansion study to investigate the safety, pharmacokinetics, and antitumor activity of the RAF dimer inhibitor BGB-3245 in patients with advanced or refractory tumors

Publisher: American Association for Cancer Research (AACR)

Date: 14-04-2023

DOI: 10.1158/1538-7445.AM2023-CT031

Abstract: Background: BGB-3245 is a RAF dimer inhibitor with preclinical activity in MAPK-altered tumor models harboring BRAF V600 mutations, atypical BRAF mutations/fusions, and RAS mutations. This study is investigating the safety, pharmacokinetics, and preliminary antitumor activity of BGB-3245 in patients (pts) with advanced or refractory MAPK-altered solid tumors. Methods: Eligible pts were ≥18 yrs old with ECOG 0-1 and had solid tumors harboring MAPK pathway alterations. Dose-escalation and cohort-size decisions were made using the Modified Toxicity Probability Interval Design. The starting dose was 5 mg QD. Treatment emergent adverse events (TEAEs) were graded per NCI CTCAE v5.0. Tumor responses were assessed by investigators using RECIST v1.1. Results: As of 1 Sep 2022, 42 pts were treated across 6 cohorts (5-60 mg QD). The median age was 60 yrs pts had received a median of 3 prior lines of treatment. All pts had TEAEs 79% had treatment-related (TR) AEs. The most common TRAEs (≥ 10%) were rash acneiform (33%), rash maculopapular (24%), fever (17%), ALT elevations and nausea (both 12%). Gr ≥3 TRAEs were reported in 29% of pts, events in ≥ 2 pts included decreased platelet count and rash maculopapular (3 each), ALT and AST elevations, and fever (2 each). Dose reductions occurred in 5 pts: rhabdomyolysis (1), LVEF decreased (1), hand-foot syndrome (1), rash maculopapular (1), and liver function abnormalities (1). Dose interruptions due to AEs occurred in 60% of pts. Dose discontinuations occurred in 79% of pts, 57% due to disease progression or death, 21% due to AE. Dose limiting toxicities were observed at 10 mg, 40 mg, and 60 mg. 40 mg QD was determined as the MTD. PK results showed generally dose-proportional increases in exposure. Tmax was at ~2 h BGB-3245 had a long terminal half-life and 7.4-fold average accumulation in exposure at steady-state. 79% of pts were efficacy evaluable. The disease control rate was 48% with 1 CR, 5 cPR, 2 uPR and 8 SD≥24 wks. Objective responders included BRAF V600E melanoma pts post-BRAF/MEK and checkpoint inhibitors (2 1 CR, 1 cPR), 1 NRAS G12S melanoma and 1 NRAS Q61K melanoma (post checkpoint inhibitors), 1 BRAF V600E LGSOC (progressed on BRAF inhibitor), 1 BRAF V600E cholangiocarcinoma (progressed on BRAF/MEK inhibitors), 1 BRAF K601E/PIK3CA endometrial cancer, and 1 KRAS G12D appendiceal cancer. Preliminary analysis of circulating tumor DNA showed correspondence to clinical response. Conclusions: BGB-3245 has a manageable safety profile and a generally dose-proportional PK. Antitumor activity was observed in pts with no approved targeted therapy options. The safety and early efficacy profile of BGB-3245 supports further investigation in selected MAPK-altered tumors. Citation Format: Alison M. Schram, Vivek Subbiah, Ryan Sullivan, Rasha Cosman, Jia Liu, Eric I. Sbar, Thuy Hoang, Jiarong Chen, Mark Johnson, Vincent Amoruccio, Todd Shearer, Adeela Kamal, Jocelyn Lewis, Wenlin Shao, Badreddin Edris, Lusong Luo, Jayesh Desai. A first-in-human, phase 1a/1b, open-label, dose-escalation and expansion study to investigate the safety, pharmacokinetics, and antitumor activity of the RAF dimer inhibitor BGB-3245 in patients with advanced or refractory tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023 Part 2 (Clinical Trials and Late-Breaking Research) 2023 Apr 14-19 Orlando, FL. Philadelphia (PA): AACR Cancer Res 2023 (8_Suppl):Abstract nr CT031.

T _STEM -like CAR-T cells exhibit improved persistence and tumor control compared with conventional CAR-T cells in preclinical models

Publisher: American Association for the Advancement of Science (AAAS)

Date: 05-04-2023

DOI: 10.1126/SCITRANSLMED.ABK1900

Abstract: Patients who receive chimeric antigen receptor (CAR)–T cells that are enriched in memory T cells exhibit better disease control as a result of increased expansion and persistence of the CAR-T cells. Human memory T cells include stem-like CD8 + memory T cell progenitors that can become either functional stem-like T (T STEM ) cells or dysfunctional T progenitor exhausted (T PEX ) cells. To that end, we demonstrated that T STEM cells were less abundant in infused CAR-T cell products in a phase 1 clinical trial testing Lewis Y-CAR-T cells (NCT03851146), and the infused CAR-T cells displayed poor persistence in patients. To address this issue, we developed a production protocol to generate T STEM -like CAR-T cells enriched for expression of genes in cell replication pathways. Compared with conventional CAR-T cells, T STEM -like CAR-T cells had enhanced proliferative capacity and increased cytokine secretion after CAR stimulation, including after chronic CAR stimulation in vitro. These responses were dependent on the presence of CD4 + T cells during T STEM -like CAR-T cell production. Adoptive transfer of T STEM -like CAR-T cells induced better control of established tumors and resistance to tumor rechallenge in preclinical models. These more favorable outcomes were associated with increased persistence of T STEM -like CAR-T cells and an increased memory T cell pool. Last, T STEM -like CAR-T cells and anti–programmed cell death protein 1 (PD-1) treatment eradicated established tumors, and this was associated with increased tumor-infiltrating CD8 + CAR + T cells producing interferon-γ. In conclusion, our CAR-T cell protocol generated T STEM -like CAR-T cells with enhanced therapeutic efficacy, resulting in increased proliferative capacity and persistence in vivo.

Safety, pharmacokinetics, and antitumor activity findings from a phase 1b, open-label, dose-escalation and expansion study investigating RAF dimer inhibitor lifirafenib in combination with MEK inhibitor mirdametinib in patients with advanced or refractory solid tumors

Publisher: American Association for Cancer Research (AACR)

Date: 14-04-2023

DOI: 10.1158/1538-7445.AM2023-CT033

Abstract: Background: RAF dimer inhibition can suppress RAF-dependent MEK reactivation leading to sustained MAPK pathway inhibition. RAF dimer inhibitor lifirafenib (L) synergized with MEK inhibitor mirdametinib (M) in RAS-mutated cancer models. In this ongoing Phase 1b study of L+M in patients (pts) with advanced/refractory solid tumors harboring MAPK pathway aberrations, we investigate preliminary safety, PK, and efficacy. Methods: Pts were enrolled by a 3+3 design and treated with L (15-20 mg QD) + M (2-4 mg QD or BID) across 9 dose levels (DLs). Primary objectives were to evaluate safety/tolerability, estimate MTD, and identify recommended Phase 2 dose (RP2D). Tumor responses were investigator assessed using RECIST v1.1. AEs were graded per NCI CTCAE v5.0. Results: Table 1 presents demographic, efficacy, and safety results as of 01 Sep 2022. Objective responses (1 CR, 14 PRs) were achieved in 15/54 (27.8%) efficacy-evaluable pts, including 10/17 low-grade serous ovarian cancer (LGSOC) (58.8% median exposure ~23 mo), 2 NSCLC (1 NRAS Q61K, 1 BRAF-V600E), 2 endometrial cancer (1 BRAF ZC3HAv1 fusion, 1 KRAS G12A), and 1 LG serous adenocarcinoma of Mullerian origin (KRAS G12V). For L and M, plasma maximum drug concentration (Cmax) and exposure (AUC) were comparable to that of each compound at same DL in monotherapy studies, suggesting low likelihood of drug-drug interaction. L+M was generally well tolerated, with limited DLTs and discontinuations. There were 2 deaths due to TEAEs considered unrelated to L+M. The MTD/RP2D were not yet determined. Conclusions: L+M demonstrated a favorable safety profile and showed antitumor activity in pts with various KRAS, NRAS, and BRAF mutations across several solid tumor types, including LGSOC, NSCLC, and endometrial cancer. The combination warrants further clinical investigation. (Acknowledgements: We thank patients/their families, investigators, and site staff for participating in this study, which is sponsored by BeiGene. Support for abstract preparation was funded by BeiGene and provided by Traci Ginnona, inSeption Group, Lansdale, PA, USA) Table 1. Demographics (N=56) Age (y), median (range) 59.5 (29-78) ECOG PS 0/1, n (%) 56 (100.0) Prior lines of therapy, median (range) 1 (1-6) Efficacy Set (N=54), n (%) LGSOC (n=17) Other than LGSOC (n=37) All malignancies (n=54) ORR (CR+PR) 10 (58.8) 5 (13.5) 15 (27.8) CR 1 (5.9) 0 1 (1.9) PR 9 (52.9) 5 (13.5) 14 (25.9) SD 6 (35.3) 18 (48.6) 24 (44.4) DCR (CR+PR+SD) 16 (94.1) 23 (62.2) 39 (72.2) Safety Set (N=56), n (%) TEAEa 55 (98.2) SAE 23 (41.1) Grade 3 TEAE 24 (42.9) TEAE leading to treatment discontinuation 3 (5.4) DLT 6 (10.7) CR, complete response DCR, disease control rate DLT, dose-limiting toxicity ECOG PS, Eastern Cooperative Oncology Group performance status LGSOC, low-grade serous ovarian cancer ORR, objective response rate PR, partial response SAE, serious adverse event SD, stable disease TEAE, treatment-emergent adverse event. a Commonly reported (& %): fatigue (55.4%), dermatitis acneiform (46.4%), and diarrhea (44.6%). Citation Format: Benjamin Solomon, Bo Gao, Vivek Subbiah, Michael Millward, Lee Rosen, Jayesh Desai, Eric I. Sbar, Neal Collins, Thuy Hoang, Xi Song, Wenlin Shao, Jaspreet Jaggi, Badreddin Edris, Paraneedharan Ramachandran, Lusong Luo, Michael Friedlander. Safety, pharmacokinetics, and antitumor activity findings from a phase 1b, open-label, dose-escalation and expansion study investigating RAF dimer inhibitor lifirafenib in combination with MEK inhibitor mirdametinib in patients with advanced or refractory solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023 Part 2 (Clinical Trials and Late-Breaking Research) 2023 Apr 14-19 Orlando, FL. Philadelphia (PA): AACR Cancer Res 2023 (8_Suppl):Abstract nr CT033.

Encorafenib Plus Cetuximab as a New Standard of Care for Previously Treated BRAF V600E–Mutant Metastatic Colorectal Cancer: Updated Survival Results and Subgroup Analyses from the BEACON Study

Publisher: American Society of Clinical Oncology (ASCO)

Date: 02-2021

DOI: 10.1200/JCO.20.02088

Abstract: BEACON CRC evaluated encorafenib plus cetuximab with or without binimetinib versus investigators' choice of irinotecan or FOLFIRI plus cetuximab in patients with BRAFV600E–mutant metastatic colorectal cancer (mCRC), after progression on 1-2 prior regimens. In the previously reported primary analysis, encorafenib, binimetinib plus cetuximab (ENCO/BINI/CETUX triplet) and encorafenib plus cetuximab (ENCO/CETUX doublet) regimens improved overall survival (OS) and objective response rate (ORR by blinded central review) versus standard of care. The purpose of this analysis was to report updated efficacy and safety data. In this open-label, phase III trial, 665 patients with BRAF V600E–mutant mCRC were randomly assigned 1:1:1 to receive triplet, doublet, or control. Primary end points were OS and independently reviewed ORR comparing triplet to control. OS for doublet versus control was a key secondary end point. Updated analyses include 6 months of additional follow-up and ORR for all randomized patients. Patients received triplet (n = 224), doublet (n = 220), or control (n = 221). Median OS was 9.3 months (95% CI, 8.2 to 10.8) for triplet and 5.9 months (95% CI, 5.1 to 7.1) for control (hazard ratio [HR], 0.60 [95% CI, 0.47 to 0.75]). Median OS for doublet was 9.3 months (95% CI, 8.0 to 11.3) (HR v control, 0.61 [95% CI, 0.48 to 0.77]). Confirmed ORR was 26.8% (95% CI, 21.1% to 33.1%) for triplet, 19.5% (95% CI, 14.5% to 25.4%) for doublet, and 1.8% (95% CI, 0.5% to 4.6%) for control. Adverse events were consistent with the prior primary analysis, with grade ≥ 3 adverse events in 65.8%, 57.4%, and 64.2% for triplet, doublet, and control, respectively. In the BEACON CRC study, encorafenib plus cetuximab improved OS, ORR, and progression-free survival in previously treated patients in the metastatic setting compared with standard chemotherapy. Based on the primary and updated analyses, encorafenib plus cetuximab is a new standard care regimen for previously treated patients with BRAF V600E mCRC.

Criteria-based curation of a therapy-focused compendium to support treatment recommendations in precision oncology

Publisher: Cold Spring Harbor Laboratory

Date: 22-12-2020

DOI: 10.1101/2020.12.18.20248521

Abstract: While several key resources exist that interpret therapeutic significance of genomic alterations in cancer, many regional real-world issues limit access to drugs. There is a need for a pragmatic, evidence-based, context-adapted tool to guide clinical management based on molecular biomarkers. A compendium of approved and experimental therapies with associated biomarkers was built following a survey of drug regulatory databases, existing knowledge bases, and published literature. Each biomarker-disease-therapy triplet was then categorized using a tiering system reflective of key therapeutic considerations: approved and reimbursed standard-of-care therapies with respect to a jurisdiction (Tier 1), evidence of efficacy or approval in another jurisdiction (Tier 2), evidence of antitumour activity (Tier 3), and plausible biological rationale (Tier 4). Two resistance categories were defined: lack of efficacy (Tier R1), and lack of antitumor activity (Tier R2). Following comprehensive literature review and appraisal, we developed a curated knowledge base focused on drugs relevant and accessible in the Australian healthcare system (TOPOGRAPH: Therapy Oriented Precision Oncology Guidelines for Recommending Anticancer Pharmaceuticals). As of November 2020, TOPOGRAPH comprised 2810 biomarker-disease-therapy triplets in 989 expert-appraised entries, including 373 therapies, 199 predictive biomarkers, and 106 cancer types. In the 345 biomarker-linked therapies catalogued, 84 (24%) and 65 (19%) therapies in contexts of different cancer types have Tier 1 and 2 designations respectively, while 271 (79%) therapies were supported by preclinical studies, early clinical trials, retrospective studies, or case series (Tiers 3 and 4). A total of 119 of 373 (33%) therapies associated with biomarkers of resistance were also catalogued. A clinical algorithm was also developed to support therapeutic decision-making using predictive biomarkers. This resource is accessible online at topograph.info/ . TOPOGRAPH is intended to support oncologists with context-appropriate clinical decision-making– optimising selection and accessibility of the most appropriate targeted therapy for any given genomic biomarker. Our approach can be readily adapted to build jurisdiction-specific resources to standardise decision-making in precision oncology.

The benefit for radiotherapy at specialised sarcoma centres: A systematic review and clinical practice guidelines from the Australia and New Zealand Sarcoma Association

Publisher: Elsevier BV

Date: 12-2022

DOI: 10.1016/J.RADONC.2022.10.037

Abstract: Patients with sarcoma are best managed at specialised sarcoma centres as supported by published literature. Optimal management requires multidisciplinary team input to formulate the diagnosis and treatment sequencing taking into consideration multiple clinical and pathologic factors. This systematic review aimed to evaluate the impact on outcomes of radiotherapy at specialised sarcoma centres. A systematic review was conducted using the population, intervention, comparison and outcome model. A literature search was performed using Medline, Embase, Cochrane Central databases for publications from 1990 to February 2022 that evaluated the local control, survival and toxicity of radiotherapy at specialised sarcoma centres. A total of 21 studies were included (17 cancer registry studies, four retrospective comparative studies). Four studies reported the local recurrence endpoint when radiotherapy was part of limb conservation treatment and showed better conformity to clinical practice guidelines and an improved local recurrence free rate when radiotherapy treatment is supported through, but may not be necessarily delivered at a specialised sarcoma centres. Only one retrospective study analysed toxicity specifically and demonstrated that patients who received preoperative radiotherapy at community centres compared to radiotherapy at a specialised sarcoma centre were more likely to develop a major wound complication. Fourteen studies reported overall survival, and 12 of these showed significantly better 5-year overall survival for patients managed at specialised sarcoma centres, however the specific impact of radiotherapy delivered at sarcoma centres could not be determined. In conclusion, patients with sarcoma should be managed through specialised sarcoma centres for better oncological outcomes. Radiotherapy in specialised sarcoma centre is associated with a lower rate of wound complications and may contribute to improved oncological outcomes as part of the limb conservation treatment at a specialised sarcoma centre.

A phase 1 trial of 4-(N-(S-penicillaminylacetyl)amino)-phenylarsonous acid (PENAO) in patients with advanced solid tumours

Publisher: Springer Science and Business Media LLC

Date: 26-01-2021

DOI: 10.1007/S00280-020-04225-7

Abstract: This phase I study was conducted to evaluate the safety and Maximum Tolerated Dose of PENAO (4-(N-(S-penicillaminylacetyl)amino)-phenylarsonous acid), a second-generation organic arsenical with anti-mitochondrial activity, when given as a continuous intravenous infusion (CIVI), in patients with advanced solid tumours. Eligibility criteria for this trial included age ≥ 18 years, advanced solid tumour, ECOG Performance Status ≤ 1 and adequate organ function. PENAO was administered by CIVI, with dose levels initially increased by infusion duration in a 21-day cycle at a fixed daily dose and then increased daily dose. Standard dose-limiting toxicity (DLT) definitions were used in a "3 + 3" design. Patients had regular monitoring of toxicity and efficacy. Pharmacokinetic assays of serum and urine As were performed. Twenty-six patients were treated across 8 dose levels. The only dose-limiting toxicity (DLT) observed was fatigue, that occurred in one patient treated at the highest dose level of 9 mg/m PENAO was administered by CIVI at dose levels up to 9 mg/m

Figure S5 from Genotype-Tailored ERK/MAPK Pathway and HDAC Inhibition Rewires the Apoptotic Rheostat to Trigger Colorectal Cancer Cell Death

Publisher: American Association for Cancer Research (AACR)

Date: 03-04-2023

DOI: 10.1158/1535-7163.22523088.V1

Abstract: Supplementary figure 5 shows mouse weight during treatment in two of the mouse studies

Responder analysis of patient-reported outcomes measurement information system (PROM'S) physical function (PF) and worst stiffness among patients with tenosynovial giant cell tumors (TGCT) in the ENLIVEN study

Publisher: American Society of Clinical Oncology (ASCO)

Date: 20-05-2019

DOI: 10.1200/JCO.2019.37.15_SUPPL.E18236

Abstract: e18236 Background: The double-blind, randomized, placebo-controlled phase 3 ENLIVEN study in TGCT demonstrated a significant tumor response at week 25 by RECIST for pexidartinib (39% vs. 0% for placebo) and improvement in joint function and symptoms. The aim of this analysis was to identify a threshold score for responder definitions for PROMIS-PF scale and Worst Stiffness Numerical Rating Scale (WS-NRS) and compared responder rates for pexidartinib versus placebo. Methods: Anchor- and distribution-based estimates were calculated, and cumulative distribution function (CDF) plots were generated to derive responder definition threshold estimates. Anchor- and distribution-based results and CDFs were evaluated through triangulation, following FDA PRO Guidance, to determine a single responder definition threshold (i.e., meaningful change) for each instrument. The proportion of responders at Week 25 between treatments was compared with Fisher’s Exact Test (2-sided). Results: 120 patients were randomized to pexidartinib (n = 61) and placebo (n = 59) and assessed through 25 weeks of treatment. Anchor-based analysis showed one-level improvement on the patient global rating of PF item was associated with a mean change of 4.0 on PROMIS-PF. Distribution-based estimates (0.5 SD and 1 SEM) for PROMIS-PF were 2.8 and 2.5, respectively. For WS-NRS, a response of “A little improved” by patients on the perception of stiffness item was associated with a mean change of 1.1. The distribution-based estimates for the WS-NRS item were 0.9 and 0.5, respectively. This resulted in the following responder definition thresholds: ≥3 points for PROMIS-PF and ≥1 for WS-NRS improvement. A greater proportion of pexidartinib as compared to placebo patients were responders by PROMIS-PF (30% vs. 5%, p 0.001) and WS-NRS (39% vs. 19%, p = 0.02) at week 25, respectively. Conclusions: Triangulation yielded responder definitions of ≥3 points for PROMIS-PF and ≥1 for WS-NRS. With these definitions, a greater proportion of patients treated with pexidartinib compared to placebo had meaningful improvement in physical function and stiffness.

Utilisation of systemic therapy options in routine treatment of metastatic colorectal cancer in Australia

Publisher: Wiley

Date: 02-2020

DOI: 10.1111/IMJ.14288

A phase I trial to determine safety and pharmacokinetics of ASLAN002, an oral MET superfamily kinase inhibitor, in patients with advanced or metastatic solid cancers.

Publisher: Springer Science and Business Media LLC

Date: 16-05-2018

DOI: 10.1007/S10637-018-0588-7

Abstract: Background The MET tyrosine kinase and its ligand, hepatocyte growth factor (HGF) also known as scatter factor, are associated with tumourigenesis and metastasis by promotion of scattering, proliferation, angiogenesis, motility and invasion. ASLAN-002 is a potent inhibitor of MET as well as related kinases. A phase I dose escalation study was conducted to determine the safety and pharmacokinetics of ASLAN-002 in patients with advanced cancer. Methods Patients with advanced or metastatic solid tumours, who had progressed on standard therapy or for whom standard therapy was not known, were administered ASLAN-002 orally. The starting dose was 100 mg once daily (QD) with subsequent cohorts to receive doses of 200 mg QD, 300 mg QD, 450 mg QD, 600 mg QD, 300 mg twice daily (BID), 450 mg BID, and 600 mg BID. Results Forty patients were included across 7 dose cohorts. Cohort 8 (600 mg BID) was not opened due to the lack of appreciable pharmacokinetic (PK) differences between 300 mg BID and 450 mg BID and higher incidences of grade 3 or 4 adverse events (AE) in Cohort 7 (450 mg BID). Fifteen patients (37.5%) experienced a grade 3 or 4 AE. The most commonly reported AEs were nausea (55%), fatigue (47.5%) and constipation (30%). One dose limiting toxicity (DLT) of atrial fibrillation was observed with 450 mg BID. Conclusions ASLAN-002 is well tolerated at 300 mg BID and is the recommended dose for future phase II studies (RP2D). Clinical Trials Registry Number: NCT01721148 .

Phase II Study of the Antiangiogenic Agent SU5416 in Patients with Advanced Soft Tissue Sarcomas

Publisher: American Association for Cancer Research (AACR)

Date: 09-2004

DOI: 10.1158/1078-0432.CCR-04-0157

Abstract: Purpose: SU5416 (semaxanib) is a small molecule inhibitor of the vascular endothelial growth factor (VEGF) receptor-2 and KIT receptor tyrosine kinases. This Phase II study was conducted to investigate the safety and efficacy of SU5416 for patients with soft tissue sarcomas. Experimental Design: Thirteen patients with locally advanced or metastatic soft tissue sarcomas were treated with SU5416 via intravenous infusion at a dose of 145 mg/m2 twice weekly. In selected cases tumor biopsies were taken before and after 2 months of treatment. Results: The median progression-free survival was 1.8 months. Median overall survival was 22.8 months. No objective tumor responses were observed. There was evidence of shorter survival among patients with high baseline urine VEGF levels (P = 0.04). No grade 4 toxicities were observed. The most common grade 3 toxicities were headache and thrombosis. Other less serious toxicities included fatigue, nausea, and abdominal pain. The median systolic blood pressure increased from 118 mmHg at baseline to 133 after 1 month of treatment (P = 0.01). Post-treatment tumor biopsies showed no significant decreases in VEGF receptor phosphorylation compared with baseline in 3 evaluable patients. One patient with gastrointestinal stromal tumor who had rapid progression during SU5416 treatment was subsequently treated with another KIT inhibitor, imatinib mesylate, and had a partial response lasting & months. Conclusions: SU5416 was relatively well tolerated but did not demonstrate significant antitumor activity against advanced soft tissue sarcoma. Correlative studies suggest that VEGF receptor or KIT inhibition was incomplete in at least some cases, providing a possible explanation for the observed lack of activity.

Figure S3 from Genotype-Tailored ERK/MAPK Pathway and HDAC Inhibition Rewires the Apoptotic Rheostat to Trigger Colorectal Cancer Cell Death

Publisher: American Association for Cancer Research (AACR)

Date: 03-04-2023

DOI: 10.1158/1535-7163.22523094.V1

Abstract: Supplementary figure 3 shows combining trametinib with different classes of HDAC inhibitors in COLO 201 cells

A phase 1a/1b first-in-human study (COMPASSION-01) evaluating cadonilimab in patients with advanced solid tumors

Publisher: Elsevier BV

Date: 10-2023

DOI: 10.1016/J.XCRM.2023.101242

Variations of Surveillance Practice for Patients with Bone Sarcoma: A Survey of Australian Sarcoma Clinicians

Publisher: Hindawi Limited

Date: 2017

DOI: 10.1155/2017/1837475

Abstract: Introduction . After treatment, bone sarcoma patients carry a high chance of relapse and late effects from multimodal therapy. We hypothesize that significant variation in surveillance practice exists between pediatric medical oncology (PO) and nonpediatric medical oncology (NP) sarcoma disciplines. Methods . Australian sarcoma clinicians were approached to do a web based survey that assessed radiologic surveillance (RS) strategies, late toxicity assessment, and posttreatment psychosocial interventions . Results . In total, 51 clinicians responded. No differences were identified in local disease RS. In metastatic disease response assessment, 100% of POs (23/23) and 93% of NPs (24/26) conducted CT chest. However, this was more likely to occur for NPs in the context of a CT chest/abdomen elvis (NP: 10/26 PO: 1/23 p = 0.006 ). POs were more likely to use CXR for RS ( p = 0.006 ). POs showed more prescriptive intensity in assessment of heart function ( p = 0.001 ), hearing ( p 0.001 ), and fertility ( p = 0.02 ). POs were more likely to deliver written information for health maintenance/treatment summary ( p = 0.04 ). The majority of respondents described enquiring about psychosocial aspects of health ( n = 33 /37, 89%), but a routine formal psychosocial screen was only used by 23% ( n = 6 /26). Conclusion . There is high variability in bone sarcoma surveillance between PO and NP clinicians. Efforts to harmonize approaches would allow early and late effects recognition/intervention and facilitate improved patient care/transition and research.

Global BRAF testing practices in metastatic colorectal cancer

Publisher: American Society of Clinical Oncology (ASCO)

Date: 20-01-2021

DOI: 10.1200/JCO.2021.39.3_SUPPL.128

Abstract: 128 Background:The BRAF V600E mutation is a marker of poor prognosis in patients with metastatic colorectal cancer (mCRC). Targeted therapy, such as encorafenib plus cetuximab, is approved in the US/Europe for the treatment (tx) of BRAF V600E-mutated mCRC and demonstrated improved survival vs historical standard of care (SOC). Determining BRAF mutation status in mCRC is recommended by NCCN and ESMO guidelines although adherence to guidelines may not be uniform. This report’s objective is to communicate global survey results of mCRC BRAF testing practices. Identifying regions where BRAF testing is not SOC may help identify where education efforts are needed improve effective tx decision making. Methods: Oncology tx centers were identified from a registry and public information. Centers were selected for research experience, historic data quality, and estimated mCRC patients. A BRAF testing practices survey using an online platform of verified centers was conducted March-August 2020 395 centers/38 countries have responded thus far. Results: Respondents indicated BRAF-mutation testing is performed as SOC for patients with mCRC in most regions Eastern Europe and South America are exceptions: only 47% (45/95) and 45% (9/20) of centers, respectively routinely performed mutation testing. Most test tumor tissue, few test both tumor tissue or blood, and none conduct blood mutation testing only. Most regions perform BRAF testing at initial diagnosis or confirmation of advanced disease. In idual country statistics will be presented. Conclusions: BRAF testing has global variability, impacting tx decisions. Increased awareness and routine testing may lead to informed decisions regarding targeted therapies, such as encorafenib plus cetuximab where approved, in patients with BRAF V600E-mutant mCRC. [Table: see text]

Impact of Diabetes Status and Medication on Presentation, Treatment, and Outcome of Stage II Colon Cancer Patients

Publisher: Hindawi Limited

Date: 2015

DOI: 10.1155/2015/189132

Abstract: Diabetes is a risk factor for colorectal cancer and several reports suggest worse cancer-specific outcomes in diabetes patients. Recent studies in multiple tumour types indicate metformin may positively impact on cancer-specific and overall survival. A population-based series of stage II colorectal cancer patients treated and followed from 2000 to 2013 were analysed for baseline characteristics, treatment, and outcomes. 1116 patients with stage II colon cancer were identified, 55.5% were male and median age was 70.9 years (range 20.5–101.2). The diabetes patients (21.6%, n = 241) were older than nondiabetes patients (median 74.0 versus 69.6, p = 0.0001). There was no impact of diabetes on cancer presentation or pathology. Diabetes patients were less likely to receive adjuvant treatment (13.7 versus 24.8%, p = 0.002) but were equally likely to complete treatment (69.7 versus 67.7%, p = 1.00). Diabetes did not significantly impact cancer recurrence (HR = 1.07, 95% CI 0.71–1.63) or overall survival (HR = 1.23, 95% CI 0.88–1.72), adjusted for age. Diabetes medication did not impact cancer recurrence or survival. Cancer presentation and outcomes in diabetes patients are comparable to those of nondiabetes patients in those with stage II colon cancer. The effect of metformin merits further evaluation in patients with colon cancer.

Impact of first-line bevacizumab therapy on the efficacy of subsequent anti-epidermal growth factor antibodies (anti-EGFR) in metastatic colorectal cancer (mCRC)

Publisher: American Society of Clinical Oncology (ASCO)

Date: 02-2016

DOI: 10.1200/JCO.2016.34.4_SUPPL.685

Abstract: 685 Background: The FIRE3 study reported that cetuximab added to first line combination chemotherapy versus the addition of bevacizumab to the same chemotherapy backbone, with a planned switch to the alternative biologic in second line therapy, resulted in improved overall survival. One possible explanation is that the sequence of biologic administration in mCRC impacts on treatment benefit. Examination of the efficacy of anti-EGFR therapy in cohorts where patients have and have not received prior bevacizumab will inform this. Methods: We interrogated our prospective database (ACCORD), which records comprehensive detail on demographics, treatments received and patient outcomes for consecutive mCRC patients in real world practice across multiple institutions in Australia. We included patients receiving 2 nd and subsequent line anti-EGFR monotherapy. Disease control rate (DCR) (partial response plus stable disease), progression free survival (PFS) and overall survival (OS) from the start of anti-EGFR were determined as a function of prior bevacizumab use. Results: From a total of 1511 patients treated between 01/10/2002 and 31/12/2014,129 patients treated with single agent anti- EGFR were identified, 75 had received prior bevacizumab. Demographics, performance status and tumour characteristics were similar between the 2 groups. 84% were confirmed KRAS exon 2 wild type. Prior treatment with bevacizumab did not impact DCR (35% vs 40%, p = 0.5065), median PFS (3.0 vs 3.0 months, p = 0.9460) or OS (8.6 vs 8.4 months, HR 0.95, p = 0.8073). Similarly, for bevacizumab treated patients, the time since last dose of bevacizumab to start of anti-EGFR ( 3 months (n = 26) vs 3-6 months (n = 17) vs 6 months (n = 32)) did not impact PFS (2.3 vs 3.6 vs 3 months) or OS (8.9 vs 10.1 vs 7.1 months, HR: 0.88, p = 0.82). Conclusions: There was no evident impact of previous bevacizumab treatment, or time from previous bevacizumab treatment, on the efficacy of single agent anti-EGFR therapy in a routine clinical practice cohort. Our data do not support the notion that prior bevacizumab renders tumors more or less sensitive to subsequent anti EGFR therapy.

Overall survival (OS) with encorafenib (enco) plus cetuximab (cetux) in BEACON CRC: Effect of prior therapy for BRAF V600E-mutant metastatic colorectal cancer (mCRC)

Publisher: American Society of Clinical Oncology (ASCO)

Date: 20-05-2021

DOI: 10.1200/JCO.2021.39.15_SUPPL.3583

Abstract: 3583 Background: Enco + cetux (doublet) has been approved in the US, EU, and Japan for the treatment of BRAF V600E-mutant mCRC after progression on 1–2 prior regimens. In the BEACON CRC study (NCT02928224), median OS (95% CI) with the doublet was 9.3 months (8.0–11.3) compared with 5.9 months (5.1–7.1) with cetux + irinotecan or FOLFIRI (control) in patients (pts) with BRAF V600E-mutant mCRC (HR 0.61 [95% CI: 0.5–0.8]). This post-hoc analysis investigates OS by prior therapies to the doublet treatment in pts with BRAF V600E-mutant mCRC from the BEACON CRC study. Methods: OS of pts treated with the doublet or control were compared according to prior treatment with bevacizumab, oxaliplatin, or FOLFOXIRI and duration of prior anticancer therapy (ACT). Results: The proportion of pts in the doublet and control arms who received prior bevacizumab were 64% and 55%, respectively. Of pts who had one prior therapy, 95% and 88% received prior oxaliplatin and 20% and 14% received prior FOLFOXIRI, respectively. OS by prior treatment in the doublet and control arms is shown in the table. In the doublet arm, pts who had bevacizumab 4 months before start of study treatment had a median OS of 8.3 months (95% CI: 6.2–11.2) those who had bevacizumab ≥4 months prior had a median OS of 10.7 (95% CI: 7.5–17.7). Within each treatment arm, OS was similar regardless of prior treatment with oxaliplatin or FOLFOXIRI. The duration of prior ACT was similar across study arms, ranging from 5.6–5.8 months for the first line of ACT. Conclusions: In the BEACON CRC study, pts treated with the doublet for BRAF V600E-mutant mCRC demonstrated similar OS regardless of prior therapies or duration of prior therapy use. This exploratory post-hoc analysis provides data that reflect the prior treatment landscape clinicians may face when deciding subsequent treatment regimens for pts with BRAF V600E-mutant mCRC. Clinical trial information: NCT02928224. [Table: see text]

Management of gastrointestinal stromal tumors in the era of tyrosine kinase inhibitors.

Publisher: Springer Science and Business Media LLC

Date: 12-2002

DOI: 10.1007/S11864-002-0068-2

Abstract: Gastrointestinal stromal tumors (GIST) represent the most common type of mesenchymal malignancy in the gastrointestinal tract. With the discovery of uncontrolled KIT tyrosine kinase signaling as a critical component in the pathogenesis of this disease, the diagnostic and treatment options for patients with GIST have evolved rapidly. Pathology review by an experienced pathologist is critical to the classification of this disease. Expert and definitive surgery remains the mainstay of treatment in patients with localized, resectable disease. Imatinib mesylate has been shown to be the first successful systemic therapy for patients with metastatic or unresectable disease and has revolutionized the treatment of this often rapidly progressive and fatal disease. Ongoing studies are evaluating the role of imatinib in the preoperative and postsurgical adjuvant settings. Although resistance to imatinib will appear over time, there is reason for optimism that the mechanisms of resistance will be identified and eventually overcome. The application of molecular understanding of GIST to the development of a selective, scientifically rational therapy is a classic ex le of multidisciplinary translational oncology research.

First-in-class, first-in-human phase 1 trial of VT3989, an inhibitor of yes-associated protein (YAP)/transcriptional enhancer activator domain (TEAD), in patients (pts) with advanced solid tumors enriched for malignant mesothelioma and other tumors with neurofibromatosis 2 (NF2) mutations

Publisher: American Association for Cancer Research (AACR)

Date: 14-04-2023

DOI: 10.1158/1538-7445.AM2023-CT006

Abstract: Background: Inactivation of the Hippo pathway is a common finding in MM and other cancers, leading to constitutive YAP activation, but has thus far been undruggable. NF2 encodes Merlin that activates Hippo kinase resulting in inactivation of YAP, which is the major effector of Hippo signaling. NF2-deficient tumors, often due to inactivating NF2 mutations (NF2m), are dependent on YAP for growth. VT3989 is an oral, highly potent and selective inhibitor of TEAD palmitoylation, which blocks YAP function and has shown promising preclinical activity. Materials and Methods: This FIH trial used a 3 + 3 dose escalation design and evaluated VT3989 from 25 to 200 mg QD continuously and 50 to 200 mg intermittently. Pts with refractory solid tumors, ECOG PS 0-1, serum albumin & 2.5, urinary protein creatinine ratio ≤ 0.5 mg/mg and albumin creatinine ratio ≤ 100 mg/g were enrolled. Objectives were to determine the safety, tolerability and recommended Phase 2 dose (RP2D) of VT3989 to evaluate antitumor activity, pharmacokinetics (PK) and correlate NF2m and other alterations in tumor and ctDNA with response. Results: 67 pts have been enrolled. Median age 63.5y (21-83y), ECOG PS 0:1 13:54 pts. Median prior therapies 3 (range 0-8). Tumor types: 42 MM (29 pleural and 13 non-pleural) and 25 solid tumors including 9 meningioma and 4 sarcoma pts. 34 pts had NF2m (29 somatic and 5 germline). All MM pts had progressed on prior platinum emetrexed all but 2 had prior immune checkpoint inhibitors. VT3989 is safe and well tolerated with no dose limiting toxicities. No MTD was defined up to 200 mg QD. The most common AEs are proteinuria, albuminuria and peripheral edema, mainly observed with the continuous schedule. There were 7 possibly related G3 AEs (fatigue, ALT, AST, dehydration, dyspnea, hypotension and peripheral edema) and 1 G4 cardiomyopathy. No pt developed decreased renal function or nephrotic syndrome. VT3989 has a 12-15 day half-life, dose proportional PK and reaches steady state within 2 weeks. Seven pts (6 refractory MM and 1 NF2m sarcoma) achieved RECIST v1.1 partial responses (PRs) with 4 confirmed, 3 unconfirmed (1 pending). 3 PRs in MM pts are ongoing up to 18+ months. The clinical benefit response rate (PR + SD & 8 weeks, per protocol) in MM pts is 57%. Of the 6 MM pts (1 pericardial, 1 pleural eritoneal and 4 peritoneal) with PR, 2 have NF2m, 3 are wildtype, and 1 is unknown. Conclusions: VT3989 is safe and well tolerated with durable RECIST v1.1 antitumor responses in pts with advanced MM and NF2m cancers, providing the first early clinical proof-of-concept for effectively drugging the Hippo-YAP-TEAD pathway. RP2D optimization including further schedule evaluation and expansion are ongoing in pts with MM and NF2m tumors. Citation Format: Timothy A. Yap, David J. Kwiatkowski, Jayesh Desai, Ibiayi Dagogo-Jack, Michael Millward, Hedy L. Kindler, Anthony W. Tolcher, Sophia Frentzas, Archie W. Thurston, Len Post, F Andrew Dorr. First-in-class, first-in-human phase 1 trial of VT3989, an inhibitor of yes-associated protein (YAP)/transcriptional enhancer activator domain (TEAD), in patients (pts) with advanced solid tumors enriched for malignant mesothelioma and other tumors with neurofibromatosis 2 (NF2) mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023 Part 2 (Clinical Trials and Late-Breaking Research) 2023 Apr 14-19 Orlando, FL. Philadelphia (PA): AACR Cancer Res 2023 (8_Suppl):Abstract nr CT006.

Phase I, Open-Label, Dose-Escalation/Dose-Expansion Study of Lifirafenib (BGB-283), an RAF Family Kinase Inhibitor, in Patients With Solid Tumors

Publisher: American Society of Clinical Oncology (ASCO)

Date: 07-2020

DOI: 10.1200/JCO.19.02654

Abstract: Lifirafenib is an investigational, reversible inhibitor of B-RAF V600E , wild-type A-RAF, B-RAF, C-RAF, and EGFR. This first-in-human, phase I, dose-escalation/dose-expansion study evaluated the safety, tolerability, and efficacy of lifirafenib in patients with B-RAF– or K-RAS/N-RAS–mutated solid tumors. During dose escalation, adult patients with histologically/cytologically confirmed advanced solid tumors received escalating doses of lifirafenib. Primary end points were safety/tolerability during dose escalation and objective response rate in preselected patients with B-RAF and K-RAS/N-RAS mutations during dose expansion. The maximum tolerated dose was established as 40 mg/d dose-limiting toxicities included reversible thrombocytopenia and nonhematologic toxicity. Across the entire study, the most common grade ≥ 3 treatment-emergent adverse events were hypertension (n = 23 17.6%) and fatigue (n = 13 9.9%). One patient with B-RAF–mutated melanoma achieved complete response, and 8 patients with B-RAF mutations had confirmed objective responses: B-RAF V600E/K melanoma (n = 5, including 1 patient treated with prior B-RAF/MEK inhibitor therapy), B-RAF V600E thyroid cancer apillary thyroid cancer (PTC n = 2), and B-RAF V600E low-grade serous ovarian cancer (LGSOC n = 1). One patient with B-RAF–mutated non–small-cell lung cancer (NSCLC) had unconfirmed partial response (PR). Patients with K-RAS–mutated endometrial cancer and K-RAS codon 12–mutated NSCLC had confirmed PR (n = 1 each). No responses were seen in patients with K-RAS/N-RAS–mutated colorectal cancer (n = 20). Lifirafenib is a novel inhibitor of key RAF family kinases and EGFR, with an acceptable risk-benefit profile and antitumor activity in patients with B-RAF V600 –mutated solid tumors, including melanoma, PTC, and LGSOC, as well as K-RAS–mutated NSCLC and endometrial carcinoma. Future comparisons with first-generation B-RAF inhibitors and exploration of lifirafenib alone or as combination therapy in patients with selected RAS mutations who are resistant/refractory to first-generation B-RAF inhibitors are warranted.

Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study

Publisher: Elsevier BV

Date: 09-2017

DOI: 10.1016/S1470-2045(17)30422-9

Clonal Evolution of Resistance to Imatinib in Patients with Metastatic Gastrointestinal Stromal Tumors

Publisher: American Association for Cancer Research (AACR)

Date: 15-09-2007

DOI: 10.1158/1078-0432.CCR-06-0858

Abstract: Purpose: Resistance to imatinib mesylate is emerging as a clinical challenge in patients with metastatic gastrointestinal stromal tumors (GIST). Novel patterns of progression have been noted in a number of these patients. The objective of this study was to correlate molecular and radiologic patterns of imitinib-refractory disease with existing conventional criteria for disease progression. Experimental Design: Patients with metastatic GIST treated with imatinib were followed with serial computed tomography/magnetic resonance imaging and [18F]fluoro-2-deoxy-d-glucose positron emission tomography. Where feasible, biopsies were done to document disease progression. Results: A total of 89 patients were followed for a median of 43 months. Forty-eight patients developed progressive disease. A unique “resistant clonal nodule” pattern (defined as a new enhancing nodular focus enclosed within a preexisting tumor mass) was seen in 23 of 48 patients and was thought to represent emergence of clones resistant to imatinib. Nodules were demonstrable a median of 5 months (range, 0-13 months) before objective progression defined by tumor size criteria and were the first sign of progression in 18 of 23 patients. Median survival among patients whose first progression was nodular was 35.1 months, compared with 44.6 months for patients whose first progression met Southwest Oncology Group criteria (P = 0.31). Comparative tumor biopsies were done in 10 patients at baseline and from progressing nodules. Genotypic analyses of KIT and PDGFRA kinases were done, revealing new activating kinase mutations in 80% (8 of 10) of these patients. Conclusion: The resistant clonal nodule is a unique pattern of disease progression seen in patients with GISTs after an initial response to imatinib and reflects the emergence of imatinib-resistant clones. Conventional tumor measurements (Southwest Oncology Group/Response Evaluation Criteria in Solid Tumors) do not detect this subtle finding. A new enhancing nodule growing within a preexisting tumor mass should be classified as a new lesion and be regarded, at least, as partial progression of GIST.

Using Genomic Sequencing to Explain an Exceptional Response to Therapy in a Malignant Phyllodes Tumor.

Publisher: American Society of Clinical Oncology (ASCO)

Date: 11-2020

DOI: 10.1200/PO.20.00305

Phase 1/2 study investigating safety, tolerability, pharmacokinetics, and preliminary antitumor activity of anti-PD-L1 monoclonal antibody bgb-A333 alone and in combination with anti-PD-1 monoclonal antibody tislelizumab in patients with advanced solid tumors

Publisher: American Society of Clinical Oncology (ASCO)

Date: 20-05-2018

DOI: 10.1200/JCO.2018.36.15_SUPPL.TPS3113

Impact of tumor site on bevacizumab (BEV) efficacy in metastatic colorectal cancer (mCRC)

Publisher: American Society of Clinical Oncology (ASCO)

Date: 20-05-2014

DOI: 10.1200/JCO.2014.32.15_SUPPL.E14558

Long-term efficacy of imatinib mesylate in patients with advanced Tenosynovial Giant Cell Tumor

Publisher: Springer Science and Business Media LLC

Date: 10-10-2019

DOI: 10.1038/S41598-019-51211-Y

Abstract: Tenosynovial giant cell tumors (TGCT), are rare colony stimulating factor-1(CSF-1)-driven proliferative disorders affecting joints. Diffuse-type TGCT often causes significant morbidity due to local recurrences necessitating multiple surgeries. Imatinib mesylate (IM) blocks the CSF-1 receptor. This study investigated the long term effects of IM in TGCT. We conducted an international multi-institutional retrospective study to assess the activity of IM: data was collected anonymously from in idual patients with locally advanced, recurrent or metastatic TGCT. Sixty-two patients from 12 institutions across Europe, Australia and the United States were identified. Four patients with metastatic TGCT progressed rapidly on IM and were excluded for further analyses. Seventeen of 58 evaluable patients achieved complete response (CR) or partial response (PR). One- and five-year progression-free survival rates were 71% and 48%, respectively. Thirty-eight (66%) patients discontinued IM after a median of 7 (range 1–80) months. Reported adverse events in 45 (78%) patients were among other edema (48%) and fatigue (50%), mostly grade 1–2 (89%). Five patients experienced grade 3–4 toxicities. This study confirms, with additional follow-up, the efficacy of IM in TGCT. In responding cases we confirmed prolonged IM activity on TGCT symptoms even after discontinuation, but with high rates of treatment interruption and additional treatments.

Figure S2 from Genotype-Tailored ERK/MAPK Pathway and HDAC Inhibition Rewires the Apoptotic Rheostat to Trigger Colorectal Cancer Cell Death

Publisher: American Association for Cancer Research (AACR)

Date: 03-04-2023

DOI: 10.1158/1535-7163.22523100

Abstract: Supplementary figure 2 shows the effect of trametinib plus panobinostat on colony formation in HCT 116 cells

Multi-activity access: How activity choice affects opportunity

Publisher: Elsevier BV

Date: 08-2020

DOI: 10.1016/J.TRD.2020.102364

Phase Ib study of atezolizumab combined with cobimetinib in patients with solid tumors

Publisher: Elsevier BV

Date: 07-2019

DOI: 10.1093/ANNONC/MDZ113

Figure S1 from Genotype-Tailored ERK/MAPK Pathway and HDAC Inhibition Rewires the Apoptotic Rheostat to Trigger Colorectal Cancer Cell Death

Publisher: American Association for Cancer Research (AACR)

Date: 03-04-2023

DOI: 10.1158/1535-7163.22523103

Abstract: Supplementary Figure 1 shows the synergistic effect of trametinib plus panobinostat in CRC cell lines and PDTO's

Multicenter retrospective analysis of metastatic colorectal cancer (CRC) with high-level microsatellite instability (MSI-H)

Publisher: Elsevier BV

Date: 05-2014

DOI: 10.1093/ANNONC/MDU100

Gender‐specific activity of chemotherapy correlates with outcomes in chemosensitive cancers of young adulthood

Publisher: Wiley

Date: 23-04-2009

DOI: 10.1002/IJC.24376

Abstract: Good evidence indicates that adolescents and young adults (AYAs) with cancer do badly compared with children with similar cancers. The reasons are poorly understood. Australian registry data on 14,824 cancers of adolescence and young adulthood seen between 1982 and 2002 were reviewed. A detailed substudy of clinical characteristics was analyzed from 179 AYAs with Hodgkin lymphoma (HL), Ewing sarcoma (ES) or osteosarcomas (OS) treated at a single institution. Despite significant improvements in survival for both groups over the period in question, for acute lymphoblastic leukaemia, rhabdomyosarcoma, ES, OS and HL, survival for AYAs was worse than for children. For ES, OS and HL, the survival gap occurred almost entirely in males (Hazard ratios compared with female AYAs of 1.8 [p < 0.01], 1.4 [p = 0.03] and 1.5 [p < 0.01] respectively). Survival outcomes from ES, OS and HL for female AYAs were not significantly different from children of either sex. For brain tumors and thyroid cancers, which are primarily treated surgically, there were no gender-related differences in outcomes. Although no differences in tumor stage or compliance were identified, male AYAs experienced less toxicity and lower response rates to chemotherapy (p = 0.008). Young males account almost entirely for excess mortality from chemosensitive cancers of adolescence and young adulthood compared to children, which may be due to relative underdosing with current chemotherapy dosing algorithms.

CD8⁺ tumor‐infiltrating lymphocytes within the primary tumor of patients with synchronous de novo metastatic colorectal carcinoma do not track with survival

Publisher: Wiley

Date: 2020

DOI: 10.1002/CTI2.1155

Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial.

Publisher: Elsevier BV

Date: 10-2006

DOI: 10.1016/S0140-6736(06)69446-4

BEACON CRC study safety lead-in (SLI) in patients with BRAF(V600E) metastatic colorectal cancer (mCRC): Efficacy and tumor markers

Publisher: American Society of Clinical Oncology (ASCO)

Date: 02-2018

DOI: 10.1200/JCO.2018.36.4_SUPPL.627

Abstract: 627 Background: The SLI of the BEACON CRC phase 3 study assessed the safety and efficacy of the combination of the BRAF inhibitor encorafenib (ENCO) + MEK inhibitor binimetinib (BINI) + anti-EGFR antibody cetuximab (CETUX) in pts with BRAF V600E -mutant mCRC after 1 or 2 prior regimens. CEA and CA19-9 are tumor markers that are widely used to monitor the effectiveness of systemic therapies for mCRC here we report on the association of CEA and CA19-9 changes while on treatment with clinical outcomes in pts from the SLI. Methods: Pts in the SLI received the triplet of ENCO 300 mg QD + BINI 45 mg BID + CETUX 400 mg/m 2 (initial dose) then 250 mg/m 2 QW in 28-day cycles. Pts were evaluated for safety, radiographic response, and change in tumor markers CEA and CA19-9. Results: 30 pts were treated. The triplet was generally well tolerated, and adverse events were consistent with known BRAF, MEK, and EGFR inhibitor toxicities. The rate of severe skin toxicities (grade 3/4) was lower than generally observed for CETUX in mCRC. Of the 29 pts with a BRAF V600E mutation, the median time on study treatment was 5.6 mo (range, 1.0–9.3 mo), and 22 (76%) remained on study treatment at the time of data cutoff. The confirmed overall response rate (ORR) was 41%, with 1 complete and 11 partial responses. In addition, 9 pts had prolonged stable disease (SD) up to 9.3 mo.CEA and CA19-9 were analyzed in 28 pts. CEA and CA19-9 decreased in 96% and 82% of these pts, respectively. Among 15 pts with treatment duration ≥5.6 mo, median/mean % decreases were 97%/79% for CEA and 92%/82% for CA19-9 in confirmed responders (n=6). Respective decreases in pts with prolonged SD (n=9) were similar: 84%/68% for CEA and 89%/68% for CA19-9. Updated safety, efficacy, and tumor marker results will be provided. Conclusions: ENCO + BINI + CETUX is generally well tolerated and has encouraging clinical activity in BRAF V 600E mCRC, with a confirmed ORR of 41%. In pts with study treatment duration ≥5.6 mo, the tumor markers CEA and CA19-9 decreased markedly and to the same degree in responders vs pts with prolonged SD, providing additional evidence of the meaningful clinical activity of this regimen. Clinical trial information: NCT02928224.

Abstract CT084: Long-term exposure (LTE) to Tislelizumab, an investigational anti-PD-1 antibody, in a first-in-human Phase I study

Publisher: American Association for Cancer Research (AACR)

Date: 07-2019

DOI: 10.1158/1538-7445.AM2019-CT084

Abstract: Background Tislelizumab (BGB-A317), an investigational monoclonal antibody with high affinity and specificity for PD-1, was engineered to minimize binding to FcγR on macrophages in order to abrogate antibody-dependent phagocytosis, a potential mechanism of resistance to anti-PD-1 therapy. Previous reports from early phase studies suggest tislelizumab was generally well tolerated and had antitumor activity in patients (pts) with advanced solid tumors. Clinical effects of tislelizumab LTE (& mo) in pts enrolled in the first-in-human study (NCT02407990) are presented here. Methods Patients with advanced solid tumors received IV tislelizumab 0.5, 2, 5, or 10 mg/kg Q2W, 2 or 5 mg/kg administered Q2W or Q3W, or 200 mg IV Q3W. Antitumor activity was assessed by RECIST v1.1 criteria PD-L1 expression was retrospectively assessed with the VENTANA PD-L1 (SP263) assay. Results As of 31 Aug 2018, 63 of the 451 pts received tislelizumab for & mo. In these 63 pts, median age was 64 yr and 70% had received ≥1 prior systemic therapy. Tislelizumab LTE was most common in NSCLC (n=9), HCC (n=7), and bladder and ovarian (n=5 each) cancers. Four of the 5 pts who achieved CR during this study had LTE to tislelizumab (Table) all 4 pts were PD-L1+ (≥1% expression on tumor cells). Across the LTE cohort, ORR was 66.7% PR and SD were observed in both PD-L1+ and PD-L1- tumors. The median time to CR/PR (3.7 mo) and duration of CR/PR (21.1 mo) were longer in pts with LTE than pts who responded but did not remain on treatment for & mo (2.1 and 6.3 mo, respectively). Rash was the only treatment-related AE (TRAE) reported in ≥15% of pts. Most TRAEs were of mild or moderate severity arthritis, diarrhea, fatigue, granuloma, hyperglycemia, and lichenoid keratosis (n=1 each) were the only grade ≥3 TRAEs reported with tislelizumab LTE. Conclusion Tislelizumab remained well tolerated for & mo and elicited durable responses in pts with a variety of tumor types regardless of PD-L1 status. PD-L1+ (n=35)PD-L1- (n=22)Missing (n=6)Total (N=63)CR4004 (6.3%)PR2113438 (60.3%)SD99220 (31.7%)PD1001 (1.6%)Abbreviations: CR, complete response PD, progressive disease PR, partial response SD stable disease. Citation Format: Jayesh Desai, Benjamin Markman, Michael Friedlander, Hui Gan, Lisa Horvath, Amanda Townsend, Michael Millward, Michael Jameson, Chia-Jui Yen, Ming-Mo Hou, Jeannie Hou, John Wu, Liang Liang, Sanjeev Deva. Long-term exposure (LTE) to Tislelizumab, an investigational anti-PD-1 antibody, in a first-in-human Phase I study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019 2019 Mar 29-Apr 3 Atlanta, GA. Philadelphia (PA): AACR Cancer Res 2019 (13 Suppl):Abstract nr CT084.

Response to Cetuximab With or Without Irinotecan in Patients With Refractory Metastatic Colorectal Cancer Harboring the KRAS G13D Mutation: Australasian Gastro-Intestinal Trials Group ICECREAM Study

Publisher: American Society of Clinical Oncology (ASCO)

Date: 07-2016

DOI: 10.1200/JCO.2015.65.6843

Abstract: RAS mutations predict lack of response to epidermal growth factor receptor monoclonal antibody therapy in patients with metastatic colorectal cancer (mCRC), but preclinical studies and retrospective clinical data suggest that patients with tumors harboring the exon 2 KRAS G13D mutation may benefit from cetuximab. We aimed to assess cetuximab monotherapy and cetuximab plus irinotecan in patients with molecularly selected (G13D mutation) chemotherapy-refractory mCRC in a randomized phase II trial of this rare molecular subtype. Patients with chemotherapy-refractory KRAS G13D mutation–positive mCRC who had progressed within 6 months of irinotecan therapy were randomly assigned to cetuximab 400 mg/m 2 loading dose and then 250 mg/m 2 once per week with or without irinotecan 180 mg/m 2 once every 2 weeks. The primary end point was 6-month progression-free survival secondary end points were response rate, overall survival, quality of life, and toxicity. Fifty-one of 53 patients recruited over 2 years were eligible. The 6-month progression-free survival rate was 10% (95% CI, 2% to 26%) for cetuximab versus 23% (95% CI, 9% to 40%) for cetuximab plus irinotecan with a hazard ratio of 0.74 (95% CI, 0.42 to 1.32). Response and stable disease rates were 0% and 58% for monotherapy versus 9% and 70% for combination treatment, respectively. Overall survival and quality of life were similar toxicities were higher with combination therapy. In patients with G13D-mutated chemotherapy-refractory mCRC, there was no statistically significant improvement in disease control at 6 months with either cetuximab monotherapy or cetuximab plus irinotecan. No responses were seen with single-agent cetuximab. The responses observed with the combination of cetuximab and irinotecan may reflect true drug synergy or persistent irinotecan sensitivity. The ICECREAM (Irinotecan Cetuximab Evaluation and Cetuximab Response Evaluation Among Patients with a G13D Mutation) study demonstrates the need to prospectively evaluate hypotheses that were previously supported by retrospective analyses and exemplifies the value of international collaboration in trials of rare molecular subtypes.

Personalized management: Inoperable gastrointestinal stromal tumors

Publisher: Elsevier BV

Date: 2014

DOI: 10.1016/J.CGH.2013.08.032

Abstract: Historically, patients with inoperable gastrointestinal stromal tumors (GISTs) had a very poor prognosis because of the highly resistant nature of these tumors to conventional chemotherapy. The rational and progressive development of tyrosine kinase inhibitors (TKIs) since the initial proof-of-concept studies with imatinib mesylate in the late 1990s, all designed to exploit key pathways that lead to GISTs being so oncogenically addicted, have revolutionized the treatment of GIST. Median overall survival has improved from less than a year to at least 5 years in patients with advanced or metastatic disease. Imatinib remains the standard first-line treatment in advanced GIST however, resistance to imatinib and subsequent other TKIs inevitably develops in most but not all patients. As much as efforts will continue to identify new drugs for patients with disease that becomes refractory to these agents, there has also been a need to focus on optimizing the use of currently available therapies by using a combination of molecular tools to stratify patients more effectively, pharmacodynamic markers and pharmacokinetic modeling to maximize these agents' activity in in idual patients, and reappraising the role of surgery in the management of patients with metastatic disease. These all form part of a modern, multidisciplinary approach to the management of GIST patients.

Nutlin-3a efficacy in sarcoma predicted by transcriptomic and epigenetic profiling

Publisher: American Association for Cancer Research (AACR)

Date: 02-2013

DOI: 10.1158/0008-5472.CAN-13-2424

Abstract: Nutlin-3a is a small-molecule antagonist of p53/MDM2 that is being explored as a treatment for sarcoma. In this study, we examined the molecular mechanisms underlying the sensitivity of sarcomas to Nutlin-3a. In an ex vivo tissue explant system, we found that TP53 pathway alterations (TP53 status, MDM2/MDM4 genomic lification/mRNA overexpression, MDM2 SNP309, and TP53 SNP72) did not confer apoptotic or cytostatic responses in sarcoma tissue biopsies (n = 24). Unexpectedly, MDM2 status did not predict Nutlin-3a sensitivity. RNA sequencing revealed that the global transcriptomic profiles of these sarcomas provided a more robust prediction of apoptotic responses to Nutlin-3a. Expression profiling revealed a subset of TP53 target genes that were transactivated specifically in sarcomas that were highly sensitive to Nutlin-3a. Of these target genes, the GADD45A promoter region was shown to be hypermethylated in 82% of wild-type TP53 sarcomas that did not respond to Nutlin-3a, thereby providing mechanistic insight into the innate ability of sarcomas to resist apoptotic death following Nutlin-3a treatment. Collectively, our findings argue that the existing benchmark biomarker for MDM2 antagonist efficacy (MDM2 lification) should not be used to predict outcome but rather global gene expression profiles and epigenetic status of sarcomas dictate their sensitivity to p53/MDM2 antagonists. Cancer Res 74(3) 921–31. ©2013 AACR.

A phase I study of AL101, a pan-NOTCH inhibitor, in patients (pts) with locally advanced or metastatic solid tumors

Publisher: American Society of Clinical Oncology (ASCO)

Date: 20-05-2018

DOI: 10.1200/JCO.2018.36.15_SUPPL.2515

Sunitinib malate in the treatment of renal cell carcinoma and gastrointestinal stromal tumor: Recommendations for patient management

Publisher: Wiley

Date: 12-2007

DOI: 10.1111/J.1743-7563.2007.00136.X

ICECREAM: randomised phase II study of cetuximab alone or in combination with irinotecan in patients with metastatic colorectal cancer with either KRAS, NRAS, BRAF and PI3KCA wild type, or G13D mutated tumours

Publisher: Springer Science and Business Media LLC

Date: 31-05-2016

DOI: 10.1186/S12885-016-2389-8

Comprehensive mapping of p53 pathway alterations reveals an apparent role for both SNP309 and MDM2 amplification in sarcomagenesis

Publisher: American Association for Cancer Research (AACR)

Date: 02-2011

DOI: 10.1158/1078-0432.CCR-10-2050

Abstract: Purpose: Reactivation of p53 tumor suppressor activity in diseases such as soft-tissue sarcoma is considered an attractive means of targeted therapy. By systematically assessing alterations affecting the p53 pathway, we aimed to (a) classify sarcoma subtypes, (b) define a potential role in malignancy, and (c) identify potential patient biomarkers in this heterogeneous disease. Experimental Design: We have mapped mutational events in a panel of 192 benign or malignant bone and soft-tissue sarcomas. Analyses included TP53 and CDKN2A mutational and SNP status, MDM2 and MDM4 lification and MDM2 SNP309 status. Results: We found an inverse relationship between MDM2 lification and TP53 mutations, with a predominantly wild-type CDKN2A background. A high rate of point mutations in TP53 was observed uniquely in leiomyosarcoma, osteosarcoma, and MFH. Both MDM2 and MDM4 were also lified in a subtype-specific manner, which was frequently seen as a co lification event. We have also analyzed the risk allele frequencies for MDM2 SNP309, and show that the G allele was strongly associated with both liposarcomas and MDM2 lification. Conclusions: Our data emphasize the critical role of p53 inactivation in sarcomagenesis, whereby different pathway alterations may be related to the heterogeneity of the disease. Moreover, we observed a strong association of malignancy with TP53 mutation, or MDM2 lification and the presence of a G allele in SNP309, especially in lipoma versus liposarcoma. We propose, therefore, that MDM2 markers along with TP53 sequencing should be considered as patient biomarkers in clinical trials of sarcomas using MDM2 antagonists. Clin Cancer Res 17(3) 416–26. ©2010 AACR.

BCL-XL inhibitors enhance the apoptotic efficacy of BRAF inhibitors in BRAFV600E colorectal cancer

Publisher: Research Square Platform LLC

Date: 25-07-2023

DOI: 10.21203/RS.3.RS-3112884/V1

Abstract: Metastatic BRAF V600E colorectal cancer (CRC) carries an extremely poor prognosis and is in urgent need of effective new treatments. While the BRAF V600E inhibitor encorafenib in combination with the EGFR inhibitor cetuximab (Enc+Cet) was recently approved for this indication, overall survival is only increased by 3.6 months and objective responses are observed in only 20% of patients. We have found that a limitation of Enc+Cet treatment is the failure to efficiently induce apoptosis in BRAF V600E CRCs, despite inducing expression of the pro-apoptotic protein BIM and repressing expression of the pro-survival protein MCL-1. Here, we show that BRAF V600E CRCs express high basal levels of the pro-survival proteins MCL-1 and BCL-X L , and that combining encorafenib with a BCL-X L inhibitor significantly enhances apoptosis in BRAF V600E CRC cell lines. This effect was directly dependent on the induction of BIM as BIM deletion markedly attenuated BRAF plus BCL-X L inhibitor-induced apoptosis. As thrombocytopenia is an established on-target toxicity of BCL-X L inhibition, we also examined the effect of combining encorafenib with the BCL-X L targeting PROTAC DT2216, and the novel BCL-2/BCL-X L inhibitor dendrimer conjugate AZD0466. Combining encorafenib with DT2216 significantly increased the induction of apoptosis in vitro, while combining encorafenib with AZD0466 was well tolerated in mice and further reduced growth of BRAF V600E CRC xenografts compared to either agent alone. Collectively, these findings demonstrate that combined BRAF and BCL-X L inhibition significantly enhances apoptosis in pre-clinical models of BRAF V600E CRC and is a combination regimen worthy of clinical investigation to improve outcomes for these patients.

Preliminary results from patients with urothelial carcinoma (UC) in a phase 1A/1B study of bgb-A317, an anti-PD-1 monoclonal antibody.

Publisher: American Society of Clinical Oncology (ASCO)

Date: 20-02-2018

DOI: 10.1200/JCO.2018.36.6_SUPPL.445

Abstract: 445 Background: Monoclonal antibodies (mAb) against programmed cell death-1 (PD-1) have demonstrated antitumor activity across multiple malignancies. BGB-A317 is a humanized IgG4 mAb with high affinity and binding specificity for PD-1. Previous reports from an ongoing Phase 1A/1B study (NCT02407990) in patients with advanced solid tumors suggested that BGB-A317 was generally well tolerated and had antitumor activity in multiple tumor types. Here, we present the preliminary results from a subset of patients with UC enrolled in this study. Methods: Patients with UC received intravenous BGB-A317 at doses of 2, 5, 10 mg/kg Q2W or Q3W and 200 mg Q3W. Tumor cell (TC) and immune cell (IC) PD-L1 expression was retrospectively assessed with the VENTANA PD-L1 (SP263) assay. Safety and tolerability was assessed by monitoring adverse events (AEs) and antitumor effects were assessed by RECIST v1.1 criteria. Results: As of 8 June 2017, 15 patients with UC (median age, 72 yr [range: 39–79]) received BGB-A317 during phases 1A (n = 8) and 1B (n = 7). All patients were Caucasian and 13 patients were male the median number of prior systemic anticancer therapies was 1 (range: 0–4). Median duration of treatment was 115 d (range: 27–476) 6 patients remain on treatment. The most common treatment-related AEs (TRAEs) were fatigue (n = 5) and rash (n = 3) grade ≥3 TRAEs included fatigue (n = 1), and hyperglycemia and type 1 diabetes mellitus (T1DM n = 1). Serious TRAEs occurred in 2 patients (infusion-related reaction [n = 1] hyperglycemia and T1DM [n = 1]). All patients were evaluable for response assessment. Confirmed complete and partial responses occurred in 1 and 3 patients, respectively, for a response rate of 27% the disease control rate (CR+PR+SD) was 53%. Nine s les were available for PD-L1 evaluation. Responses were observed in 3 of 6 patients with PD-L1 + tumors (defined as ≥25% TC or IC expressing PD-L1 by IHC) while 1 in 3 patients with PD-L1 – tumors responded. Conclusions: BGB-A317 was generally well tolerated in patients with UC and objective responses were observed in both PD-L1 + and PD-L1 – diseases. BGB-A317 is currently being investigated in China as monotherapy for patients with PD-L1 + UC (CTR20170071). Clinical trial information: NCT02407990.

Regular aspirin (ASA) use and survival in patients with PIK3CA-mutated metastatic colorectal cancer (CRC)

Publisher: American Society of Clinical Oncology (ASCO)

Date: 20-01-2014

DOI: 10.1200/JCO.2014.32.3_SUPPL.386

Abstract: 386 Background: Recent data has demonstrated that regular ASA use improves overall and cancer-specific survival in the subset of CRC patients harboring PIK3CA mutations. However, as this series only analyzed 15 PIK3CA mutant CRC patients with metastatic disease at diagnosis, it remains uncertain whether the survival benefit associated with regular ASA use extends to patients with metastatic disease. We combined data from two large academic institutions to explore the association between regular ASA use and survival in metastatic CRC. Methods: Patients with PIK3CA mutated CRC were identified at Moffitt Cancer Center (MCC) in T a, FL and Royal Melbourne Hospital (RMH) in Australia. Prospective clinicopathological data (including age, sex, site of disease) and survival data were available. At MCC, PIK3CA mutations were identified by exome sequencing using an Illumina Next Generation Sequencing platform with 50-100X coverage. At RMH, Sanger sequencing was used to identify PIK3CA mutations. Survival analyses were conducted using Cox regression. Results: We identified 187 CRC patients who harbored a PIK3CA mutation. Median age was 72 years and median follow up was 48 months. 49 (26%) patients used ASA regularly. 47 (25%) patients had metastatic disease at diagnosis. In univariate analyses, regular ASA use was not associated with improved overall survival (HR 0.87, p = 0.60), although there was a trend towards improved cancer-specific survival (HR 0.48, p = 0.06). In patients with stage-II or stage-III disease, regular ASA use did not improve overall, cancer-specific or recurrence-free survival. However, in stage-IV patients, regular ASA use was significantly associated with improved overall (HR 0.35, p = 0.04) and cancer-specific (HR 0.28, p = 0.02) survival in a univariate analysis. Conclusions: Our study demonstrates that in patients with metastatic CRC harboring a PIK3CA mutation, regular ASA use is associated with a significant overall and cancer-specific survival advantage. However, we were not able to confirm the survival advantage across all stages. To our knowledge, our study is the largest to examine ASA use in PIK3CA mutated CRC.

Impact of clinical and molecular features on risk of recurrence following curative intent resection of metastases in metastatic colorectal cancer

Publisher: American Society of Clinical Oncology (ASCO)

Date: 02-2017

DOI: 10.1200/JCO.2017.35.4_SUPPL.785

Abstract: 785 Background: Resection of metastases with curative intent is an integral component of mCRC management. However, relapse rates are high and identifying patients most likely to benefit from this approach is of considerable importance. Among patients with mCRC, mutations (mt) in RAS and BRAF genes portent a worse prognosis. Our hypothesis, therefore, is that patients harbouring these mutations may have a higher relapse rate after resection of metastases. We also wished to analyse clinical predictors of relapse, including site of metastases. Methods: We interrogated the TRACC database of patients undergoing resection with curative intent who had mutation status available. The frequency of RAS and BRAF mt was established and their association with clinical parameters determined. Relapse free (RFS) and overall survival (OS), from the date of resection, was estimated for the mt and wild type (wt) groups using the Kaplan Meier method. Multivariate analysis is planned to investigate factors associated with RFS, including stage of the primary tumour, synchronous metastases, site and number of metastases, CEA, peri-operative chemotherapy use, site of the primary (left v right) and RAS and BRAF mutation status. Results: 188 patients were identified. 89 were KRAS/BRAF wt, 92 KRAS mt and 7 BRAF mt. 40% had presented with metastatic disease and 27% had a right sided primary. 76%, 22% and 2% underwent resection of liver, lung or both metastases. Microscopic resection margin was involved in 6%. Resection was performed prior to any chemotherapy in 48%. No difference was seen in relapse free or overall survival between the mt and wt groups. Conclusions: We found no difference in relapse free or overall survival by mutation subgroup suggesting this should not influence suitability for curative intent resection, but analyses is planned on a much larger cohort once data is available. A multivariate analysis, adjusting for important prognostic variables, is planned.

Phase 1, open-label, first-in-human study of AMG 900, an orally administered pan-aurora kinase inhibitor, in adult patients (pts) with advanced solid tumors

Publisher: American Association for Cancer Research (AACR)

Date: 15-07-2016

DOI: 10.1158/1538-7445.AM2016-CT045

Abstract: Purpose: Aurora kinases are associated with high proliferation, poor prognosis, and therapeutic resistance in several human tumor types. AMG 900 is an investigational, oral, highly potent, selective, pan-aurora kinase inhibitor. We evaluated the safety, tolerability, pharmacokinetics, and clinical activity of AMG 900 in pts with advanced solid tumors (NCT00858377). Methods: In the dose escalation phase, eligible pts were ? 18 years old, with advanced solid tumors that were refractory to standard treatment, measurable disease per RECIST, ECOG ? 2, and life expectancy & 3 months. In the dose expansion phase, eligible pts had taxane- and platinum-resistant epithelial ovarian cancer (OC), taxane-resistant triple-negative breast cancer (TNBC), or castration-resistant and taxane- or cisplatin-etoposide-resistant stage IV prostate cancer (CRPC). AMG 900 was administered 4 days on/10 days off at doses of 1 to 50 mg/day (dose escalation), and at the maximum tolerated dose of 40 mg/day with G-CSF support (dose-expansion). The primary objective was safety. Tumor response was determined per RECIST for all pts and additionally by GCIG CA-125 for pts with OC. Results: Treatment-related AEs were reported by 98 of 105 pts (93.3%). Myelotoxicities were the most common grade ? 3 treatment-related AEs. In the dose escalation (N = 50), 1 pt with OC (30-mg cohort) had a partial response (PR) by RECIST and GCIG. In the dose expansion (N = 55), 3 of 29 pts (10.3%) with OC had a PR by RECIST, and 7 of 29 pts (24.1%) had a PR by GCIG 72.4% of pts with OC had stable disease (SD), and the disease control rate (PR + SD) was 82.8%. Median (95% CI) duration of response in pts with OC per RECIST was 24.1 (16.1, 34.1) weeks, and median (80% CI) PFS was 31.1 (23.6, 34.1) weeks. See table for additional results. Conclusions: AMG 900 had manageable toxicity with G-CSF support and promising single-agent activity in pts with heavily pretreated taxane- and platinum-resistant OC. Patient demographics, prior therapy, AEs, and best tumor responseDose escalation - advanced solid tumors (N = 50)OC (N = 29)TNBC (N = 14)CRPC (N = 12)Overall (N = 105)Male, n (%)21 (42.0)0 (0.0)0 (0.0)12 (100.0)33 (31.4)Female, n (%)29 (58.0)29 (100.0)14 (100.0)0 (0.0)72 (68.6)White or Caucasian, n (%)35 (70.0)23 (79.3)12 (85.7)11 (91.7)81 (77.1)Age, mean (SD), years56.5 (11.6)61.1 (11.4)54.6 (11.4)67.7 (8.0)58.8 (11.7)Prior lines of anti-cancer therapy, mean (SD)4.9 (3.2)5.3 (4.3)5.8 (3.0)4.5 (2.6)5.1 (3.4)Treatment-related AEs by preferred term (any grade), n (%)Fatigue21 (42.0)15 (51.7)6 (42.9)6 (50.0)48 (45.7)Neutropenia24 (48.0)14 (48.3)4 (28.6)4 (33.3)46 (43.8)Anemia15 (30.0)16 (55.2)6 (42.9)3 (25.0)40 (38.1)Nausea18 (36.0)10 (34.5)5 (35.7)5 (41.7)38 (36.2)Thrombocytopenia15 (30.0)11 (37.9)1 (7.1)2 (16.7)29 (27.6)Diarrhea14 (28.0)10 (34.5)1 (7.1)2 (16.7)27 (25.7)Alopecia13 (26.0)11 (37.9)1 (7.1)1 (8.3)26 (24.8)Decreased appetite11 (22.0)7 (24.1)2 (14.3)4 (33.3)24 (22.9)Vomiting9 (18.0)7 (24.1)5 (35.7)3 (25.0)24 (22.9)Leukopenia19 (38.0)3 (10.3)0 (0.0)1 (8.3)23 (21.9)Best tumor response - RECIST 1.1 criteria (central read), n (%)Complete response0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)Partial response1 (2.0)3 (10.3)0 (0.0)0 (0.0)4 (3.8)Stable disease29 (58.0)21 (72.4)7 (50.0)9 (75.0)66 (62.9)Progressive disease12 (24.0)3 (10.3)4 (28.6)1 (8.3)20 (19.0)Unable to evaluate8 (16.0)2 (6.9)3 (21.4)2 (16.7)15 (14.3) Citation Format: Montasser Shaheen, Ben Markman, Michael Carducci, Sara Hurvitz, Daruka Mahadevan, Dusan Kotasek, Oscar Goodman, Erick Gamelin, Vincent Chow, Gloria Juan, Erik Rasmussen, Gregory R. Friberg, Florian D. Vogl, Jayesh Desai. Phase 1, open-label, first-in-human study of AMG 900, an orally administered pan-aurora kinase inhibitor, in adult patients (pts) with advanced solid tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research 2016 Apr 16-20 New Orleans, LA. Philadelphia (PA): AACR Cancer Res 2016 (14 Suppl):Abstract nr CT045.

Can systemic inflammation at diagnosis predict benefit from primary resection in metastatic colorectal cancer (mCRC)?

Publisher: American Society of Clinical Oncology (ASCO)

Date: 02-2013

DOI: 10.1200/JCO.2013.31.4_SUPPL.410

Abstract: 410 Background: In CRC, the tumor associated immune response can manifest as, (1) a good prognostic anti-tumor local (intra-tumoral) inflammatory response or (2) a poor prognostic tumor promoting systemic inflammatory response. As suggested for renal cancer, the survival advantage associated with primary resection in mCRC patients (pts) might relate to modification of the tumor associated immune response, through reduction in tumor bulk and the resulting reduction in tumor promoting cytokines. We examine if systemic inflammation at diagnosis predicts benefit from primary resection in mCRC. Methods: A prospectively collected multi-disciplinary CRC database was used to explore clinicopathological data from pts diagnosed with de novo mCRC from Jan 2009 to Jul 2012. Evidence of systemic inflammation was defined as serum albumin (SA) g/L or neutrophil-lymphocyte ratio (NLR) at diagnosis. Pts with primary resection days from diagnosis were excluded. Survival analyses utilised the Kaplan-Meier method and log-rank test. Results: Of 212 pts diagnosed with mCRC, 154 (72%) had de novo mCRC. 92 (60%) of these underwent primary resection, 62 (40%) had primary left in situ. SA was available in 141 pts, 71 (50%) had SA g/L. NLR was available in all pts, 93 (60%) had NLR . Primary resection was associated with superior overall survival (OS): median 32.5mo v 8.4mo (HR 0.29, p .001). Systemic inflammation was associated with inferior OS using either SA g/L (median 8.4mo v 19.8mo, HR 2.54, p .001) or NLR (median 16.8 mo v 13.1 mo, HR 1.59, p=0.03). There was no difference in OS advantages associated with primary resection in pts with SA g/L (HR 0.25, p .001) compared to normal SA (HR 0.28, p .001) at diagnosis a non significant difference was observed for NLR ≤4 (HR 0.15, p .001) compared to NLR (HR 0.42, p=0.001). Data regarding resolution of systemic inflammation following primary resection will be presented. Conclusions: Our study confirms the OS benefit from primary resection in mCRC and the adverse prognostic impact of systemic inflammation. Based on our current data, any benefit from primary tumour resection cannot be explained by an impact on the tumor associated immune response.

Controversies in the management of gastrointestinal stromal tumors

Publisher: Wiley

Date: 27-03-2014

DOI: 10.1111/AJCO.12187

Abstract: Major advances in the medical treatment of gastrointestinal tumors (GISTs) have improved survival for both patients with advanced disease and those diagnosed with high-risk primary tumors. The Consensus approaches to best practice management of gastrointestinal stromal tumors, published in this journal in 2008, provided guidance for the management of GIST to both clinicians and regulatory authorities. Since then, clinical trials have demonstrated the benefit of adjuvant imatinib in high-risk patients, and mature data from advanced GIST studies suggest that a small but significant proportion of patients with advanced disease can achieve long-term benefit with ongoing imatinib treatment. Other evolving management strategies include the controversial use of palliative or debulking surgery to improve outcomes in advanced GIST and the development of promising new multikinase inhibitors, such as regorafenib, which has established benefit in the third-line setting. This review provides an update of recent developments in GIST management and discusses new controversies that these advances have generated.

Chondroblastic Osteosarcoma Arising in a Bone Infarct in a Patient with a Prior History of Hodgkin Lymphoma

Publisher: Mary Ann Liebert Inc

Date: 12-2014

DOI: 10.1089/JAYAO.2014.0021

Gastrointestinal stromal tumor: New nodule-within-a-mass pattern of recurrence after partial response to imatinib mesylate

Publisher: Radiological Society of North America (RSNA)

Date: 06-2005

DOI: 10.1148/RADIOL.2353040332

Abstract: To investigate a new pattern of tumor recurrence observed at imaging in patients with metastatic gastrointestinal stromal tumor (GIST) after initial partial response to imatinib mesylate. Ninety-two patients with metastatic GIST who underwent treatment in a clinical trial with oral imatinib mesylate were followed up for 29 months. An institutional review board-approved protocol was used. The study complied with the Health Insurance Portability and Accountability Act, and written informed consent was obtained from all patients. Images of the chest, abdomen, and pelvis, acquired with computed tomography (CT), positron emission tomography (PET), and, in some cases, magnetic resonance imaging, were evaluated for treatment response and disease recurrence. Thirty-nine patients (29 men, 10 women age range, 18-84 years mean, 49.2 years) had recurrent disease after an initial variable period of response (range, 2-24 months median, 14.4 months). Initial response was determined with findings of decreased uptake of fluorine 18 fluorodeoxyglucose at PET, shrinkage of tumor, and decreased attenuation at CT. Images were evaluated for disease recurrence by two experienced radiologists who were blinded to each other's interpretation but not to clinical details. Final reading was performed by consensus. A nodule within a mass was seen in 21 of 39 patients (in intrahepatic tumor [n = 8], extrahepatic tumor [n = 10], or both intra- and extrahepatic tumors [n = 3]) and was the first sign of disease progression in 17 of 21 patients. Other patterns of recurrence included new site of disease (n = 7), regrowth of preexistent lesion (n = 20), and mixed (more than one) pattern (n = 9). Disease progression was verified at needle biopsy (n = 16), follow-up imaging (n = 14), and/or surgical resection (n = 9). A nodule within a mass is an important sign of recurrent GIST, but measurements of overall tumor size may not enable detection of such nodules.

Developing a national database for metastatic colorectal cancer management: perspectives and challenges

Publisher: Wiley

Date: 11-2013

DOI: 10.1111/IMJ.12230

Abstract: The changing treatment landscape for metastatic colorectal cancer creates multiple potential treatment strategies. An Australian-centric database capturing comprehensive information across a range of treatment locations would create a valuable resource enabling multiple important research questions to be addressed. To establish a collection of a consensus dataset capturing treatment and outcomes at multiple public and private hospitals across Australia. An electronic database was developed by a panel of clinicians, to capture an agreed dataset for patients with newly diagnosed metastatic colorectal cancer. Of particular interest were clinician decision-making, the impact of comorbidities and the frequency of major adverse events. Since July 2009, data collection has been established at six public and eight private hospitals across three Australian states and territories. Successful linkage and analysis, with support from BioGrid Australia, of selected data on the initial 864 patients demonstrates that data can be captured from erse sites, including public and private practice, that multiple factors impact on treatment delivered and outcomes achieved and that comprehensive data on rare but important adverse events can be captured. As a clinical research tool, the project has been highly successful, generating multiple presentations at national and international conferences related to a erse range of research questions. Multistate, project-specific data collection involving large numbers of patients is achievable. Providing invaluable insight into the routine clinical management of metastatic colorectal cancer in the era of targeted therapies, this also creates a significant resource for research, including many questions not being addressed by clinical trials.

Impact of regular aspirin use on overall and cancer-specific survival in patients with colorectal cancer harboring a PIK3CA mutation

Publisher: Informa UK Limited

Date: 22-03-2015

DOI: 10.3109/0284186X.2014.990158

Analysis of local chronic inflammatory cell infiltrate combined with systemic inflammation improves prognostication in stage II colon cancer independent of standard clinicopathologic criteria

Publisher: Wiley

Date: 02-09-2015

DOI: 10.1002/IJC.29805

Abstract: In Stage II colon cancer, multiple independent studies have shown that a dense intratumoural immune infiltrate (local inflammation) is associated with improved outcomes, while systemic inflammation, measured by various markers, has been associated with poorer outcomes. However, previous studies have not considered the interaction between local and systemic inflammation, nor have they assessed the type of inflammatory response compared with standard clinicopathologic criteria. In order to evaluate the potential clinical utility of inflammatory markers in Stage II colon cancer, we examined local and systemic inflammation in a consecutive series of patients with resected Stage II colon cancer between 2000 and 2010 who were identified from a prospective clinical database. Increased intratumoural chronic inflammatory cell (CIC) density, as assessed by pathologist review of hematoxylin and eosin stained slides, was used to represent local inflammation. Neutrophil-to-lymphocyte ratio (NLR) >5, as calculated from pre-operative full blood counts, was used to represent systemic inflammation. In 396 eligible patients identified, there was a non-significant inverse relationship between local and systemic inflammation. Increased CIC density was significantly associated with improved overall (HR 0.45, p = 0.001) and recurrence-free survival (HR 0.37, p = 0.003). High NLR was significantly associated with poorer overall survival (HR 2.56, p < 0.001). The combination of these markers further stratified prognosis independent of standard high-risk criteria, with a dominant systemic inflammatory response (low CIC/high NLR) associated with the worst outcome (5-year overall survival 55.8%). With further validation this simple, inexpensive combined inflammatory biomarker might assist in patient selection for adjuvant chemotherapy in Stage II colon cancer.

Circulating tumor DNA analysis detects minimal residual disease and predicts recurrence in patients with stage II colon cancer

Publisher: American Association for the Advancement of Science (AAAS)

Date: 06-07-2016

DOI: 10.1126/SCITRANSLMED.AAF6219

Abstract: Detection of circulating tumor DNA in patients with resected stage II colon cancer provides evidence of residual disease.

A phase I dose-escalation study of BGB-A317, an anti-programmed death-1 (PD-1) mAb in patients with advanced solid tumors.

Publisher: American Society of Clinical Oncology (ASCO)

Date: 20-05-2016

DOI: 10.1200/JCO.2016.34.15_SUPPL.3066

A Malignant Neoplasm From the Jejunum With aMALAT1-GLI1Fusion and 26-Year Survival History

Publisher: SAGE Publications

Date: 13-01-2020

DOI: 10.1177/1066896919900548

Abstract: The transcription factor GLI1 is a critical effector of the sonic hedgehog pathway. Gene fusions that activate GLI1 have recently been reported in several tumor types including gastroblastoma, plexiform fibromyxoma, a subset of pericytomas, and other soft tissue tumors. These tumors arise in a wide variety of anatomical origins and have variable malignant potentials, morphologies, and immunohistochemistry profiles. In this case report, we describe a malignant tumor from the jejunum with a MALAT1-GLI1 gene fusion that expressed a truncated constitutively active GLI1 protein and GLI1 targets that were detectable by immunohistochemistry. The tumor showed high-grade epithelioid and spindle cell morphology, strongly expressed CD56, and focally expressed other neuroendocrine markers and cytokeratins, but not S100 protein or SMA. The tumor recurred multiple times in liver, soft tissue, and lung over the course of 26 years, the longest reported follow-up for a GLI1 fusion-associated tumor. These metastatic tumors were also composed of epithelioid and spindle cells, but showed lower morphological grade than the primary tumor. The metastatic tumors resembled the recently reported “malignant epithelioid neoplasms with GLI1 rearrangements.” The tumor also had a relatively high tumor mutation burden for a sarcoma. This case report expands the sites of origin for GLI1 rearranged neoplasms and shows that despite being associated with high-grade morphology, these malignancies can be associated with very long-term survival.

Data from Genotype-Tailored ERK/MAPK Pathway and HDAC Inhibition Rewires the Apoptotic Rheostat to Trigger Colorectal Cancer Cell Death

Publisher: American Association for Cancer Research (AACR)

Date: 03-04-2023

DOI: 10.1158/1535-7163.C.6543591.V1

Abstract: Abstract The EGFR/RAS/MEK/ERK signaling pathway (ERK/MAPK) is hyperactivated in most colorectal cancers. A current limitation of inhibitors of this pathway is that they primarily induce cytostatic effects in colorectal cancer cells. Nevertheless, these drugs do induce expression of proapoptotic factors, suggesting they may prime colorectal cancer cells to undergo apoptosis. As histone deacetylase inhibitors (HDACis) induce expression of multiple proapoptotic proteins, we examined whether they could synergize with ERK/MAPK inhibitors to trigger colorectal cancer cell apoptosis. Combined MEK/ERK and HDAC inhibition synergistically induced apoptosis in colorectal cancer cell lines and patient-derived tumor organoids i in vitro /i , and attenuated i Apc /i -initiated adenoma formation i in vivo /i . Mechanistically, combined MAPK/HDAC inhibition enhanced expression of the BH3-only proapoptotic proteins BIM and BMF, and their knockdown significantly attenuated MAPK/HDAC inhibitor–induced apoptosis. Importantly, we demonstrate that the paradigm of combined MAPK/HDAC inhibitor treatment to induce apoptosis can be tailored to specific MAPK genotypes in colorectal cancers, by combining an HDAC inhibitor with either an EGFR, KRAS sup G12C /sup or BRAF sup V600 /sup inhibitor in i KRAS/BRAF sup WT /sup /i i KRAS sup G12C /sup /i , i BRAF sup V600E /sup /i colorectal cancer cell lines, respectively. These findings identify a series of ERK/MAPK genotype-tailored treatment strategies that can readily undergo clinical testing for the treatment of colorectal cancer. /

Nivolumab +/- ipilimumab in treatment (tx) of patients (pts) with metastatic colorectal cancer (mCRC) with and without high microsatellite instability (MSI-H): CheckMate-142 interim results

Publisher: American Society of Clinical Oncology (ASCO)

Date: 20-05-2016

DOI: 10.1200/JCO.2016.34.15_SUPPL.3501

Safety and efficacy of the BCL2 inhibitor venetoclax in estrogen receptor (ER) and BCL2-positive metastatic breast cancer: The mBEP study

Publisher: American Society of Clinical Oncology (ASCO)

Date: 20-05-2017

DOI: 10.1200/JCO.2017.35.15_SUPPL.1044

Abstract: 1044 Background: The anti-apoptotic protein BCL2 is overexpressed in ~85% of ER + breast cancer (BC). Venetoclax (ABT-199), a BCL2 inhibitor approved for CLL (400 mg/day), synergizes with tamoxifen in preclinical patient derived xenograft models by increasing apoptosis. In the first study to evaluate venetoclax in solid tumors, we tested the safety and efficacy of this combination in ER + BCL2 + metastatic BC. Methods: A ‘3+3 design’ dose escalation phase 1b study enrolled women with ER + ( 1%), BCL2 + ( 10%, mod-high) and HER2 non- lified metastatic BC. Patients received escalating doses of venetoclax 200, 400, 600 or 800 mg/day with tamoxifen 20 mg/day. The primary objective was to determine dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) over 4 weeks. There was no limit to the number of prior lines of therapy. Results: Fifteen patients were enrolled (mean age 62 years, range 44-78 previous tamoxifen, 10 pts). Mean lines of prior therapy for metastatic BC was 2.5 (median 2, range 0-6) and included tamoxifen (6 pts). ESR1 mutations were present in ctDNA of 4 patients. Treatment was well tolerated, with no DLT observed. MTD was not reached 6 patients received the maximal planned dose (800 mg). The most common adverse event (AE) was lymphopenia (67% Grade 1-2 13% Grade 3 No Grade 4), followed by nausea (46%, Grade 1-2), which was readily managed. Of 13 women with measurable disease (RECIST v1.1), 4 (31%) had a partial response and 5 (38%) had stable disease (clinical benefit rate, 69%). For patients with a partial response, tumor regression was rapid (evident at first restaging) and occurred in the 400-800 mg dose levels. Two patients with non-measurable bone-only disease had clinically stable disease (1 ongoing 64 weeks). The median duration of response has not yet been reached (range, 12 to 64 weeks). Conclusions: We demonstrated the safety of tamoxifen and venetoclax in ER + BCL2 + metastatic BC, with preliminary evidence of clinically relevant activity. A dose expansion study including serial biopsy, ctDNA and PET scans is ongoing at the 800 mg/day recommended phase 2 dose. Sponsor: Royal Melbourne Hospital Clinical trial information: ISRCTN98335443 , ACTRN12615000702516.

Clinical activity and safety of cobimetinib (cobi) and atezolizumab in colorectal cancer (CRC)

Publisher: American Society of Clinical Oncology (ASCO)

Date: 20-05-2016

DOI: 10.1200/JCO.2016.34.15_SUPPL.3502

BREAKWATER: Randomized phase 3 study of encorafenib (enco) plus cetuximab (cet) +/- chemotherapy for first-line treatment (tx) of BRAFV600E-mutant (BRAFV600) metastatic colorectal cancer (mCRC)

Publisher: American Society of Clinical Oncology (ASCO)

Date: 02-2022

DOI: 10.1200/JCO.2022.40.4_SUPPL.TPS211

Abstract: TPS211 Background: Approximately 10% of patients (pts) with mCRC have BRAF mutations (mostly V600E). First-line tx options for BRAF V600E mCRC are limited to cytotoxic chemotherapy ± anti-VEGF or anti-EGFR or immune checkpoint inhibitors in pts with MSI-H tumors. In Europe, Japan, and USA, the combination of BRAF inhibitor enco + EGFR inhibitor cet is approved for tx of BRAF V600E mCRC after prior therapy. In BEACON CRC, enco + cet resulted in a median overall survival (OS) of 9.3 months (95% confidence interval [CI]: 8.0–11.3) and an objective response rate (ORR) of 19.5% (95% CI: 14.5%–25.4%) in previously treated pts with BRAF V600E mCRC (median follow-up: 12.8 months) 57.4% of pts had grade 3/4 adverse events (AEs), and 9% discontinued due to AEs. Given the poor prognosis of pts with BRAF V600E mCRC and based on the efficacy and tolerability of enco + cet from BEACON CRC, the BREAKWATER study will evaluate the efficacy and safety of enco + cet ± chemotherapy in tx-naive pts with BRAF V600E mCRC. Methods: BREAKWATER is an open-label, global, multicenter, randomized, phase 3 study with a safety lead-in (SLI). Approximately 60 and 870 pts will be enrolled in the SLI and phase 3 parts of the study, respectively. Pts must have mCRC with BRAF V600E-mutation (determined using tumor tissue or blood) ECOG performance status 0/1 and adequate bone marrow, hepatic, and renal function. Pts in the SLI must have evaluable disease (RECIST v1.1) and have received ≤ 1 prior tx regimen those previously treated with a BRAF or EGFR inhibitor, or both oxaliplatin and irinotecan, will be excluded. Pts in the phase 3 study must have measurable disease and be tx naive for metastatic disease. Study tx and endpoints are shown in the table. Enrollment began on 06-Jan-2021. Clinical trial information: NCT04607421. [Table: see text]

MACROD2 Haploinsufficiency Impairs Catalytic Activity of PARP1 and Promotes Chromosome Instability and Growth of Intestinal Tumors

Publisher: American Association for Cancer Research (AACR)

Date: 08-2018

DOI: 10.1158/2159-8290.CD-17-0909

Abstract: ADP-ribosylation is an important posttranslational protein modification that regulates erse biological processes, controlled by dedicated transferases and hydrolases. Here, we show that frequent deletions (∼30%) of the MACROD2 mono-ADP-ribosylhydrolase locus in human colorectal cancer cause impaired PARP1 transferase activity in a gene dosage–dependent manner. MACROD2 haploinsufficiency alters DNA repair and sensitivity to DNA damage and results in chromosome instability. Heterozygous and homozygous depletion of Macrod2 enhances intestinal tumorigenesis in ApcMin/+ mice and the growth of human colorectal cancer xenografts. MACROD2 deletion in sporadic colorectal cancer is associated with the extent of chromosome instability, independent of clinical parameters and other known genetic drivers. We conclude that MACROD2 acts as a haploinsufficient tumor suppressor, with loss of function promoting chromosome instability, thereby driving cancer evolution. Significance: Chromosome instability (CIN) is a hallmark of cancer. We identify MACROD2 deletion as a cause of CIN in human colorectal cancer. MACROD2 loss causes repression of PARP1 activity, impairing DNA repair. MACROD2 haploinsufficiency promotes CIN and intestinal tumor growth. Our results reveal MACROD2 as a major caretaker tumor suppressor gene. Cancer Discov 8(8) 988–1005. ©2018 AACR. See related commentary by Jin and Burkard, p. 921. This article is highlighted in the In This Issue feature, p. 899

Survival impact of the Australian National Bowel Cancer Screening Programme

Publisher: Wiley

Date: 02-2016

DOI: 10.1111/IMJ.12916

Abstract: The Australian National Bowel Cancer Screening Program (NBCSP) has been offering age-based faecal occult blood testing since 2006. With the rapid expansion of this programme, the NBCSP will ultimately offer biennial screening to all 50-74 years old by 2020. Participation rates remain low. Previous reports have described an increased proportion of earlier stage cancers in patients with NBCSP-detected tumours. Data on consecutive patients enrolled into a prospective, comprehensive, multidisciplinary database at six Victorian hospitals were examined. Clinicopathologic and outcome data were compared for NBCSP and symptomatic presentation patients. We identified 3743 patients that presented with colorectal cancer (CRC) at participating hospitals since May 2006. Of 1930 patients aged between 50 and 70 years, 141 (7.3%) had a NBCSP detected cancer, 1441 (74.7%) presented with symptoms and 266 (13.8%) were diagnosed through screening outside of the NBCSP. Based on the American Society of Anaesthesiology score, the NBCSP patients were fitter. They had an earlier stage of diagnosis and were more likely to be female and less likely to have lymphovascular invasion or to present as an emergency. NBCSP detected patients had a lower rate of recurrence (HR 0.17, P = 0.0001) and fewer deaths (HR 0.19, P = 0.005). Patients with NBCSP-detected CRC have a markedly reduced risk of CRC recurrence and death compared with patients with a symptomatic presentation. The dominant driver of this appears to be earlier stage at diagnosis. Increased promotion of the impact of the NBCSP, including data related to the survival impact, should be undertaken to increase participation rates and achieve further survival gains.

Long-Term Outcomes and Molecular Correlates of Sotorasib Efficacy in Patients With Pretreated KRAS G12C-Mutated Non–Small-Cell Lung Cancer: 2-Year Analysis of CodeBreaK 100

Publisher: American Society of Clinical Oncology (ASCO)

Date: 20-06-2023

DOI: 10.1200/JCO.22.02524

Abstract: Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. In the longest follow-up, to our knowledge, for a KRAS G12C inhibitor, we assessed the long-term efficacy, safety, and biomarkers of sotorasib in patients with KRAS G12C-mutated advanced non–small-cell lung cancer (NSCLC) from the CodeBreaK 100 clinical trial (ClinicalTrials.gov identifier: NCT03600883 ). This multicenter, single-group, open-label phase I hase II trial enrolled 174 patients with KRAS G12C-mutated, locally advanced or metastatic NSCLC after progression on prior therapies. Patients (N = 174) received sotorasib 960 mg once daily with the primary end points for phase I of safety and tolerability and for phase II of objective response rate (ORR). Sotorasib produced an ORR of 41%, median duration of response of 12.3 months, progression-free survival (PFS) of 6.3 months, overall survival (OS) of 12.5 months, and 2-year OS rate of 33%. Long-term clinical benefit (PFS ≥ 12 months) was observed in 40 (23%) patients across PD-L1 expression levels, in a proportion of patients with somatic STK11 and/or KEAP1 alterations, and was associated with lower baseline circulating tumor DNA levels. Sotorasib was well tolerated, with few late-onset treatment-related toxicities, none of which led to treatment discontinuation. These results demonstrate the long-term benefit of sotorasib, including in subgroups with poor prognosis.

A first-in-human phase I study of VGX-100, a selective anti-VEGF-C antibody, alone and in combination with bevacizumab in patients with advanced solid tumors

Publisher: American Society of Clinical Oncology (ASCO)

Date: 20-05-2014

DOI: 10.1200/JCO.2014.32.15_SUPPL.2524

Survival impact of adjuvant chemotherapy for resected early-stage rectal adenocarcinoma

Publisher: American Society of Clinical Oncology (ASCO)

Date: 20-01-2015

DOI: 10.1200/JCO.2015.33.3_SUPPL.712

Abstract: 712 Background: Recent data have created uncertainty regarding the benefit of the current standard of care adjuvant fluoropyrimidine-containing chemotherapy following preoperative chemoradiotherapy and surgical resection for locally advanced rectal cancer. In particular, patients with a pathologic complete response may derive no benefit from adjuvant chemotherapy. Methods: This is a retrospective analysis of patients with early stage rectal adenocarcinoma, diagnosed between 1 January 2003 and 30 June 2013 at three Melbourne health services (Eastern Health, Royal Melbourne Hospital, and Western Health). Patients were identified from a search of the ACCORD (Australian Comprehensive Cancer Outcomes and Research Database) database, where a defined data set is prospectively collected on consecutive patients. Patient demographics, pre-treatment staging, post-operative treatment, recurrence, and survival were analyed. Results: A total of 580 patients with localized rectal cancer were identified, of whom 451 had received neoadjuvant long-course chemoradiation followed by resection of the primary tumor. 369 patients (82%) subsequently received adjuvant 5-fluorouracil. At a median follow-up of 45.9 months, 63 (19%) patients in the adjuvant chemotherapy group and 21 (29%) in the surveillance only group had relapsed. Median relapse-free survival (RFS) has not been reached in either group 3-year RFS was 81% in the adjuvant chemotherapy group compared to 71% in the surveillance only group (p=0.034). Five-year overall survival was 83% in the adjuvant chemotherapy group compared to 71% in the surveillance only group (p=0.038). The impact of age, surgical complications, treatment-related toxicity, and pathological complete response post-neoadjuvant therapy on the uptake of post-operative chemotherapy and on survival are being evaluated. Conclusions: A high proportion of patients in routine practice receive adjuvant chemotherapy following neoadjuvant treatment and surgery for early stage rectal cancer. Adjuvant chemotherapy was associated with a significant improvement in 3-year relapse-free and 5-year overall survival.

BEACON CRC (binimetinib [BIM], encorafenib [ENCO], and cetuximab [CTX] combined to treat BRAF-mutant metastatic colorectal cancer [mCRC]): A multicenter, randomized, open-label, three-arm phase III study of ENCO plus CTX plus or minus BINI vs irinotecan (IRI)/CTX or infusional 5-fluorouracil/folinic acid/IRI (FOLFIRI)ICTX with

Publisher: American Society of Clinical Oncology (ASCO)

Date: 20-05-2017

DOI: 10.1200/JCO.2017.35.15_SUPPL.TPS3622

Abstract: TPS3622 Background: BRAF mutations are found in ≈10% of mCRC cases. Pts with BRAF V600E mCRC have a poor prognosis, with shorter progression-free survival (PFS) and overall survival (OS) than pts with BRAF wt mCRC (Van Cutsem et al 2011 Modest et al 2012 Sorbye et al 2015). The benefits of combined BRAF + EGFR inhibition in mCRC have been demonstrated in vitro (Corcoran et al 2012 Prahallad et al 2012 Yang et al 2012), and preclinical evidence suggests that adding MEK signaling inhibition improves antitumor activity. Early clinical data indicate that BRAF + EGFR + MEK inhibition has greater activity than BRAF + EGFR inhibition in pts with BRAF V600E mCRC (Van Cutsem et al 2016). Our study will examine the combination of BINI (a MEK inhibitor) + ENCO (a selective BRAF kinase inhibitor) + CTX (an anti-EGFR antibody) and of ENCO + CTX in pts with BRAF V600E mCRC. Methods: BEACON CRC (NCT02928224) is enrolling pts with BRAF V600E mCRC whose disease has progressed after 1 or 2 prior regimens in the metastatic setting. A safety lead-in phase (≈30 pts) will determine the safety and tolerability of oral ENCO 300 mg QD + oral BINI 45 mg BID + intravenous CTX 400 mg/m 2 followed by 250 mg/m 2 QW. In the phase 3 portion, ≈615 pts will be randomized 1:1:1 to triplet (ENCO + BINI + CTX), doublet (ENCO + CTX), or control (investigator’s choice of IRI/CTX or FOLFIRI/CTX) arms. Pts will be treated in 28-day cycles until disease progression, unacceptable toxicity, withdrawal of consent, initiation of subsequent anticancer therapy, or death. The primary endpoint is OS (triplet vs control). Secondary endpoints include OS (doublet vs control), confirmed investigator-assessed objective response rate according to RECIST version 1.1 (triplet or doublet vs control triplet vs doublet), PFS (triplet or doublet vs control), duration of response, time to response, pharmacokinetics, and pt-reported outcomes. Safety will be summarized using standard adverse event reporting. Clinical trial information: NCT02928224.

Gemcitabine and vinorelbine combination chemotherapy for patients with advanced soft tissue sarcomas: Results of a phase II trial

Publisher: Wiley

Date: 08-2023

DOI: 10.1002/CNCR.22609

Abstract: Single-agent gemcitabine and vinorelbine have activity in treatment of patients with soft-tissue sarcomas. The combination of gemcitabine plus vinorelbine has activity against several forms of metastatic carcinoma with acceptable toxicity. This study evaluated the efficacy and tolerability of gemcitabine plus vinorelbine in advanced soft-tissue sarcoma. A single academic center performed this phase II trial. Eligible patients had unresectable or metastatic soft-tissue sarcomas, Eastern Cooperative Group performance status of 0-2, adequate organ function, and 4 months. There has been 1 CR lasting >1 year in a patient with high-grade pleomorphic spindle-cell sarcoma. Gemcitabine given by a fixed-dose rate of infusion combined with vinorelbine was associated with clinically meaningful rates of disease control in patients with advanced soft-tissue sarcoma. Toxicity was acceptable. This study contributed to data that have supported the administration of fixed-dose rate gemcitabine-based drug regimens in soft-tissue sarcomas.

Examining the impact of regular aspirin use and PIK3CA mutations on survival in stage 2 colon cancer

Publisher: Wiley

Date: 2017

DOI: 10.1111/IMJ.13312

Abstract: Data suggest aspirin improves survival in colorectal cancer (CRC) harbouring PIK3CA mutations. The impact of aspirin is thought predominantly to be through an anti-inflammatory effect. The aim of this study is to explore the effect of aspirin use on survival in a real-world cohort of stage 2 colon cancer (CC) patients. A prospective CRC database identified patients diagnosed with stage 2 CC between 2000 and 2011. PIK3CA mutation status was determined by next generation sequencing. Neutrophil-lymphocyte ratio greater than 5 at diagnosis represented systemic inflammation. Chart review was used to record regular aspirin use at diagnosis. Clinico-pathological features and survival data were available. Survival analyses used the Cox proportional hazards method. Of 488 patients with stage 2 CC, 95 patients were aspirin users and 70 patients had PIK3CA mutations. Aspirin users were more likely to be older (median: 76.4 years vs 68.3 years, P < 0.001), to be less fit (American Society of Anaesthetists Score 3-4: 58% vs 31%, P 5: 39% vs 27%, P = 0.027). Regular aspirin use did not significantly improve recurrence-free survival. In the PIK3CA mutated group, there was a trend towards improved recurrence-free survival (hazard ratio: 0.45, P = 0.42). Our study did not demonstrate a significant survival advantage from aspirin use in stage 2 PIK3CA mutated CC. The 'real-world' nature of our cohort and the subsequent uncontrolled differences in age and fitness in aspirin users are likely to have contributed to this result. Defining the true impact of aspirin in CRC requires prospective randomised clinical trials.

A mutant BRAF V600E-specific immunohistochemical assay: correlation with molecular mutation status and clinical outcome in colorectal cancer

Publisher: Springer Science and Business Media LLC

Date: 27-05-2014

DOI: 10.1007/S11523-014-0319-8

CART-WHEEL.org: An Ethically Approved Online Database for Patient-Entered Data to Facilitate Rare Cancer Research

Publisher: American Society of Clinical Oncology (ASCO)

Date: 11-2020

DOI: 10.1200/CCI.19.00085

Abstract: Rare cancers are challenging for researchers, as clinicians and scientists have difficulty recruiting sufficient patient cases to power studies appropriately. Likewise, patients often are frustrated by a lack of specific information or evidence base for their cancer and, although eager to participate in research, have limited opportunities. We established CART-WHEEL.org, an online patient-entered database, to directly engage patients in the research process, collect rare cancer data, and facilitate their entry into additional research. Patients access CART-WHEEL.org directly online. Clinical information is collected from users via a streamlined questionnaire developed collaboratively with consumer groups to ensure accessibility and relevance. Data collected include the following: patient demographics, comorbidities, and risk factors and tumor diagnostic, biomarker, and treatment history. Patients can download a medical summary for personal use consent for research use of data and indicate willingness to be contacted about other research or clinical trials. We describe data collected to date and its validation, and we provide ex les of how CART-WHEEL.org can facilitate rare cancer research. From January 2010 to March 2018, 558 patients provided consent and entered their rare cancer data. One hundred distinct rare tumor types and patients from 22 countries were included. Validation of data entered by 21 patients with sarcoma against a hospital database demonstrated accuracy sufficient to facilitate future research in key fields, such as tumor site (95%) and histopathologic diagnosis (90%). Ex les of CART-WHEEL–based disease-specific projects, subsequent recruitment to other rare cancer projects, and rare cancer patient cases of interest are described. Online platforms like CART-WHEEL.org can engage consumers directly, facilitating collection of patient-entered rare cancer data for hypothesis generation, and connect patients with researchers to enable specific rare cancer research and clinical trials.

PI3Kα Translocation Mediates Nuclear PtdIns(3,4,5)P₃ Effector Signaling in Colorectal Cancer.

Publisher: Elsevier BV

Date: 04-2023

DOI: 10.1016/J.MCPRO.2023.100529

A phase Ib study of safety and clinical activity of atezolizumab (A) and cobimetinib (C) in patients (pts) with metastatic colorectal cancer (mCRC)

Publisher: American Society of Clinical Oncology (ASCO)

Date: 02-2018

DOI: 10.1200/JCO.2018.36.4_SUPPL.560

Abstract: 560 Background: The majority of pts with mCRC have microsatellite stable (MSS) tumors with minimal response to PD-L1/PD-1 blockade. MEK inhibition upregulates tumor major histocompatibility complex-I expression, promotes intratumoral T-cell accumulation and improves anti–PD-L1 responses (Ebert, Immunity. 2016), supporting clinical evaluation of combined anti–PD-L1 (A) plus MEKi (C) in pts with mCRC. Methods: Pts with chemotherapy-refractory or locally advanced mCRC were evaluated. A was administered IV q2w at 800 mg. C was dosed PO daily at 20 to 60 mg during dose escalation and 60 mg during dose expansion (14/14 or 21/7 d on/off schedule). Primary endpoints were safety and tolerability. Investigator-assessed ORR and PFS by RECIST v1.1 and OS were secondary endpoints. Microsatellite instability (MSI) status was locally reported and centrally confirmed by NGS-based scoring. Results: As of May 10, 2017, 84 pts (57 KRASmt, 25 KRASwt, 2 unknown) were enrolled and evaluable. 66 pts had received 5+ prior therapies 38 had known MSI status at baseline (MSS [n = 29], MSI-low [n = 8], MSI-H [n = 1]). A + C combination was tolerable. Treatment-related Gr 1-2 and Gr 3-4 AEs occurred at 60% and 37%, respectively. The most frequent related Gr 3-4 AEs were increased blood CPK, rash, diarrhea and fatigue (5% each). No treatment-related Gr 5 AEs occurred. 13% and 24% of pts experienced AEs leading to A and C withdrawal, respectively. Median follow-up was 14.3 mo (range, 0.5-29.8). Confirmed PR was observed in 7 pts (8% locally reported MSS [n = 3], MSI-low [n = 1], MSI unknown [n = 3]). Median DOR was 14.8 mo (95% CI: 6.0, NE) DCR (PR + SD) was 31%. Median PFS was 1.9 mo (95% CI: 1.8, 2.3) median OS was 10.0 mo (95% CI: 6.2, 14.1). The 6-mo and 1-y OS rates were 65% (95% CI: 54, 76) and 46% (95% CI: 34, 58), respectively. Molecular determinants and immune biomarkers of response will be presented. Conclusions: A + C demonstrated a tolerable safety profile and improvements in OS vs those reported with SOC in heavily pretreated pts with mCRC. Objective responses observed in pts with MSS/MSI-low mCRC were durable, suggesting benefit of this novel combination in a pt population refractory to immune therapies. Clinical trial information: NCT01988896.

BREAKWATER safety lead-in (SLI): Encorafenib plus cetuximab (EC) +/- chemotherapy for first-line (1L) treatment (tx) of BRAF V600E-mutant (BRAF(V600E)) metastatic colorectal cancer (mCRC)

Publisher: American Society of Clinical Oncology (ASCO)

Date: 02-2022

DOI: 10.1200/JCO.2022.40.4_SUPPL.134

Abstract: 134 Background: Currently, there are no 1L tx options indicated specifically for patients (pts) with BRAF V600E mCRC. Based on results of BEACON CRC (NCT02928224), BRAF inhibitor encorafenib + EGFR inhibitor cetuximab was approved for tx of previously treated pts with BRAF V600E mCRC. BREAKWATER (NCT04607421), an ongoing, open-label, global, multicenter, randomized phase 3 study, evaluates 1L EC ± chemotherapy for tx of pts with BRAF V600E mCRC. Here we present preliminary data on safety and pharmacokinetics (PK) from the BREAKWATER SLI, which aimed to identify the chemotherapy backbone for EC for the phase 3 portion of BREAKWATER. Methods: SLI inclusion criteria were BRAF V600E mCRC (determined using tumor tissue or blood) evaluable disease (RECIST v1.1) ≤1 prior systemic tx for mCRC European Cooperative Oncology Group performance status (ECOG PS) 0/1 and adequate bone marrow, hepatic, and renal function. Pts previously treated with BRAF/EGFR inhibitors or both oxaliplatin and irinotecan were excluded. Pts received encorafenib 300 mg daily + cetuximab 500 mg/m 2 every 2 weeks (Q2W) + either FOLFIRI Q2W or mFOLFOX6 Q2W in 28-day cycles. The primary endpoint was frequency of dose-limiting toxicities (DLTs). PK were a secondary endpoint. Data cutoff date: Sep 13, 2021. Results: 57 pts were enrolled (EC + FOLFIRI, n = 30 EC + mFOLFOX6, n = 27). Median (range) age was 57 (28–78) years 25% were Asian 65% had ECOG PS 0 37% had ≥3 organs involved 58% were treatment naive. At cutoff date, tx was ongoing in 45 (79%) pts. Median (range) duration of tx for encorafenib in EC + FOLFIRI and EC + mFOLFOX6 was 15 (0–31) and 14 (0–27) weeks, respectively. One DLT was observed: grade 4 neutropenia in 1 pt in EC + FOLFIRI. Tx-emergent all-cause serious adverse events (AEs) occurred in 20% and 19% and grade ≥3 AEs in 33% and 56% of pts in EC + FOLFIRI and EC + mFOLFOX6, respectively. The table shows frequent (all grade in ≥30% pts or grade ≥3 in ≥10% with either tx) tx-emergent all-cause AEs. One pt died due to disease progression. In EC + FOLFIRI, in the presence of steady-state encorafenib, AUC inf of irinotecan and its active metabolite, SN-38, significantly decreased ̃25% and ̃40%, respectively, compared with values in the absence of encorafenib. In EC + mFOLFOX6, oxaliplatin PK was not significantly altered by steady-state encorafenib. Conclusions: Based on these data, BREAKWATER phase 3 will compare EC ± mFOLFOX6 with mFOLFOX6/FOLFOXIRI/CAPOX ± bevacizumab. Clinical trial information: NCT04607421. [Table: see text]

The value of networks in driving phase I trials: the Peter MacCallum Cancer Centre experience

Publisher: AME Publishing Company

Date: 06-2019

DOI: 10.21037/CCO.2019.05.02

Abstract: The Peter MacCallum Cancer Centre is strongly focused on the conduct of translational research in driving towards better outcomes for patients. Central to this is our clinical trials program, with a strategic focus on early phase trials. Our efforts in developing a world-class program focused on early phase trials have been critically dependent on the creation and collaboration with key networks: local, regional and global. In this paper, we will articulate how the early drug development landscape has evolved in Australia, and how and why collaboration has been such a critical enabler for us in driving success.

The potential of circulating tumor DNA (ctDNA) to reshape the design of clinical trials testing adjuvant therapy in patients with early stage cancers

Publisher: American Society of Clinical Oncology (ASCO)

Date: 20-05-2016

DOI: 10.1200/JCO.2016.34.15_SUPPL.3511

Impact of Body Mass Index on Colorectal Cancer Treatment and Outcomes: Need for Prospective and Comprehensive Data

Publisher: American Society of Clinical Oncology (ASCO)

Date: 20-03-2009

DOI: 10.1200/JCO.2008.20.8827

Best clinical management of tenosynovial giant cell tumour (TGCT): A consensus paper from the community of experts

Publisher: Elsevier BV

Date: 2023

DOI: 10.1016/J.CTRV.2022.102491

Impact of diabetes on clinicopathologic and genetic features of colorectal cancer formation

Publisher: American Society of Clinical Oncology (ASCO)

Date: 02-2013

DOI: 10.1200/JCO.2013.31.4_SUPPL.426

Abstract: 426 Background: Diabetes mellitus is reported to increase the risk of colorectal cancer (CRC) development and has been associated with poor tumour-specific outcomes. Here we assessed the impact of diabetes on the clinicopathologic features and tumour mutation profiles of CRC. Methods: Analysis of a prospective series of patients diagnosed with CRC between January 2000 and December 2010. Fresh-frozen and formalin-fixed, paraffin-embedded tumour specimens were retrieved and genomic DNA extracted for analysis of microsatellite instability (MSI), CpG island methylator phenotype (CIMP) and mutations in BRAF, KRAS, PIK3CA, TP53 and APC genes. Propensity-score matching and logistic regression were used to estimate the association of diabetes with tumour molecular profile, controlling for age, sex, tumour stage, body mass index (BMI), smoking and socio-economic status. Results: Of the 1,348 patients assessed, 288 (21.4%) had a history of diabetes mellitus. Compared to patients without diabetes, diabetics were more likely to be older (age 70 yrs: 56% vs 47%, p = 0.006), male (57% vs 47%, p = 0.002) and have a higher BMI (BMI 25: 82% vs 65%, p 0.0001). There were no statistically significant differences in tumour site, differentiation or lymphovascular invasion. Propensity scores were used to match 260 diabetic patients to an equal number of nondiabetics. In multivariate regression analysis, diabetes was associated with BRAF-mutated tumours (OR 2.81, 95% CI 1.16-7.59, p = 0.029) and showed a trend towards MSI-high tumours (OR 1.54, 95% CI 0.91-2.63, p = 0.110). Results are shown in the Table. Survival analysis is planned. Conclusions: CRC patients with diabetes are older, more likely male and have higher BMI than non-diabetics. In this preliminary analysis, an association between diabetes and BRAF-mutant CRC was found, and may explain reported differences in outcomes for diabetic CRC patients. [Table: see text]

Neurofibromatosis type 1-associated wild-type gastrointestinal stromal tumor treated with anti-IGF-1R monoclonal antibody

Publisher: Springer Science and Business Media LLC

Date: 27-08-2011

DOI: 10.1007/S12032-010-9665-2

An Australasian perspective on sarcoma research, translational biology and clinical trials: the Australasian Sarcoma Study Group (ASSG)

Publisher: Elsevier BV

Date: 02-2014

DOI: 10.1097/PAT.0000000000000051

Nivolumab for the treatment of colorectal cancer

Publisher: Informa UK Limited

Date: 11-06-2018

DOI: 10.1080/14737140.2018.1480942

Abstract: Despite a variety of therapies for advanced metastatic colorectal cancer being available, the outcomes in this malignancy remain suboptimal. Immunotherapy has been slow to impact the management of this patient group. Checkpoint inhibitors, such as nivolumab, have had disappointing results when used broadly. However, for the subset of patients with microsatellite unstable colorectal cancer, the use of checkpoint inhibitors such as nivolumab appears to be transformative, and will provide a new therapeutic option for patient with advanced disease. Areas covered: Nivolumab gained regulatory approval for the treatment of dMMR/MSI-H metastatic colorectal cancer in mid 2017. The current review will summarize the clinical evidence of checkpoint inhibitors in metastatic colorectal cancer, with a focus on nivolumab. Expert commentary: For patients with dMMR/MSI-H mCRC, the use of nivolumab has now been shown to have objective and sustained clinical responses in a pivotal phase II trial. While additional data are limited, the therapeutic role for augmenting an immune response in metastatic colorectal cancer is likely to continue to expand. Further combination trials of nivolumab with immunologic and non-immunologic agents are ongoing.

Optimizing targeted therapeutic development: Analysis of a colorectal cancer patient population with the BRAF^V600E mutation

Publisher: Wiley

Date: 08-03-2011

DOI: 10.1002/IJC.25555

Abstract: BRAF(V600E) mutations are found in 10% of colorectal cancers (CRCs). The low frequency of this mutation therefore makes it a challenging target for drug development, unless subsets of patients with higher rates of BRAF(V600E) can be defined. Knowledge of the concordance between primary-metastasis pairs and the impact of BRAF(V600E) on outcome would also assist in optimal drug development. We selected primary CRCs from 525 patients (stages I-IV) evenly matched for age (<70 and ≥70), gender and tumor location (right, left and rectum), and 81 primary-metastasis pairs. BRAF(V600E), KRAS mutation and microsatellite instability (MSI) were determined and correlated with clinical features and patient outcomes. In multivariate analyses, increasing patient age (p = 0.04), female gender (p = 0.0005) and right-sided tumor location (p 70) females with KRAS wild-type right-sided colon cancers (50%) compared to the unselected cohort (10%). BRAF(V600E) was associated with inferior overall survival in metastatic CRC (HR = 2.02 95% CI 1.26-3.26), particularly evident in patients treated with chemotherapy, and is independent of MSI status. BRAF status was concordant in all primary tumors and matched metastases (79 wild-type pairs and two mutant pairs). Clinicopathological and molecular features can identify CRC patients with a higher prevalence of BRAF(V600E). Patients with BRAF(V600E) wild-type primary tumor do not appear to acquire the mutation in their metastases, and BRAF(V600E) is associated with poorer outcomes in metastatic patients. Our findings are timely and will help inform the rational development of BRAF(V600E) inhibitors in CRC.

Outcomes of patients with maxillofacial osteosarcoma: A review of 15 cases

Publisher: Elsevier BV

Date: 03-2012

DOI: 10.1016/J.JOMS.2011.03.020

Abstract: To assess clinical behavior, response to treatment, and factors affecting survival in maxillofacial osteosarcoma treated at a tertiary referral center. Ethics-approved retrospective review of clinical and pathological records was undertaken for 15 patients managed by the Royal Melbourne Hospital Head and Neck Oncology Tumor Stream. Treatment was a combination of surgery and chemotherapy. Chemotherapy was given as adjuvant, neoadjuvant, or in combination. The overall 2-, 5-, and 15-year disease-free survival rates in this study were 92%, 74%, and 74%, respectively. Using Kaplan-Meier analysis with log rank tests, increasing T stage (P = .01) and positive margins (P = .003) were found to affect survival significantly. Neoadjuvant chemotherapy was not significantly associated with tumor necrosis or improved survival. Tumor size and adequacy of local control were found to be the most important predictors of outcome.

Phase 1 study evaluating the safety, tolerability, pharmacokinetics (PK), and efficacy of AMG 510, a novel small molecule KRAS(G12c) inhibitor, in advanced solid tumors

Publisher: American Society of Clinical Oncology (ASCO)

Date: 20-05-2019

DOI: 10.1200/JCO.2019.37.15_SUPPL.3003

Abstract: 3003 Background: The KRAS G12C mutation is found in approximately 13% of lung adenocarcinomas and 1–3% of other solid tumors, but there is no approved therapy that targets this mutation. AMG 510 is a novel small molecule that specifically and irreversibly inhibits KRAS G12C by locking it in an inactive GDP-bound state. Methods: This phase 1, first-in-human, open-label, multicenter study (NCT03600883) is evaluating the safety, tolerability, PK, and efficacy of AMG 510 in adult patients (pts) with locally-advanced or metastatic KRAS G12C mutant solid tumors. The primary endpoint is safety key secondary endpoints include PK, ORR (assessed every 6 weeks [wks]), DOR, and PFS. Key inclusion criteria: KRAS G12C mutation identified through DNA sequencing, measurable or evaluable disease, ECOG PS ≤2, life expectancy months (mo). Key exclusion criteria: active brain metastases, myocardial infarction within 6 mo. A dose exploration will determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). A dose expansion will enroll pts with NSCLC, CRC, and other advanced solid tumors carrying the KRAS G12C mutation. AMG 510 will be given PO until disease progression, intolerance, or withdrawal of consent. Results: 22 pts (8 men, 14 women median age 55.5 y) were enrolled in the first 3 dose cohorts. Tumor types: 6 NSCLC, 15 CRC, 1 other. Most pts (n=17) had ≥3 prior lines of treatment (tx). Median tx duration was 28 d (range: 8–134). 5 pts reported 10 treatment-related AEs (grade 1, n=9 grade 2, n=1) there were no DLTs. Tumor response was evaluated in 9 pts (4 with ≥2 assessments) 13 pts have not reached their first assessment.1 pt had a PR (NSCLC at wks 6 and 12, tx ongoing), 6 pts had SD (4 CRC and 2 NSCLC median tx duration 9.7 wks [range: 6.3–19.1], tx ongoing), 2 pts had PD. 20 pts are continuing to receive AMG 510. A second PR (NSCLC at wk 6, tx ongoing) was reported after data cutoff. Conclusions: AMG 510 has been well tolerated at the dose levels tested and has shown antitumor activity when administered as monotherapy to patients with advanced KRAS G12C mutant solid tumors. MTD has not been determined, and enrollment into the dose exploration is ongoing. Clinical trial information: NCT03600883.

Ultra‐rare sarcomas: A consensus paper from the Connective Tissue Oncology Society community of experts on the incidence threshold and the list of entities

Publisher: Wiley

Date: 28-04-2021

DOI: 10.1002/CNCR.33618

Abstract: Among sarcomas, which are rare cancers, many types are exceedingly rare however, a definition of ultra‐rare cancers has not been established. The problem of ultra‐rare sarcomas is particularly relevant because they represent unique diseases, and their rarity poses major challenges for diagnosis, understanding disease biology, generating clinical evidence to support new drug development, and achieving formal authorization for novel therapies. The Connective Tissue Oncology Society promoted a consensus effort in November 2019 to establish how to define ultra‐rare sarcomas through expert consensus and epidemiologic data and to work out a comprehensive list of these diseases. The list of ultra‐rare sarcomas was based on the 2020 World Health Organization classification, The incidence rates were estimated using the Information Network on Rare Cancers (RARECARENet) database and NETSARC (the French Sarcoma Network's clinical‐pathologic registry). Incidence rates were further validated in collaboration with the Asian cancer registries of Japan, Korea, and Taiwan. It was agreed that the best criterion for a definition of ultra‐rare sarcomas would be incidence. Ultra‐rare sarcomas were defined as those with an incidence of approximately ≤1 per 1,000,000, to include those entities whose rarity renders them extremely difficult to conduct well powered, prospective clinical studies. On the basis of this threshold, a list of ultra‐rare sarcomas was defined, which comprised 56 soft tissue sarcoma types and 21 bone sarcoma types. Altogether, the incidence of ultra‐rare sarcomas accounts for roughly 20% of all soft tissue and bone sarcomas. This confirms that the challenges inherent in ultra‐rare sarcomas affect large numbers of patients.

Activity of the Gamma Secretase Inhibitor AL101 in Desmoid Tumors: A Case Report of 2 Adult Cases

Publisher: MDPI AG

Date: 21-09-2021

DOI: 10.3390/CURRONCOL28050312

Abstract: Desmoid tumors (aggressive fibromatosis) are soft tissue mesenchymal tumors that can be locally invasive and life-threatening. Depending on the location, these tumors are often unresectable or tend to recur after surgery. To date, there are no approved systemic therapies for desmoid tumors. These tumors typically harbor mutations in the β-catenin oncogene CTNNB1 or the tumor suppressor gene adenomatous polyposis coli, resulting in constitutive activation of the WNT pathway. The Notch pathway is part of the underlying cause for desmoid tumor development, possibly due to crosstalk with the WNT pathway, providing a rationale for Notch inhibition as a therapeutic strategy. The gamma secretase activation of the Notch receptor can be targeted with investigational gamma secretase inhibitors. In this case report, we follow the course of 2 patients with desmoid tumors treated with the highly potent, parenterally administered investigational gamma secretase inhibitor AL101, resulting in long-lasting responses. Case 1 reports on a patient with a mesenteric desmoid tumor who participated in a phase 1 trial and then transitioned into a compassionate use program Case 2 reports on a patient with recurrent pelvic tumors receiving AL101 through a compassionate use program. After tumor progression on other systemic therapies, Cases 1 and 2 had confirmed partial responses (41% and 60% maximal tumor size decrease from baseline) recorded after 1.0 and 1.6 years of treatment with AL101, with a duration of response of 8.6+ and 2.6+ years, respectively. Also, in a phase 1 study of AL102, a potent orally administered gamma secretase inhibitor that shares structural features with AL101, a patient with a desmoid tumor was noted to have tumor shrinkage. Formal clinical testing of AL102 for the treatment of patients with desmoid tumors that are not amenable to surgery or are refractory to/recurrent from other prior therapies is currently underway.

Safe administration of etoposide phosphate after hypersensitivity reaction to intravenous etoposide

Publisher: Springer Science and Business Media LLC

Date: 2002

DOI: 10.1038/SJ.BJC.6600003

Consensus approaches to best practice management of gastrointestinal stromal tumors

Publisher: Wiley

Date: 12-2008

DOI: 10.1111/J.1743-7563.2008.00218.X

Wild-type APC predicts poor prognosis in microsatellite-stable proximal colon cancer

Publisher: Springer Science and Business Media LLC

Date: 25-08-2015

DOI: 10.1038/BJC.2015.296

Figure S1 from Genotype-Tailored ERK/MAPK Pathway and HDAC Inhibition Rewires the Apoptotic Rheostat to Trigger Colorectal Cancer Cell Death

Publisher: American Association for Cancer Research (AACR)

Date: 03-04-2023

DOI: 10.1158/1535-7163.22523103.V1

Abstract: Supplementary Figure 1 shows the synergistic effect of trametinib plus panobinostat in CRC cell lines and PDTO's

A First-Time-In-Human Phase I Clinical Trial of Bispecific Antibody-Targeted, Paclitaxel-Packaged Bacterial Minicells.

Publisher: Public Library of Science (PLoS)

Date: 11-12-2015

DOI: 10.1371/JOURNAL.PONE.0144559

Cetuximab Alone or With Irinotecan for Resistant KRAS-, NRAS-, BRAF- and PIK3CA-wild-type Metastatic Colorectal Cancer: The AGITG Randomized Phase II ICECREAM Study

Publisher: Elsevier BV

Date: 12-2018

DOI: 10.1016/J.CLCC.2018.06.002

Abstract: The Irinotecan Cetuximab Evaluation and Cetuximab Response Evaluation (ICECREAM) study assessed the efficacy of cetuximab monotherapy compared with cetuximab combined with chemotherapy for quadruple wild-type (KRAS, NRAS, BRAF, or P13KCA exon 20) metastatic colorectal cancer. Patients were enrolled in an open-label, multicenter, phase II trial and randomly assigned to cetuximab 400 mg/m From 2012 to 2016, 48 patients were recruited. Two were ineligible, and 2 were not evaluable for response. Characteristics were balanced, except gender (male, 62% vs. 72%) and primary sidedness (left, 95% vs. 68%). For cetuximab compared with cetuximab-irinotecan, progression-free survival was 14% versus 41% (hazard ratio, 0.39 95% confidence interval, 0.20-0.78 P = .008) response rate was 10% (2 partial responses) versus 38% (1 complete, 8 partial) P = .04. Grade 3 to 4 toxicities were less with cetuximab monotherapy (23% vs. 50%) global and specific quality of life scores did not differ. In comparison with cetuximab alone, cetuximab plus irinotecan increases the response rate and delays progression in irinotecan-resistant RAS wild-type colorectal cancer. This echoes data from molecularly unselected patients.

Management of adverse events from the treatment of encorafenib plus cetuximab for patients with BRAF V600E-mutant metastatic colorectal cancer: insights from the BEACON CRC study

Publisher: Elsevier BV

Date: 12-2021

DOI: 10.1016/J.ESMOOP.2021.100328

Impact of BRAF mutation and microsatellite instability on the pattern of metastatic spread and prognosis in metastatic colorectal cancer

Publisher: Wiley

Date: 31-03-2011

DOI: 10.1002/CNCR.26086

Global BRAF testing practices in metastatic colorectal cancer (mCRC)

Publisher: American Society of Clinical Oncology (ASCO)

Date: 20-05-2021

DOI: 10.1200/JCO.2021.39.15_SUPPL.E15523

Abstract: e15523 Background: The BRAF V600E mutation is a marker of poor prognosis in patients with mCRC. Targeted therapy, such as encorafenib + cetuximab, is approved in the US/Europe for the treatment of BRAF V600E-mutated mCRC and demonstrated improved survival vs historical standard of care (SOC). Determining BRAF mutation status in mCRC is recommended by NCCN and ESMO guidelines although adherence to these guidelines may not be uniform. This report’s objective is to communicate global survey results of mCRC BRAF testing practices. Identifying regions where BRAF testing is not SOC may help identify where education efforts are needed to improve effective treatment decision making. Methods: Oncology treatment centers were identified from a registry and from public information. Centers were selected for research experience, historic data quality, and estimated numbers of mCRC patients. A BRAF testing practices survey using an online platform of verified centers was conducted from March to November 2020 425 sites in 39 countries responded. Results: BRAF testing is performed as SOC most commonly in Northern and Western Europe (97%) and East Asia (95%). Conversely, BRAF testing as SOC is least common in Eastern Europe (47%) and South America (52%). Surveyed regions generally test patients when confirming advanced disease prior to first-line (1L) treatment (35% to 78%) or at initial histological diagnosis (9% to 41%). Most regions test tumor tissue few test both tumor tissue and blood and none conduct blood mutation testing only. Testing practices in the US by type of site (academic vs community) will be presented. Conclusions: BRAF testing has global variability, impacting treatment decisions. Increased awareness and routine testing may lead to informed decisions regarding targeted therapies, such as encorafenib + cetuximab (where approved), in patients with BRAF V600E-mutant mCRC.[Table: see text]

Recombinant human erythropoietin in cancer-related anemia: An evidence-based review

Publisher: Elsevier BV

Date: 09-2005

DOI: 10.1016/J.BEHA.2005.01.018

Abstract: Anemia is a common complication of cancer or anticancer therapy, with a significant negative impact on the functional status of patients and their quality of life (QOL). Recombinant human erythropoietin (EPO) was developed in the 1980's and was initially developed for the treatment of anemia associated with chronic renal failure. Subsequently, randomized, placebo-controlled clinical trials in the oncology setting were performed in the early 1990's. These studies demonstrated in cancer patients that EPO could increase the levels of hemoglobin (Hb), decrease the need for red blood cell transfusions, and also suggested that these outcomes were associated with improved QOL metrics as reported by the patients themselves. Based on the results of these studies, EPO was granted regulatory approval to be used for the treatment of anemia in patients with non-myeloid malignancies where anemia was due to the effect of concomitantly administered chemotherapy. To further expand the findings of the registration studies, and to develop more complete QOL data, three similarly designed open-label community-based studies were performed, enrolling a total of approximately 7000 patients. These studies consistently demonstrated in the supportive care of cancer patients receiving chemotherapy that the use of EPO could induce increases in the levels of Hb and that these correlated with patient-reported improvements in QOL metrics. The correlation between an improvement in Hb and QOL has also been confirmed in a larger randomized, placebo-controlled trial. Careful analyses of data from this study also helped support earlier findings that EPO could be effective for patients with varying degrees of anemia, and that increasing and maintaining Hb levels close to the physiologically normal levels resulted in the optimal improvements in QOL. While further investigations of EPO as a mechanism to improve the antineoplastic efficacy of chemoradiotherapy have not yet been positive, the overall experience with this agent remains very favorable after extensive studies and long-term clinical use in oncology.

BMS-986205, an indoleamine 2, 3-dioxygenase 1 inhibitor (IDO1i), in combination with nivolumab (nivo): Updated safety across all tumor cohorts and efficacy in advanced bladder cancer (advBC)

Publisher: American Society of Clinical Oncology (ASCO)

Date: 03-2019

DOI: 10.1200/JCO.2019.37.7_SUPPL.358

Abstract: 358 Background: Nivo (anti–PD-1) has shown durable responses and manageable safety (ORR, 19.6% grade 3‒4 treatment-related AEs [TRAEs], 18%) in advBC (Sharma et al. Lancet Oncol 2017), but prolonging survival in more pts requires additional approaches to overcome tumor evasion mechanisms. IDO1 allows tumor escape through kynurenine (KYN) production, which stimulates regulatory T cells and suppresses effector T-cell proliferation. Anti─PD-1 can upregulate IDO1, supporting the rationale for combining nivo with an IDO1i. BMS-986205 is a selective, potent, once-daily (QD) oral IDO1i that works early in the IDO1 pathway to reduce KYN production. BMS-986205 + nivo showed favorable safety and efficacy in heavily pretreated pts with select solid tumors (Luke et al. SITC 2017 NCT02658890). Updated safety across all tumor cohorts and efficacy in the immuno-oncology (I-O)–naive advBC cohort are reported. Methods: Dose-escalation methods in this phase 1/2a, open-label study were previously described during expansion, pts received BMS-986205 100 or 200 mg QD + nivo 240 mg IV Q2W or 480 mg IV Q4W. Objectives included safety and ORR by RECIST v1.1 (includes unconfirmed responses). Results: As of Mar 2018, 516 pts received BMS-986205 + nivo 45% had ≥2 prior regimens. TRAEs occurred in 57% of pts (grade 3‒4, 12%), the most common being fatigue (15%) and nausea (12%) 19 pts (4%) discontinued due to TRAEs, and 3 pts ( 1%) died due to a TRAE (myocarditis, Stevens-Johnson syndrome, and hepatic failure). In all treated pts and within the advBC cohort (n = 30), the frequency and severity of TRAEs and rate of discontinuation due to TRAEs was lower with the 100- vs 200-mg BMS-986205 dose. Among the 27 pts with I-O–naive advBC, with a median duration of follow-up of 24 wk, ORR was 37% (3 CRs, 7 PRs), and the DCR was 56% ORR in pts with tumor PD-L1 ≥1% (Dako PD-L1 IHC 28-8 pharmDx assay n = 14) vs 1% (n = 10) was 50% vs 30%. Conclusions: BMS-986205 + nivo was well tolerated in heavily pretreated pts, and tolerability was improved with the 100-mg BMS-986205 dose. Preliminary evidence of efficacy was observed in advBC, supporting further evaluation of BMS-986205 + nivo. Clinical trial information: NCT02658890.

Lack of clinical activity with crizotinib in a patient with FUS rearranged rhabdomyosarcoma with ALK protein overexpression

Publisher: Elsevier BV

Date: 10-2019

DOI: 10.1016/J.PATHOL.2019.07.004

Blood-Based Biomarkers of SU11248 Activity and Clinical Outcome in Patients with Metastatic Imatinib-Resistant Gastrointestinal Stromal Tumor

Publisher: American Association for Cancer Research (AACR)

Date: 05-2007

DOI: 10.1158/1078-0432.CCR-06-0919

Abstract: Purpose: There is an unmet need for noninvasive markers to measure the biological effects of targeted agents, particularly those inhibiting the vascular endothelial growth factor (VEGF) receptor (VEGFR) pathway, and identify patients most likely to benefit from treatment. In this study, we investigated potential blood-based biomarkers for SU11248 (sunitinib malate), a multitargeted tyrosine kinase inhibitor, in patients with metastatic imatinib-refractory gastrointestinal stromal tumors. Experimental Design: Patients (n = 73) enrolled in a phase I/II trial received SU11248 daily for 14 or 28 days followed by 14 days without treatment per cycle. Clinical benefit was defined as progression-free survival of & months. We assessed plasma markers, including VEGF and soluble VEGFR-2 (sVEGFR-2), and two cellular populations bearing VEGF receptors: monocytes and, in a subset of patients, mature circulating endothelial cells (CEC). Results: Compared to patients with progressive disease, patients with clinical benefit had significantly greater increases in CECs (0.52 versus −−0.01 CEC/μL/d, P = 0.03) and smaller decreases in monocyte levels (47% versus 60%, P = 0.007) during cycle 1. VEGF increased by 2.2-fold and sVEGFR-2 decreased 25% during the first 2 weeks of treatment. Neither plasma marker correlated with clinical outcome although a modest inverse correlation was observed between sVEGFR-2 changes and plasma drug levels. Monocytes, VEGF, and sVEGFR-2 all rebounded towards baseline off treatment. Conclusions: Monocytes, VEGF, and sVEGFR-2 were consistently modulated by treatment, suggesting that they may serve as pharmacodynamic markers for SU11248. Changes in CECs and monocytes, but not the plasma markers, differed between the patients with clinical benefit and those with progressive disease. These end points merit further investigation in future trials to determine their utility as markers of SU11248 activity and clinical benefit in gastrointestinal stromal tumors and other tumor types.

Point-of-care capture of clinical interventions for metastatic colorectal cancer (mCRC) to develop and validate novel markers of the quality of cancer care

Publisher: American Society of Clinical Oncology (ASCO)

Date: 20-05-2014

DOI: 10.1200/JCO.2014.32.15_SUPPL.E17637

Pexidartinib improves physical functioning and stiffness in patients with tenosynovial giant cell tumor: results from the ENLIVEN randomized clinical trial

Publisher: Medical Journals Sweden AB

Date: 12-05-2021

DOI: 10.1080/17453674.2021.1922161

Cost-effectiveness analysis of imaging surveillance in stage II and III extremity soft tissue sarcoma: an Australian perspective

Publisher: Springer Science and Business Media LLC

Date: 03-02-2020

DOI: 10.1186/S12962-020-0202-7

Abstract: Surveillance imaging is used to detect local and/or distant recurrence following primary treatment of localised soft tissue sarcoma (STS), however evidence supporting optimal surveillance modality or frequency is lacking. We used prospectively collected sarcoma data to describe current surveillance imaging practice in patients with AJCC stage II and III extremity STS and evaluate its cost-effectiveness. From three selected Australian sarcoma referral centres, we identified patients with stage II and III extremity STS treated between 2009 and 2013. Medical records were reviewed to ascertain surveillance imaging practices, including modality, frequency and patient outcomes. A discrete event simulation model was developed and calibrated using clinical data to estimate health service costs and quality adjusted life years (QALYs) associated with alternative surveillance strategies. Of 133 patients treated for stage II and III extremity STS, the majority were followed up with CT chest (86%), most commonly at 3-monthly intervals and 62% of patients had the primary site imaged with MRI at 6-monthly. There was limited use of chest-X-ray. A discrete event simulation model demonstrated that CT chest screening was the most cost effective surveillance strategy, gaining additional QALYs at a mean incremental cost of $30,743. MRI alone and PET-CT alone were not cost-effective, whilst a combined strategy of CT + MRI had an incremental cost per QALY gained of $96,556. Wide variations were observed in surveillance imaging practices in this high-risk STS cohort. Modelling demonstrated the value of CT chest for distant recurrence surveillance over other forms of imaging in terms of cost and QALYs. Further work is required to evaluate cost-effectiveness in a prospective manner.

POTENTIAL MECHANISMS OF RESISTANCE IDENTIFIED THROUGH ANALYSIS OF MULTIPLE BIOMARKERS IN IMMUNE HOT NON-RESPONDERS WITH NON-SMALL CELL LUNG CANCER (NSCLC) TREATED WITH TISLELIZUMAB

Publisher: BMJ Publishing Group Ltd

Date: 11-2020

DOI: 10.1136/JITC-2020-SITC2020.0076

Figure S4 from Genotype-Tailored ERK/MAPK Pathway and HDAC Inhibition Rewires the Apoptotic Rheostat to Trigger Colorectal Cancer Cell Death

Publisher: American Association for Cancer Research (AACR)

Date: 03-04-2023

DOI: 10.1158/1535-7163.22523091

Abstract: Supplementary figure 4 shows phosphorylated ERK staining in an adenoma from a ACDX2 mouse

Pexidartinib Provides Modest Pain Relief in Patients With Tenosynovial Giant Cell Tumor: Results From ENLIVEN

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 24-08-2022

DOI: 10.1097/CORR.0000000000002335

Abstract: The double-blind, randomized, placebo-controlled phase 3 study of orally administered PLX3397 in patients with pigmented villonodular synovitis or giant cell tumor of the tendon sheath (ENLIVEN) showed that pexidartinib provides a robust objective tumor response in adults with tenosynovial giant cell tumors (TGCT) not amenable to improvement with surgery. Based on these results, in 2019, pexidartinib received accelerated approval in the United States in this population as a breakthrough therapy under an orphan drug designation. However, the ability of pexidartinib to relieve pain in ENLIVEN was not fully detailed, and the relationship between pain relief and objective tumor response was not described. (1) What level of pain relief was achieved by pexidartinib treatment in ENLIVEN? (2) How was pain relief related to objective tumor responses? (3) How durable was pain relief? The current study included planned primary and exploratory assessments of patient-assessed worst pain at the site of the tumor in the ENLIVEN trial. ENLIVEN was a phase 3 randomized, placebo-controlled clinical trial in which adults with TGCT not amenable to improvement with surgery received pexidartinib or placebo for 24 weeks, after which eligible patients could receive open-label pexidartinib. Of 174 patients assessed for eligibility, 121 were randomized (50% [60] to placebo, 50% [61] to pexidartinib), and 120 were given either placebo or pexidartinib (59 received placebo and 61 received pexidartinib) and were included in an intent-to-treat analysis. Fifty-nine percent (71 of 120) of the overall treated population was female, and 88% (106 of 120) were White. Mean age was 45 ± 13 years. Tumors were mostly in the lower extremities (92% [110 of 120]), most commonly in the knee (61% [73 of 120]) and ankle (18% [21 of 120]). As a secondary outcome, patients scored worst pain at the site of the tumor in the past 24 hours on an 11-point numeric rating scale (NRS). The primary definition of a pain response was a decrease of at least 30% in the weekly mean worst-pain NRS score and increase of less than 30% in narcotic analgesic use between baseline and week 25. Planned exploratory assessments of pain included the frequency of a pain response using alternative thresholds, including a decrease in worst-pain NRS score of 50% or more and a decrease of at least 2 points (minimum clinically important difference [MCID]), the magnitude of pain reduction between baseline and week 25, correlation between worst-pain NRS score and tumor shrinkage by RECIST 1.1 criteria, and the durability of the pain response during the open-label extension. Pain responses during the randomized portion of the trial were compared according to intention-to-treat analysis, with a one-sided threshold of p 0.025 to reduce the risk of false-positive results. Pain assessment was complete for 59% (35 of 59) of patients in the placebo group and 54% (33 of 61) of patients in the pexidartinib group. Demographic and disease characteristics did not differ between the two treatment groups. A difference in the primary assessment of a pain response was not detected between pexidartinib and placebo (response percentage 31% [19 of 61] [95% CI 21% to 44%] versus 15% [9 of 59] [95% CI 8% to 27%] one-sided p = 0.03). In the exploratory analyses, pexidartinib provided a modest improvement in pain (response percentage 26% [16 of 61] [95% CI 17% to 38%] versus 10% [6 of 59] [95% CI 5% to 20%] one-sided p = 0.02 using the 50% threshold and 31% [19 of 61] [95% CI 21% to 44%] versus 14% [8 of 59] [95% CI 7% to 25%] one-sided p = 0.02 using the MCID threshold). The least-squares mean change in the weekly mean worst-pain NRS score between baseline and week 25 was larger in patients treated with pexidartinib than placebo (-2.5 [95% CI -3.0 to -1.9] versus -0.3 [95% CI -0.9 to 0.3] p 0.001), although the mean difference between the two groups (-2.2 [95% CI -3.0 to -1.4]) was just over the MCID. Improvement in the weekly mean worst-pain NRS score correlated with the reduction in tumor size (r = 0.44 p 0.001) and tumor volume score (r = 0.61 p 0.001). For patients in the open-label extension, the change in the worst-pain NRS score from baseline was similar to the change at the end of the randomized portion and just above the MCID (mean -2.7 ± 2.2 after 25 weeks and -3.3 ± 1.7 after 50 weeks of receiving pexidartinib). Based on the current study, a modest reduction in pain, just larger than the MCID, may be an added benefit of pexidartinib in these patients, although the findings are insufficient to justify the routine use of pexidartinib for pain relief. Level II, therapeutic study.

Supplementary Data DS1 from A Phase Ib/II Trial of Combined BRAF and EGFR Inhibition in <i>BRAF</i> V600E Positive Metastatic Colorectal Cancer and Other Cancers: The EVICT (Erlotinib and

Publisher: American Association for Cancer Research (AACR)

Date: 04-2023

DOI: 10.1158/1078-0432.22490194.V1

Abstract: Supplementary material

Precision oncology using a clinician‐directed, tailored approach to molecular profiling

Publisher: Wiley

Date: 30-10-2017

DOI: 10.1111/AJCO.12787

Abstract: Precision oncology involves molecularly matching patients to targeted agents usually in early drug development (EDD) programs. Molecular profiling (MP) identifies actionable targets. Comprehensive commercial MP platforms are costly and in resource limited environments, a more practical approach to MP is necessary to support EDD and precision oncology. We adopted a clinician-directed, tailored approach to MP to enrol patients onto molecularly targeted trials. We report the feasibility of this approach. All patients referred to the Royal Melbourne Hospital (RMH) EDD between September 2013 and September 2015 were identified in a prospective database. Key captured data included clinicopathological data, MP platform ordered (if any), molecular targets identified and subsequent enrolment onto clinical trials. EDD-clinician decisions to order MP and the platform utilized was guided by patient consultation, tumor type, trial availability and requirement for molecular information. We identified 377 patients referred to RMH EDD. A total of 216 (57%) had MP ordered. The remainder had known actionable targets (19%), or were inappropriate for clinical trials (24%). In those undergoing MP, 187 genetic aberrations were found in 113 patients with 98 considered actionable targets in 86 patients. Ninety-eight (25%) patients were enrolled onto a clinical trial, including 40 (11%) receiving molecularly matched treatments. Median progression-free survival was improved in patients enrolled onto molecularly matched trials compared to those on unmatched trials (3.6 months vs 1.9 months, HR 0.58 [0.38-0.89], P = 0.013). A clinician-directed, tailored approach to the use of MP is feasible, resulting in 11% of patients enrolled onto molecularly matched trials.

Concordance of DNA mismatch repair deficient (dMMR)/microsatellite instability (MSI) assessment by local and central testing in patients with metastatic CRC (mCRC) receiving nivolumab (nivo) in CheckM

Publisher: American Society of Clinical Oncology (ASCO)

Date: 20-05-2017

DOI: 10.1200/JCO.2017.35.15_SUPPL.3548

Abstract: 3548 Background: MMR or MSI testing is recommended for mCRC pts and is often done locally by IHC or PCR testing, respectively (NCCN V1.2017) Nivo, a fully human anti-PD-1 mAb, demonstrated durable responses and a 12-mo OS rate of 73.8% in pts with mCRC locally assessed for dMMR/MSI-H status in the CheckMate 142 study (NCT02060188 Overman M, et al. 2017). Here we describe the results of local and central testing with respect to MMR/MSI status and clinical outcomes in the CheckMate 142 study. Methods: MMR/MSI status was assessed locally on archival tumor using IHC/PCR at screening and confirmed centrally by PCR (modified Bethesda panel) testing of tumor biopsy at enrollment. dMMR was defined by IHC as a loss of expression in ≥1 mismatch repair proteins. Stable microsatellite (MSS), low MSI (MSI-L), and high MSI (MSI-H), were defined as instability in 0, 1, or ≥2 markers, respectively. Pts with dMMR/MSI-H mCRC who progressed on or were intolerant of ≥1 prior line of therapy received nivo 3 mg/kg Q2W. Results: 74 pts were dMMR/MSI-H by local testing. Of these pts, 53 (72%) were centrally confirmed as MSI-H, 7 pts had insufficient tissue s le for PCR testing, and 14 pts had a central test that did not match local test results. Of the 14 pts, 3 pts with a clinical history of LS were identified locally as dMMR but centrally as MSS (Table). INV-reported ORR was 31.1% in 74 pts locally determined as dMMR/MSI-H, 35.8% in 53 pts locally and centrally confirmed as MSI-H, and 21.4% in 14 pts not centrally confirmed as MSI-H. Conclusions: The similar clinical activity between pts locally confirmed as MSI-H and pts who were centrally confirmed as MSI-H suggest local testing is appropriate for identifying the dMMR/MSI-H pts who may benefit from nivo monotherapy. Clinical trial information: NCT02060188. [Table: see text]

Primary Tumor Resection in Patients With Metastatic Colorectal Cancer Is Associated With Reversal of Systemic Inflammation and Improved Survival

Publisher: Elsevier BV

Date: 09-2015

DOI: 10.1016/J.CLCC.2015.02.004

Abstract: The true survival benefit of noncurative primary tumor resection in patients with de novo metastatic colorectal cancer (mCRC) remains uncertain. The present study examined the effect of primary tumor resection on systemic inflammation and survival in patients with mCRC. Consecutive patients with de novo mCRC who had undergone primary tumor resection were identified from a prospective database. Patients were excluded if they had undergone resection of metastases, had undergone delayed primary resection, or if blood s les were unavailable. The neutrophil/lymphocyte ratio (NLR) was used as a biomarker of systemic inflammation. Overall survival (OS) was compared between patient groups according to the pre- and postprimary resection NLR. The associations between the reversal of an elevated NLR and primary tumor bulk or performance status were explored. A total of 145 eligible patients were identified from the database, with a median age of 70 years. The baseline NLR was elevated (> 5) in 65 patients, 36 (55%) of whom had a low NLR after surgery. The reversal of an elevated NLR was associated with significantly improved OS (hazard ratio, 0.53 P = .017). A similar benefit was seen after excluding patients undergoing emergency primary resection. NLR reversal was more frequent in patients with larger primary tumors or good performance status. The present study is the first to demonstrate a relationship between the reversal of a systemic inflammatory response and the improved survival after primary resection in those with mCRC. A greater effect was seen in patients with large primary tumors. If validated, these observations could guide clinical decision-making in patients with mCRC at presentation.

Pexidartinib versus placebo for advanced tenosynovial giant cell tumour (ENLIVEN): a randomised phase 3 trial

Publisher: Elsevier BV

Date: 08-2019

DOI: 10.1016/S0140-6736(19)30764-0

Survival in stage II/III colorectal cancer is independently predicted by chromosomal and microsatellite instability, but not by specific driver mutations

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 11-2013

DOI: 10.1038/AJG.2013.292

Abstract: Microsatellite instability (MSI) is an established marker of good prognosis in colorectal cancer (CRC). Chromosomal instability (CIN) is strongly negatively associated with MSI and has been shown to be a marker of poor prognosis in a small number of studies. However, a substantial group of "double-negative" (MSI-/CIN-) CRCs exists. The prognosis of these patients is unclear. Furthermore, MSI and CIN are each associated with specific molecular changes, such as mutations in KRAS and BRAF, that have been associated with prognosis. It is not known which of MSI, CIN, and the specific gene mutations are primary predictors of survival. We evaluated the prognostic value (disease-free survival, DFS) of CIN, MSI, mutations in KRAS, NRAS, BRAF, PIK3CA, FBXW7, and TP53, and chromosome 18q loss-of-heterozygosity (LOH) in 822 patients from the VICTOR trial of stage II/III CRC. We followed up promising associations in an Australian community-based cohort (N=375). In the VICTOR patients, no specific mutation was associated with DFS, but in idually MSI and CIN showed significant associations after adjusting for stage, age, gender, tumor location, and therapy. A combined analysis of the VICTOR and community-based cohorts showed that MSI and CIN were independent predictors of DFS (for MSI, hazard ratio (HR)=0.58, 95% confidence interval (CI) 0.36-0.93, and P=0.021 for CIN, HR=1.54, 95% CI 1.14-2.08, and P=0.005), and joint CIN/MSI testing significantly improved the prognostic prediction of MSI alone (P=0.028). Higher levels of CIN were monotonically associated with progressively poorer DFS, and a semi-quantitative measure of CIN was a better predictor of outcome than a simple CIN+/- variable. All measures of CIN predicted DFS better than the recently described Watanabe LOH ratio. MSI and CIN are independent predictors of DFS for stage II/III CRC. Prognostic molecular tests for CRC relapse should currently use MSI and a quantitative measure of CIN rather than specific gene mutations.

New biomarkers for checkpoint inhibitor therapy

Publisher: Elsevier BV

Date: 2020

DOI: 10.1136/ESMOOPEN-2019-000597

Novel Vaccine Targeting Colonic Adenoma: a Pre-clinical Model.

Publisher: Springer Science and Business Media LLC

Date: 08-01-2019

DOI: 10.1007/S11605-018-4060-Y

Abstract: Colorectal cancer (CRC) is the second leading cause of cancer-related mortality in the USA. Over 80% of CRC develop from adenomatous polyps. Hence, early treatment and prevention of adenomas would lead to a significant decrease of disease burden for CRC. MYB is a transcription factor that is overexpressed in both precancerous adenomatous polyps and colorectal cancer, and hence an ideal immunotherapeutic target. We have developed a cancer vaccine, TetMYB, that targets MYB and aim to evaluate its efficacy in the prophylactic and therapeutic management of adenomatous polyps. Six- to eight-week-old Apc In both the prophylactic and therapeutic setting, mice vaccinated with TetMYB had a significantly improved outcome, with the vaccinated Apc TetMYB vaccine has shown benefit in a prophylactic and therapeutic setting in the management of colonic adenoma in a murine model. This will form the basis for a future clinical trial to prevent and treat colonic adenomatous polyps.

Supplementary Table 1 from Genotype-Tailored ERK/MAPK Pathway and HDAC Inhibition Rewires the Apoptotic Rheostat to Trigger Colorectal Cancer Cell Death

Publisher: American Association for Cancer Research (AACR)

Date: 03-04-2023

DOI: 10.1158/1535-7163.22523085

Abstract: Supplementary table 1

Figure S5 from Genotype-Tailored ERK/MAPK Pathway and HDAC Inhibition Rewires the Apoptotic Rheostat to Trigger Colorectal Cancer Cell Death

Publisher: American Association for Cancer Research (AACR)

Date: 03-04-2023

DOI: 10.1158/1535-7163.22523088

Abstract: Supplementary figure 5 shows mouse weight during treatment in two of the mouse studies

Single-Agent Divarasib (GDC-6036) in Solid Tumors with a KRAS G12C Mutation

Publisher: Massachusetts Medical Society

Date: 24-08-2023

DOI: 10.1056/NEJMOA2303810

Exploring the feasibility and utility of exome‐scale tumour sequencing in a clinical setting

Publisher: Wiley

Date: 07-2018

DOI: 10.1111/IMJ.13806

Abstract: Technology has progressed from single gene panel to large-scale genomic sequencing. This is raising expectations from clinicians and patients alike. The utility and performance of this technology in a clinical setting needs to be evaluated. This pilot study investigated the feasibility of using exome-scale sequencing (ESS) to identify molecular drivers within cancers in real-time for Precision Oncology in the clinic. Between March 2014 and March 2015, the Victorian Comprehensive Cancer Centre Alliance explored the feasibility and utility of ESS in a pilot study. DNA extracted from the tumour specimens underwent both ESS and targeted 'hotspot' sequencing (TS). Blood was taken for germline analysis. A multi-disciplinary molecular tumour board determined the clinical relevance of identified mutations in particular, whether they were 'actionable' and/or 'druggable'. Of 23 patients screened, 15 (65%) met the tissue requirements for genomic analysis. TS and ESS were successful in all cases. ESS identified pathogenic somatic variants in 73% (11/15 cases) versus 53% (8/15 cases) using TS. Clinically focused ESS identified 63 variants, consisting of 30 somatic variants (including all 13 identified by TS) and 33 germline variants. Overall, there were 48 unique variants. ESS had a clinical impact in 53% (8/15 cases) 47% (7/15 cases) were referred to the familial cancer clinic, and 'druggable' targets were identified in 53% (8/15 cases). ESS of tumour DNA impacted clinical decision-making in 53%, with 20% more pathogenic variants identified through ESS than TS. The identification of germline variants in 47% was an unexpected finding.

Overview of biomarkers in metastatic colorectal cancer: Tumour, blood and patient-related factors

Publisher: Elsevier BV

Date: 02-2013

DOI: 10.1016/J.CRITREVONC.2012.06.001

Abstract: During the last 20 years there have been major therapeutic developments in colorectal cancer (CRC) with the introduction of multiple novel therapeutic agents into routine clinical practice. This has improved survival in both the adjuvant and advanced disease settings. However, improvements have come with substantial increases in expense to the community and potential toxicity to the patient. There has been substantial research to identify tumour factors in CRC that predict treatment response and survival outcomes. This research has identified clinically useful predictive biomarkers to aid clinical decision making, such as the presence or absence of KRAS gene mutations which can determine the benefit of using epidermal growth factor receptor (EGFR) inhibiting antibodies. However, less attention has been paid to the identification and impact of predictive patient-derived factors such as age, gender and the presence of comorbid conditions or evidence of a systemic inflammatory response. In this article, the current concepts of tumour and patient-related predictive factors in CRC management are reviewed.

Microsatellite Instability Status Is Critical to Analysis of Survival in Stage II Colon Cancer

Publisher: American Society of Clinical Oncology (ASCO)

Date: 20-02-2012

DOI: 10.1200/JCO.2011.39.7000

BMS-986205, an indoleamine 2,3-dioxygenase 1 inhibitor (IDO1i), in combination with nivolumab (NIVO): Updated safety across all tumor cohorts and efficacy in pts with advanced bladder cancer (advBC)

Publisher: American Society of Clinical Oncology (ASCO)

Date: 20-05-2018

DOI: 10.1200/JCO.2018.36.15_SUPPL.4512

The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity

Publisher: Springer Science and Business Media LLC

Date: 30-10-2019

DOI: 10.1038/S41586-019-1694-1

Abstract: KRAS is the most frequently mutated oncogene in cancer and encodes a key signalling protein in tumours

On-treatment progression-free survival analysis of aflibercept-FOLFIRI treatment within 28 days of progression in metastatic colorectal cancer: Updated efficacy results from the VELOUR study

Publisher: American Society of Clinical Oncology (ASCO)

Date: 02-2013

DOI: 10.1200/JCO.2013.31.4_SUPPL.469

Abstract: 469 Background: The phase III VELOUR study demonstrated that adding the novel antiangiogenic agent aflibercept (known as ziv-aflibercept in the United States) to FOLFIRI in patients with metastatic colorectal cancer previously treated with oxaliplatin significantly improved overall survival, progression-free survival (PFS), and overall response rate versus placebo-FOLFIRI. We performed an additional analysis of PFS “on-treatment,” censoring events that occurred more than 28 days after last treatment dose. Methods: Patients were randomized to receive aflibercept 4 mg/kg or placebo every 2 weeks in combination with FOLFIRI. An independent review committee determined progression based on radiologic review. PFS was estimated using Kaplan-Meier analysis, with censoring of events after the last dose plus 28 days. Treatment groups were compared using a log-rank test stratified by ECOG performance status and prior bevacizumab therapy. Hazard ratio (HR) and confidence interval (CI) were estimated using a Cox proportional hazard model. Results: On-treatment PFS results are shown in the Table. Patients on aflibercept-FOLFIRI showed significantly increased on-treatment PFS compared with patients on placebo-FOLFIRI. More patients were censored in the aflibercept arm due to adverse events, thus decreasing the number of events. Conclusions: On-treatment PFS with aflibercept-FOLFIRI was significantly increased compared with placebo-FOLFIRI, which is consistent with the PFS benefit observed in the primary analysis. Clinical trial information: NCT00561470. [Table: see text]

A Phase Ib/II Trial of Combined BRAF and EGFR Inhibition inBRAFV600E Positive Metastatic Colorectal Cancer and Other Cancers: The EVICT (Erlotinib and Vemurafenib In Combination Trial) Study

Publisher: American Association for Cancer Research (AACR)

Date: 13-01-2023

DOI: 10.1158/1078-0432.CCR-22-3094

Abstract: BRAF V600E mutant metastatic colorectal cancer represents a significant clinical problem, with combination approaches being developed clinically with oral BRAF inhibitors combined with EGFR-targeting antibodies. While compelling preclinical data have highlighted the effectiveness of combination therapy with vemurafenib and small-molecule EGFR inhibitors, gefitinib or erlotinib, in colorectal cancer, this therapeutic strategy has not been investigated in clinical studies. We conducted a phase Ib/II dose-escalation/expansion trial investigating the safety/efficacy of the BRAF inhibitor vemurafenib and EGFR inhibitor erlotinib. Thirty-two patients with BRAF V600E positive metastatic colorectal cancer (mCRC) and 7 patients with other cancers were enrolled. No dose-limiting toxicities were observed in escalation, with vemurafenib 960 mg twice daily with erlotinib 150 mg daily selected as the recommended phase II dose. Among 31 evaluable patients with mCRC and 7 with other cancers, overall response rates were 32% [10/31, 16% (5/31) confirmed] and 43% (3/7), respectively, with clinical benefit rates of 65% and 100%. Early ctDNA dynamics were predictive of treatment efficacy, and serial ctDNA monitoring revealed distinct patterns of convergent genomic evolution associated with acquired treatment resistance, with frequent emergence of MAPK pathway alterations, including polyclonal KRAS, NRAS, and MAP2K1 mutations, and MET lification. The Erlotinib and Vemurafenib In Combination Trial study demonstrated a safe and novel combination of two oral inhibitors targeting BRAF and EGFR. The dynamic assessment of serial ctDNA was a useful measure of underlying genomic changes in response to this combination and in understanding potential mechanisms of resistance.

BMS-754807, an oral, dual IGF-1R/insulin receptor (IR) inhibitor: Early pharmacodynamic (PD) and positron emission tomography (PET) imaging results from a daily-dose study in cancer subjects

Publisher: American Association for Cancer Research (AACR)

Date: 12-2009

DOI: 10.1158/1535-7163.TARG-09-A109

Abstract: Background: Inhibiting both IGF-1R and IR signaling may be required to disrupt the malignant phenotype regulated by the receptor family. BMS-754807 is a potent and selective reversible inhibitor of IGF-1R/IR family kinases (IGF-1R, IR Ki & nM). In non-clinical studies BMS-754807 is an effective inhibitor in a broad range of human tumor types in vitro and in vivo and demonstrates synergies when combined with cytotoxic and targeted agents. Methods: CA191002 is an ascending multiple-dose study to evaluate safety, tolerability, pharmacokinetics, and pharmacodynamics of BMS-754807 in subjects with solid tumors. Dosing occurs daily 2 hours after a light breakfast and is followed by a 4 hour fast. PD effects on IR are studied by assessments of plasma glucose, insulin and C-peptide. 2-deoxy-2-[18F] fluoro-D-glucose (FDG)- and 3′-deoxy-3′-[18F] fluorothymidine (FLT)-PET imaging is performed both as imaging markers for PD and to assess anti-tumor activity. Results: Sixteen subjects have been treated at daily doses of 4, 10, 20, 30 or 50 mg. No dose limiting toxicities have been observed and dose escalation is ongoing. Duration of dosing was between 8 and 197 days. Preliminary analysis shows dose related increases of plasma glucose, insulin and C-peptide at 2 hours post-dose (Table 1). The range [median] of plasma glucose at all time points was 68 –187 [95], 50 – 168 [103] and 54 –333 [124] mg/dL in subjects treated at the 4, 10 and 20, and 30 and 50 mg dose levels, respectively. 65 PET scans have been collected from 14 subjects. Preliminary analysis shows that 1 subject with osteosarcoma and 1 subject with adenoid cystic carcinoma achieved 57 and 28 % reduction of tracer uptake, respectively, on FLT-PET by D12. Both had stable metabolic disease on FDG-PET by D12 and D56. Conclusion: PD effects of IR inhibition differentiate BMS-754807 from IGF-1R specific agents. PET results suggest anti-tumor activity. Future analysis of PD effects, PET imaging data, safety information and response assessments will provide the basis for a rational selection of subjects and a dose or dose range to be further explored. Dose level (number of subjects) Plasma glucose [mg/dL] D1 and 8 2 h post-dose range [median] Insulin [µU/mL] D1 and 8 2 h post-dose range [median] C-peptide [ng/mL] D1 and 8 2 h post-dose range [median] 4 mg (3) 77 – 101 [94] 2 – 82 [12.5] 0.8 – 7 [1.8] 10 and 20 mg (7) 90 – 144 [97] 27 – 251 [58] 3 – 18 [4.6] 30 and 50 mg (6) 110 – 200 [137] 120 – 361 [210] 5 – 17 [12.1] Citation Information: Mol Cancer Ther 2009 (12 Suppl):A109.

Wiki-based clinical practice guidelines for the management of adult onset sarcoma: A new paradigm in sarcoma evidence

Publisher: Hindawi Limited

Date: 2015

DOI: 10.1155/2015/614179

Abstract: In 2013 Australia introduced Wiki-based Clinical Practice Guidelines for the Management of Adult Onset Sarcoma. These guidelines utilized a customized MediaWiki software application for guideline development and are the first evidence-based guidelines for clinical management of sarcoma. This paper presents our experience with developing and implementing web-based interactive guidelines and reviews some of the challenges and lessons from adopting an evidence-based (rather than consensus-based) approach to clinical sarcoma guidelines. Digital guidelines can be easily updated with new evidence, continuously reviewed and widely disseminated. They provide an accessible method of enabling clinicians and consumers to access evidence-based clinical practice recommendations and, as evidenced by over 2000 views in the first four months after release, with 49% of those visits being from countries outside of Australia. The lessons learned have relevance to other rare cancers in addition to the international sarcoma community.

Novel RET Fusion

Publisher: American Society of Clinical Oncology (ASCO)

Date: 11-2021

DOI: 10.1200/PO.21.00127

Comparing Survival Outcomes for Advanced Cancer Patients Who Received Complex Genomic Profiling Using a Synthetic Control Arm

Publisher: Springer Science and Business Media LLC

Date: 09-2022

DOI: 10.1007/S11523-022-00910-0

Selective kinase inhibition with daily imatinib intensifies toxicity of chemotherapy in patients with solid tumours

Publisher: Elsevier BV

Date: 05-2006

DOI: 10.1016/J.EJCA.2005.12.010

Abstract: The aim of this study was to determine the safety and maximum-tolerated doses of imatinib combined with cytotoxic chemotherapy (either gemcitabine or doxorubicin). Patients with advanced solid tumours were enrolled separately in two different combinations of imatinib with chemotherapy (imatinib + gemcitabine or imatinib + doxorubicin). A standard modified Fibonacci inter-cohort dose escalation was planned for each combination. Sixteen patients were accrued. Seven patients received gemcitabine and imatinib. A separate cohort of nine patients received imatinib and doxorubicin. In both groups, dose-limiting toxicity (DLT) was observed at the initial dose level requiring dose reductions for subsequent cohorts. Further DLTs were observed necessitating closure of the protocol. Daily dosing of imatinib with concurrent administration of cytotoxic chemotherapy (either gemcitabine or doxorubicin) at standard doses was associated with toxicity that was clinically unacceptable. It remains unclear whether addition of growth factors might improve tolerability for imatininb in combination with cytotoxic chemotherapy.

What is the future potential of the PI3K pathway in colorectal cancer treatment?

Publisher: Future Medicine Ltd

Date: 04-2014

DOI: 10.2217/CRC.14.11

Retrospective observational studies in ultra-rare sarcomas: A consensus paper from the Connective Tissue Oncology Society (CTOS) community of experts on the minimum requirements for the evaluation of

Publisher: Elsevier BV

Date: 11-2022

DOI: 10.1016/J.CTRV.2022.102455

Abstract: In ultra-rare sarcomas (URS) the conduction of prospective, randomized trials is challenging. Data from retrospective observational studies (ROS) may represent the best evidence available. ROS implicit limitations led to poor acceptance by the scientific community and regulatory authorities. In this context, an expert panel from the Connective Tissue Oncology Society (CTOS), agreed on the need to establish a set of minimum requirements for conducting high-quality ROS on the activity of systemic therapies in URS. Representatives from > 25 worldwide sarcoma reference centres met in November 2020 and identified a list of topics summarizing the main issues encountered in ROS on URS. An online survey on these topics was distributed to the panel results were summarized by descriptive statistics and discussed during a second meeting (November 2021). Topics identified by the panel included the use of ROS results as external control data, the criteria for contributing centers selection, modalities for ensuring a correct pathological diagnosis and radiologic assessment, consistency of surveillance policies across centers, study end-points, risk of data duplication, results publication. Based on the answers to the survey (55 of 62 invited experts) and discussion the panel agreed on 18 statements summarizing principles of recommended practice. These recommendations will be disseminated by CTOS across the sarcoma community and incorporated in future ROS on URS, to maximize their quality and favor their use as control data when results from prospective studies are unavailable. These recommendations could help the optimal conduction of ROS also in other rare tumors.

Systematic review of NTRK 1/2/3 fusion prevalence pan-cancer and across solid tumours

Publisher: Springer Science and Business Media LLC

Date: 13-03-2023

DOI: 10.1038/S41598-023-31055-3

Abstract: NTRK gene fusions are rare somatic mutations found across cancer types with promising targeted therapies emerging. Healthcare systems face significant challenges in integrating these treatments, with uncertainty in prevalence and optimal testing methods to identify eligible patients. We performed a systematic review of NTRK fusion prevalence to inform efficient diagnostic screening and scale of therapeutic uptake. We searched Medline, Embase and Cochrane databases on 31/03/2021. Inclusion criteria were studies reporting fusion rates in solid tumours, English language, post-2010 publication and minimum s le size. Critical appraisal was performed using a custom 11-item checklist . Rates were collated by cancer type and pooled if additional synthesis criteria were met. 160 studies were included, with estimates for 15 pan-cancer and 429 specific cancer types (63 paediatric). Adult pan-cancer estimates ranged 0.03–0.70%, with higher rates found in RNA-based assays . In common cancers, rates were consistently below 0.5%. Rare morphological subtypes, colorectal microsatellite instability, and driver mutation exclusion cancers had higher rates. Only 35.6% of extracted estimates used appropriate methods and s le size to identify NTRK fusions. NTRK fusion-positive cancers are rare and widely distributed across solid tumours. Small-scale, heterogeneous data confound prevalence prediction. Further large-scale, standardised genomic data are needed to characterise NTRK fusion epidemiology.

High-spatial-resolution mapping of superhydrophobic cicada wing surface chemistry using infrared microspectroscopy and infrared imaging at two synchrotron beamlines

Publisher: International Union of Crystallography (IUCr)

Date: 22-03-2013

DOI: 10.1107/S0909049513004056

Abstract: The wings of some insects, such as cicadae, have been reported to possess a number of interesting and unusual qualities such as superhydrophobicity, anisotropic wetting and antibacterial properties. Here, the chemical composition of the wings of the Clanger cicada ( Psaltoda claripennis ) were characterized using infrared (IR) microspectroscopy. In addition, the data generated from two separate synchrotron IR facilities, the Australian Synchrotron Infrared Microspectroscopy beamline (AS-IRM) and the Synchrotron Radiation Center (SRC), University of Wisconsin-Madison, IRENI beamline, were analysed and compared. Characteristic peaks in the IR spectra of the wings were assigned primarily to aliphatic hydrocarbon and amide functionalities, which were considered to be an indication of the presence of waxy and proteinaceous components, respectively, in good agreement with the literature. Chemical distribution maps showed that, while the protein component was homogeneously distributed, a significant degree of heterogeneity was observed in the distribution of the waxy component, which may contribute to the self-cleaning and aerodynamic properties of the cicada wing. When comparing the data generated from the two beamlines, it was determined that the SRC IRENI beamline was capable of producing higher-spatial-resolution distribution images in a shorter time than was achievable at the AS-IRM beamline, but that spectral noise levels per pixel were considerably lower on the AS-IRM beamline, resulting in more favourable data where the detection of weak absorbances is required. The data generated by the two complementary synchrotron IR methods on the chemical composition of cicada wings will be immensely useful in understanding their unusual properties with a view to reproducing their characteristics in, for ex le, industry applications.

Antiangiogenic Therapies Targeting the Vascular Endothelia Growth Factor Signaling System

Publisher: Begell House

Date: 2012

DOI: 10.1615/CRITREVONCOG.V17.I1.50

Abstract: Angiogenesis is critical to the growth of human tumors and the development of metastasis. Amongst the many proangiogenic mechanisms identified, the vascular endothelial growth factor (VEGF) signaling pathway has been implicated as the key regulator of tumor neovascularisation. Various therapeutic agents targeting the VEGF pathway have been successfully developed, with many now approved and in routine clinical use. In general, VEGF-mediated angiogenesis can be inhibited by 2 approaches: antibodies directed against VEGF ligands or VEGF receptors (VEGFRs) and tyrosine kinase inhibitors targeting the VEGFRs. Thus far, clinical benefits achieved with VEGF-targeted agents are limited by their modest efficacy and the development of resistance. With no shortage of drugs in development, the lack of well-validated biomarkers to predict for response or resistance to VEGF-directed therapies is now becoming a key factor limiting the further rational development of this class of anticancer agent. This review discusses the biology of VEGF signaling, the clinical efficacy of VEGF-targeting therapies, potential mechanisms of resistance, and emerging predictive biomarkers.

Molecular correlates of clinical benefit in previously treated patients (pts) with BRAF V600E-mutant metastatic colorectal cancer (mCRC) from the BEACON study

Publisher: American Society of Clinical Oncology (ASCO)

Date: 20-05-2021

DOI: 10.1200/JCO.2021.39.15_SUPPL.3513

Abstract: 3513 Background: Encorafenib + binimetinib + cetuximab (enco/bini/cetux triplet) and enco + cetux (doublet) regimens improved overall survival and objective response rate vs standard of care in pts with previously treated BRAF V600E-mutant mCRC in the randomized phase 3 BEACON study. To identify molecular correlates of clinical outcome, we performed molecular profiling in tumors from pts in the study. Methods: Baseline tumor s les were retrospectively analyzed by whole-exome sequencing (WES) and whole transcriptome sequencing (WTS) using ImmunoID NeXT (Personalis, Menlo Park, CA, USA). BRAF-mutant (BM) and consensus molecular subtypes (CMS) were determined using published classifiers. Pathway activities were evaluated with gene set variation analysis. Objective tumor response was evaluated according to each subtype. Additional association and interaction analyses between molecular features and clinical outcomes by treatments are ongoing and will be presented. Results: Baseline tumor s les were analyzed by WES and/or WTS from 527 of 665 (79.2%) randomized pts. The biomarker analyses set is representative of the total pt population and had similar clinical outcomes. Of the 460 pts analyzed by WTS (165/224 [73.7%] in the triplet arm, 146/220 [66.4%] in the doublet arm, and 149/221 [67.4%] in the control arm), 84.6% were classified as either CMS1 (n = 225) or CMS4 (n = 164). The proportion of pts classified as BM1 was 32.2% (n = 148) and the majority (84.5%) of these were CMS4, whereas many of those classified as BM2 (67.8%, n = 312) were CMS1 (64.7%). In the BM1 and CMS4 tumors, expression of inflammatory response and epithelial mesenchymal transition genes were elevated, and expression of cell cycle genes was reduced. The response rate in pts with CMS4 and/or BM1 tumors was higher in the triplet arm (CMS4: 33.3% [95% CI: 21.7–46.7] BM1: 33.3% [95% CI: 21.4–47.1]) compared with the doublet arm (CMS4: 19.2% [95% CI: 9.6–32.5] BM1: 14.9% [95% CI: 6.2–28.3]). Conclusions: Molecular characteristics and biological properties observed in BRAF V600E-mutant mCRC suggest that a subset of pts with specific molecular features may derive greater clinical benefit from triplet than doublet therapy. Additionally, these findings support the utility of gaining further understanding of the biological landscape in BRAF-mutant mCRC to enable potential hypotheses for pt selection to improve clinical outcome in future studies. Clinical trial information: NCT02928224.

Soft-tissue Sarcomas in the Asia-Pacific Region: A Systematic Review

Publisher: Asian Pacific Organization for Cancer Prevention

Date: 30-11-2013

DOI: 10.7314/APJCP.2013.14.11.6821

Abstract: Soft-tissue sarcomas require tailored and multidisciplinary treatment and management. However, little is known about how sarcomas are treated and managed throughout the Asia-Pacific region. MEDLINE was systematically searched using prespecified criteria. Publications (previous 10 years) that reported tumour characteristics, treatment patterns, survival outcomes, and/or safety outcomes of patients with soft-tissue sarcoma were selected. Exclusion criteria were studies of patients 20% benign tumours sarcomas located in bones or joints gastrointestinal stromal tumour Kaposi's sarcoma or not reporting relevant outcomes. Of the 1,822 publications retrieved, 35 (32 studies) were included. Nearly all patients (98%, 1,992/2,024 31 studies) were treated with surgery, and more studies used adjuvant radiotherapy than chemotherapy (24 vs 17 studies). Survival outcomes and recurrence rates varied among the studies because of the different histotypes, sites, and disease stages assessed. Only 5 studies reported safety findings. These findings highlight the lack of specific data available about soft-tissue sarcomas in the Asia-Pacific region. Better efforts to understand how the sarcoma is managed and treated will help improve patient outcomes in the region.

Safety and efficacy of the anti-CD73 monoclonal antibody (mAb) oleclumab +/- durvalumab in patients (pts) with advanced colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), or EGFR-mutant non-small cell lung cancer (EGFRm NSCLC)

Publisher: American Society of Clinical Oncology (ASCO)

Date: 20-05-2021

DOI: 10.1200/JCO.2021.39.15_SUPPL.9047

Abstract: 9047 Background: Upregulation of CD73 in multiple cancers increases adenosine production, leading to local immunosuppression. Oleclumab, a human IgG1λ mAb, inhibits CD73 function and may increase antitumor immunity. Initial data from a Phase I, first-in-human, dose-escalation and expansion study showed that oleclumab ± durvalumab had manageable safety and encouraging clinical activity in pts with advanced CRC or PDAC. We report updated safety and activity in these cohorts and the first results in an expansion cohort of pts with advanced EGFRm NSCLC. Methods: Previously treated pts with histologically or cytologically confirmed microsatellite stable CRC, PDAC, or EGFRm NSCLC received oleclumab 5–40 mg/kg (escalation) and 40 mg/kg (expansion) IV Q2W, alone (escalation only) or with durvalumab 10 mg/kg IV Q2W. The primary objective was safety secondary efficacy objectives included objective response (OR) per RECIST v1.1 and duration of response (DoR). Results: 66 pts were enrolled in the escalation phase (35 CRC, 31 PDAC) and 126 in the expansion phase (42 CRC, 42 PDAC, 42 EGFRm NSCLC). At data cutoff (DCO June 9, 2020), the median number of oleclumab doses was 4 in pts on monotherapy (range 1–26) and 4 in pts on combination therapy across both phases (range 1–76). In the escalation phase, there were no DLTs in pts on monotherapy or combination therapy treatment-related adverse events (TRAEs) occurred in 54.8% of pts on monotherapy (Grade 3–4 in 7.1%) and 54.2% of pts on combination therapy (Grade 3–4 in 20.8%) fatigue was the most common TRAE with both regimens. No TRAEs resulted in death. In previous interim analyses before this DCO, no ORs were reported in the escalation phase. In the expansion phase, 5 pts were treated for ≥12 mos 6 pts were ongoing at DCO. TRAEs occurred in 54.0% (Grade 3–5 in 15.1%) the most common TRAEs were fatigue (15.1%), diarrhea (9.5%), and rash (7.1%). One pt had a TRAE resulting in death (systemic inflammatory response syndrome). ORs were seen in 1 CRC pt (DoR 35.9+ mos [+ = ongoing response]), 2 PDAC pts (DoR 22.1+ and 28.6+ mos), and 4 EGFRm NSCLC pts (DoR range 5.6 to 15.7+ mos, median not reached only 1 of the 4 pts had ≥25% programmed cell death ligand-1 [PD-L1]+ tumor cells). Nine CRC pts, 8 PDAC pts, and 9 EGFRm NSCLC pts had SD. Of 6 pts with matched biopsies who received combination therapy, 5 had increases in CD8+ T cells, PD-L1, and granzyme B. Baseline tumor CD73 expression and association with clinical response will be presented. Conclusions: Oleclumab ± durvalumab had a tolerable safety profile and combination therapy showed promising antitumor activity in EGFRm NSCLC. ORs and SD were durable, even in tumor types that are generally immunotherapy-resistant. Clinical trial information: NCT02503774.

Supplementary Data DS1 from A Phase Ib/II Trial of Combined BRAF and EGFR Inhibition in <i>BRAF</i> V600E Positive Metastatic Colorectal Cancer and Other Cancers: The EVICT (Erlotinib and

Publisher: American Association for Cancer Research (AACR)

Date: 04-2023

DOI: 10.1158/1078-0432.22490194

Abstract: Supplementary material

DNA Copy-Number Alterations Underlie Gene Expression Differences between Microsatellite Stable and Unstable Colorectal Cancers

Publisher: American Association for Cancer Research (AACR)

Date: 15-12-2008

DOI: 10.1158/1078-0432.CCR-08-1431

Abstract: Purpose: About 15% of colorectal cancers harbor microsatellite instability (MSI). MSI-associated gene expression changes have been identified in colorectal cancers, but little overlap exists between signatures hindering an assessment of overall consistency. Little is known about the causes and downstream effects of differential gene expression. Experimental Design: DNA microarray data on 89 MSI and 140 microsatellite-stable (MSS) colorectal cancers from this study and 58 MSI and 77 MSS cases from three published reports were randomly ided into test and training sets. MSI-associated gene expression changes were assessed for cross-study consistency using training s les and validated as MSI classifier using test s les. Differences in biological pathways were identified by functional category analysis. Causation of differential gene expression was investigated by comparison to DNA copy-number data. Results: MSI-associated gene expression changes in colorectal cancers were found to be highly consistent across multiple studies of primary tumors and cancer cell lines from patients of different ethnicities (P & 0.001). Clustering based on consistent changes separated additional test cases by MSI status, and classification of in idual s les predicted MSI status with a sensitivity of 96% and specificity of 85%. Genes associated with immune response were up-regulated in MSI cancers, whereas genes associated with cell-cell adhesion, ion binding, and regulation of metabolism were down-regulated. Differential gene expression was shown to reflect systematic differences in DNA copy-number aberrations between MSI and MSS tumors (P & 0.001). Conclusions: Our results show cross-study consistency of MSI-associated gene expression changes in colorectal cancers. DNA copy-number alterations partly cause the differences in gene expression between MSI and MSS cancers.

KRAS mutation testing of metastatic colorectal cancer in Australia: Where are we at?

Publisher: Wiley

Date: 09-05-2014

DOI: 10.1111/AJCO.12201

Abstract: To carry out a nationwide study of KRAS testing in metastatic colorectal cancer as reported by nine major molecular pathology service providers in Australia, including mutation frequencies and turnaround times that might impact on patient care. Participating laboratories contributed information on KRAS mutation frequencies, including the G13D mutation type, as well as turnaround times for tumor block retrieval and testing. The KRAS mutation frequency observed by nine different test sites for a total of 3688 metastatic colorectal cancers ranged from 34.4% to 40.7%, with an average across all sites of 38.8%. The average frequency of the G13D mutation type among all cases was 8.0%. The median turnaround time was 17 days (range 0-191), with 20% of cases requiring more than 4 weeks for a KRAS test result. The major contributor to long turnaround times was the time taken to retrieve archived blocks of primary tumor, particularly from sources external to the test site. The frequency of KRAS mutations in metastatic colorectal cancer reported by the major Australian test sites is very similar to that reported by other large overseas studies. More widespread introduction of routine testing at the time of initial diagnosis should eliminate the long turnaround times currently being experienced in a significant proportion of cases. Future expansion of testing to include other KRAS and NRAS mutation hotspots may spur the introduction of next-generation sequencing platforms.

Systematic Review of Clinical Outcomes Following Various Treatment Options for Patients with Extraabdominal Desmoid Tumors

Publisher: Springer Science and Business Media LLC

Date: 11-04-2018

DOI: 10.1245/S10434-018-6408-7

Abstract: Desmoid tumors (DT) are rare clonal proliferations that arise from mesenchymal cells. These tumors do not metastasize but are locally aggressive, and their growth may lead to significant morbidity. Their clinical course is both variable and unpredictable tumors may rapidly progress but in other instances remain stable or regress without intervention. To examine current treatment of DT and assist with decision-making at time of presentation. A literature search was conducted of MEDLINE and Cochrane databases for published studies (1995-July 2015) using the search terms fibromatosis aggressive, desmoid with drug therapy, radiation therapy, prevention and control, radiotherapy, surgery, and therapy. Articles were categorized as surgery, radiation, surgery + radiation, systemic therapy, and front-line observation. Articles were included if they reported a retrospective or prospective comparative or observational study with an analyzed s le size of 10 patients or more with confirmed diagnosis of desmoid tumor and described one of the following clinical outcomes: relapse- or progression-free survival, local control rate, response rate. 258 articles were reviewed following screening for eligibility, 54 were identified following full-text screen, 31 were included in final evaluation. The control rate for patients treated with a "wait and see" observational approach compared favorably with management with surgery and resulted in disease control rates of between 60 and 92%. Decision-making in this rare tumor is complicated by the range of treatment options available. Our evidence supports use of an upfront observational approach.

Hypothyroidism after sunitinib treatment for patients with gastrointestinal stromal tumors

Publisher: American College of Physicians

Date: 07-11-2006

DOI: 10.7326/0003-4819-145-9-200611070-00008

Abstract: Sunitinib malate is an oral tyrosine kinase inhibitor recently approved for the treatment of gastrointestinal stromal tumors and renal cell carcinoma. Because the ret proto-oncogene is also inhibited by this agent, clinical evaluation of thyroid function was performed. To describe the prevalence and clinical presentation of thyroid dysfunction related to sunitinib therapy. Prospective, observational cohort study. Tertiary care hospital. 42 patients treated for a median of 37 weeks (range, 10 to 167 weeks). Following analysis of serial thyroid-stimulating hormone (TSH) measurements collected prospectively during a clinical trial of sunitinib, the authors determined the proportion of patients with thyroid dysfunction. Abnormal serum TSH concentrations were documented in 26 of 42 patients (62%): 15 (36%) developed persistent, primary hypothyroidism 4 (10%) developed isolated TSH suppression and 7 (17%) experienced transient, mild TSH elevations. The risk for hypothyroidism increased with the duration of sunitinib therapy. Six of 15 (40%) hypothyroid patients had suppressed TSH concentrations before developing hypothyroidism, suggesting thyroiditis. Two hypothyroid patients evaluated with thyroid ultrasonography had no visualized thyroid tissue despite normal baseline thyroid function. The exploratory nature of this study precluded more frequent biochemical and sonographic analysis that may better define the mechanism of sunitinib-associated thyroid dysfunction. Hypothyroidism is a frequent complication of sunitinib therapy. Regular surveillance of thyroid function is warranted in patients receiving the drug. Although the mechanism by which this complication occurs is unknown, the observations of preceding TSH suppression and subsequent absence of visualized thyroid tissue in some patients suggest that sunitinib may induce a destructive thyroiditis through follicular cell apoptosis. This provides a rationale for further investigation of sunitinib treatment in patients with advanced thyroid cancer.

Data from A Phase Ib/II Trial of Combined BRAF and EGFR Inhibition in <i>BRAF</i> V600E Positive Metastatic Colorectal Cancer and Other Cancers: The EVICT (Erlotinib and Vemurafenib In Com

Publisher: American Association for Cancer Research (AACR)

Date: 04-2023

DOI: 10.1158/1078-0432.C.6533113.V1

Abstract: AbstractPurpose: BRAF V600E mutant metastatic colorectal cancer represents a significant clinical problem, with combination approaches being developed clinically with oral BRAF inhibitors combined with EGFR-targeting antibodies. While compelling preclinical data have highlighted the effectiveness of combination therapy with vemurafenib and small-molecule EGFR inhibitors, gefitinib or erlotinib, in colorectal cancer, this therapeutic strategy has not been investigated in clinical studies. Patients and Methods: We conducted a phase Ib/II dose-escalation/expansion trial investigating the safety/efficacy of the BRAF inhibitor vemurafenib and EGFR inhibitor erlotinib. Results: Thirty-two patients with i BRAF /i V600E positive metastatic colorectal cancer (mCRC) and 7 patients with other cancers were enrolled. No dose-limiting toxicities were observed in escalation, with vemurafenib 960 mg twice daily with erlotinib 150 mg daily selected as the recommended phase II dose. Among 31 evaluable patients with mCRC and 7 with other cancers, overall response rates were 32% [10/31, 16% (5/31) confirmed] and 43% (3/7), respectively, with clinical benefit rates of 65% and 100%. Early ctDNA dynamics were predictive of treatment efficacy, and serial ctDNA monitoring revealed distinct patterns of convergent genomic evolution associated with acquired treatment resistance, with frequent emergence of MAPK pathway alterations, including polyclonal i KRAS /i , i NRAS /i , and i MAP2K1 /i mutations, and i MET /i lification. Conclusions: The Erlotinib and Vemurafenib In Combination Trial study demonstrated a safe and novel combination of two oral inhibitors targeting BRAF and EGFR. The dynamic assessment of serial ctDNA was a useful measure of underlying genomic changes in response to this combination and in understanding potential mechanisms of resistance. /

Towards the biomarker-guided rational use of antiangiogenic agents in the treatment of metastatic colorectal cancer

Publisher: Future Medicine Ltd

Date: 04-2012

DOI: 10.2217/CRC.12.9

Abstract: SUMMARY Clinical oncology experience with recently marketed antiangiogenic agents, which inhibit proteins important for tumor angiogenesis, has exposed significant limitations to their efficacy. Bevacizumab, a humanized neutralizing anti-VEGF-A monoclonal antibody, used in combination with cytotoxic chemotherapy for the treatment of metastatic colorectal cancer, represents the best-studied clinical ex le of targeted antiangiogenic therapy. In this context, bevacizumab provides modestly improved progression-free and overall survival in unselected patient populations via poorly understood mechanisms. Here we review concepts central to the identification and development of biomarkers in order to refine clinical use of bevacizumab in treating colorectal cancer and outline a phenotype-driven strategy for the discovery of high-value candidate biomarkers based on large-scale screening by molecular perturbation.

Resistance to BRAF Inhibition in BRAF-Mutant Colon Cancer Can Be Overcome with PI3K Inhibition or Demethylating Agents

Publisher: American Association for Cancer Research (AACR)

Date: 31-01-2013

DOI: 10.1158/1078-0432.CCR-11-1446

Abstract: Purpose: Vemurafenib, a selective inhibitor of BRAFV600, has shown significant activity in BRAFV600 melanoma but not in less than 10% of metastatic BRAFV600 colorectal cancers (CRC), suggesting that studies of the unique hypermethylated phenotype and concurrent oncogenic activation of BRAFmut CRC may provide combinatorial strategies. Experimental Design: We conducted comparative proteomic analysis of BRAFV600E melanoma and CRC cell lines, followed by correlation of phosphoinositide 3-kinase (PI3K) pathway activation and sensitivity to the vemurafenib analogue PLX4720. Pharmacologic inhibitors and siRNA were used in combination with PLX4720 to inhibit PI3K and methyltransferase in cell lines and murine models. Results: Compared with melanoma, CRC lines show higher levels of PI3K/AKT pathway activation. CRC cell lines with mutations in PTEN or PIK3CA were less sensitive to growth inhibition by PLX4720 (P = 0.03), and knockdown of PTEN expression in sensitive CRC cells reduced growth inhibition by the drug. Combined treatment of PLX4720 with PI3K inhibitors caused synergistic growth inhibition in BRAF-mutant CRC cells with both primary and secondary resistance. In addition, methyltransferase inhibition was synergistic with PLX4720 and decreased AKT activation. In vivo, PLX4720 combined with either inhibitors of AKT or methyltransferase showed greater tumor growth inhibition than PLX4720 alone. Clones with acquired resistance to PLX4720 in vitro showed PI3K/AKT activation with EGF receptor (EGFR) or KRAS lification. Conclusions: We show that activation of the PI3K/AKT pathway is a mechanism of both innate and acquired resistance to BRAF inhibitors in BRAFV600E CRC and suggest combinatorial approaches to improve outcomes in this poor prognosis subset of patients. Clin Cancer Res 19(3) 657–67. ©2012 AACR.

A multi-arm phase I dose escalating study of an oral NOTCH inhibitor BMS-986115 in patients with advanced solid tumours

Publisher: Springer Science and Business Media LLC

Date: 10-04-2018

DOI: 10.1007/S10637-018-0597-6

MORPHEUS: A phase Ib/II study platform evaluating the safety and clinical efficacy of cancer immunotherapy (CIT)-based combinations in gastrointestinal (GI) cancers

Publisher: American Society of Clinical Oncology (ASCO)

Date: 02-2019

DOI: 10.1200/JCO.2019.37.4_SUPPL.TPS467

Abstract: TPS467 Background: CIT has significant survival benefits across multiple tumor types, but durable response is experienced by only subsets of patients (pts). To extend clinical benefit to more pts, efficacious CIT combinations (combos) targeting multiple cancer immune escape mechanisms need to be identified. The MORPHEUS platform includes multiple ph Ib/II trials designed to identify early signals of safety and efficacy of CIT combos. Using a randomized trial design, multiple treatment (tx) arms are compared with a single control arm in each pt cohort. We present three GI-specific MORPHEUS trials, each assessing CIT combos that could concurrently enhance multiple aspects of the cancer immune response. Methods: The MORPHEUS trials described here are global, open-label, randomized, Ph Ib/II trials enrolling pts with pancreatic ductal adenocarcinoma (PDAC), gastric or gastroesophageal junction cancers or colorectal cancer (CRC). New arms with novel CIT combos (table) are opened as new txs become available, and arms with minimal efficacy or unacceptable toxicity are closed. Studies include multiple cohorts for pts receiving different lines of tx (1L and 2L PDAC and gastric 3L CRC). Pts with loss of clinical benefit or unacceptable toxicity may be eligible to enroll in a different CIT combo arm. Primary endpoints include safety and investigator-assessed ORR (RECIST v1.1) secondary endpoints: PFS, OS, DCR and DOR. Clinical trial information: NCT03193190, NCT03281369, NCT03555149. [Table: see text]

Patterns of care for patients with advanced soft tissue sarcoma: experience from Australian sarcoma services

Publisher: Springer Science and Business Media LLC

Date: 11-07-2016

DOI: 10.1186/S13569-016-0052-4

Clinical use of therapies targeting tumor vasculature and stroma

Publisher: Bentham Science Publishers Ltd.

Date: 09-2008

DOI: 10.2174/156800908785699388

Abstract: Many recent advances in cancer therapy have been based on an understanding of the basic biology of the cancer cell itself, particularly with respect to abnormalities in various signalling pathways. It has become increasingly apparent that malignant cells exist in a complex cellular and extracellular microenvironment, which can play key roles in the initiation and maintenance of the malignant phenotype. These interactions can provide therapeutic targets that are now being exploited in the clinic. Much attention has been paid to agents that disrupt angiogenesis or existing tumor vasculature, however other cellular and non-cellular components of the tumor mass mediate critical functions and can also be useful treatment targets. Treatments directed at these interactions bring new challenges in terms of how best to develop these strategies, and require approaches that differ in many ways from conventional anticancer therapies.

Evaluation of baseline BRAF V600E mutation in circulating tumor DNA and efficacy response from the BEACON study

Publisher: American Society of Clinical Oncology (ASCO)

Date: 02-2022

DOI: 10.1200/JCO.2022.40.4_SUPPL.162

Abstract: 162 Background: In the randomized phase 3 BEACON study, encorafenib + binimetinib + cetuximab (triplet) and encorafenib + cetuximab (doublet) regimens improved overall survival (OS) and objective response rate (ORR) versus standard of care (control) in patients (pts) with previously treated BRAF V600E-mutant metastatic colorectal cancer. To identify whether detection of a BRAF V600E mutation in baseline circulating tumor DNA (ctDNA) correlated with response, we evaluated the status and allele frequency of BRAF V600E compared with clinical outcomes. Methods: Plasma s les were collected at Cycle 1 Day 1 and end of treatment for ctDNA analysis and analyzed using GuardantOMNI. Variant allele frequency (VAF) of BRAF V600E was grouped into high ( median) and low (≤median) categories. Low VAF s les included those where BRAF V600E mutation was not detected or no ctDNA was detected. ORR, based on blinded independent central review, and OS were compared between treatment arms according to VAF levels. ORR comparisons used Chi-square test and logistic regression. OS was summarized using the Kaplan-Meier method. HRs and 95% CIs were estimated using a Cox model. Additional correlation analyses between BRAF V600E status in baseline tumor tissue, as well as clonality, will be presented. Results: Baseline plasma s les were analyzed from 544 of 631 pts in the ctDNA analysis: 88.3% (196/222) in the triplet arm, 86.6% (187/216) in the doublet arm, and 83.4% (161/193) in the control arm. BRAF V600E mutations were detected in 90.4% (492/544) of pts (90.3% [177/196] triplet, 90.4% [169/187] doublet, and 90.7% [146/161] control). Pts with BRAF V600E mutations with high VAF had significantly ( P≤0.0001) increased ORR (95% CI) in the triplet and doublet arms (27.3% [19.5–36.8] and 15.9% [9.7–25.0], respectively) compared with control (0% [0.0–4.3]). Similar response trends were observed in pts with BRAF V600E mutations with low VAF (triplet: 28.9% [20.8–38.9] doublet: 25.3% [17.7–34.6] control: 5.3% [2.1–12.8]). OS decreased in BRAF V600E pts with high VAF (median OS [95% CI]: triplet 7.2 [6.0–8.0] months, n = 99 doublet 5.4 [4.4–6.1] months, n = 88 control 4.2 [3.4–4.8] months, n = 85) compared with pts with low VAF (triplet 14.8 [10.2–19.8] months, n = 97 doublet 14.8 [11.7–23.0] months, n = 99 control 9.3 [7.5–11.3] months, n = 76). Conclusions: ctDNA analyses showed the majority of pts in BEACON analyzed at baseline had a detectable BRAF V600E mutation. Increased response rates were observed in pts treated with triplet or doublet therapy compared with control, independent of VAF. Pts with a higher VAF for BRAF V600E may have a worse prognosis. Clinical trial information: NCT04607421.

A phase 1b dose-escalation study of BYL719 plus binimetinib (MEK162) in patients with selected advanced solid tumors.

Publisher: American Society of Clinical Oncology (ASCO)

Date: 20-05-2014

DOI: 10.1200/JCO.2014.32.15_SUPPL.9051

A Phase 1/2 study of the PD-L1 inhibitor, BGB-A333, alone and in combination with the PD-1 inhibitor, tislelizumab, in patients with advanced solid tumours

Publisher: Springer Science and Business Media LLC

Date: 16-02-2023

DOI: 10.1038/S41416-022-02128-3

Abstract: Many patients do not respond or eventually relapse on treatment with programmed cell death protein-1 (PD-1) rogrammed death-ligand 1 (PD-L1) checkpoint inhibitors due to secondary or acquired resistance therefore, there is a need to investigate novel PD-1/PD-L1 inhibitors. This open-label, non-randomised study investigated the safety and anti-tumour activity of BGB-A333, a PD-L1 inhibitor, alone and in combination with tislelizumab in patients with advanced solid tumours with progression during/after standard therapy. The primary objectives were to determine the recommended Phase 2 dose (RP2D), safety and tolerability for BGB-A333 alone and in combination with tislelizumab (Phase 1a/1b) and to determine the overall response rate (ORR) with BGB-A333 plus tislelizumab (Phase 2). Overall, 39 patients across Phase 1a ( N = 15), 1b ( N = 12) and 2 ( N = 12) were enroled. In Phase 1a, an RP2D of 1350 mg was determined. In Phase 1a and 1b/2, serious treatment-emergent adverse events (TEAEs) were reported in five and eight patients, respectively. Two patients experienced TEAEs that led to death. In Phase 2, the ORR was 41.7% ( n = 5/12 95% confidence interval: 15.17%, 72.33%). TEAEs reported with BGB-A333 were consistent with other PD-L1 inhibitors. Encouraging preliminary anti-tumour activity was observed with BGB-A333 in combination with tislelizumab. NCT03379259.

An initial watch and wait approach is a valid strategy for selected patients with newly diagnosed metastatic colorectal cancer

Publisher: Elsevier BV

Date: 10-2012

DOI: 10.1093/ANNONC/MDS184

Abstract: A range of treatments are available for patients with metastatic colorectal cancer (mCRC). An initial period without active treatment, a 'watch and wait approach', is variably employed in routine practice however, there is no data to support this approach. We prospectively collected data regarding clinician treatment recommendations for patients with newly diagnosed mCRC in addition to subsequent treatment and outcomes. Follow-up and management was according to standard protocols. Seven hundred and thirty-six patients (59.1% male, 40.9% female) with mCRC (January 2003-December 2010) were analysed the median age was 67.9 years (range 26.2-95.5). Three hundred and seventy-seven patients (51.2%) received immediate chemotherapy. For 133 (18.1%), treatment was considered inappropriate. 34 patients (4.6%) declined therapy. For 192 (26.1%), a watch and wait policy was adopted and 168 (87.5%) of these received treatment, at a median of 3.7 months (range 2-35 months) from diagnosis. Compared with patients immediately treated, the number receiving all active chemotherapy agents (30.4 versus 39.3%) was similar and median survival (27 versus 17 months, P = 0.0008) was superior. Our study demonstrates that a substantial minority of patients underwent an initial watch and wait approach. Ultimately, they received a similar treatment exposure to patients treated immediately and the survival outcomes were not compromised.

Phase II study of ganitumab, a fully human anti-type-1 insulin-like growth factor receptor antibody, in patients with metastatic ewing family tumors or desmoplastic small round cell tumors

Publisher: American Society of Clinical Oncology (ASCO)

Date: 20-05-2012

DOI: 10.1200/JCO.2011.37.2359

Abstract: Ganitumab is a fully human monoclonal antibody against type-1 insulin-like growth factor receptor (IGF1R). An open-label phase II study was conducted to evaluate the efficacy and safety of ganitumab monotherapy in patients with metastatic Ewing family tumors (EFT) or desmoplastic small round cell tumors (DSRCT). Patients ≥16 years of age with relapsed or refractory EFT or DSRCT received 12 mg/kg of ganitumab every 2 weeks. Objective response rate (ORR) was the primary end point. Secondary end points included clinical benefit rate (CBR = complete + partial responses + stable disease [SD] ≥ 24 weeks) and safety and pharmacokinetic profiles of ganitumab. The relationship between tumor response and EWS gene translocation status and IGF-1 levels was evaluated. Thirty-eight patients (22 with EFT 16 with DSRCT) received one or more doses of ganitumab. Twenty-four patients (63%) experienced ganitumab-related adverse events. Grade 3 related events included hyperglycemia (n = 2), thrombocytopenia (n = 5), neutropenia (n = 2), leukopenia (n = 1), and transient ischemic attack (n = 1). There were no grade 4 or 5 treatment-related events. Of 35 patients assessed for response, two had partial responses (ORR, 6%) and 17 (49%) had SD. Four patients had SD ≥ 24 weeks, contributing to a CBR of 17%. The pharmacokinetic profile of ganitumab was similar to that observed in the first-in-human trial. Elevation of IGF-1 levels was observed postdose. EWS-Fli1 translocations were analyzed by RNA sequencing and fluorescent in situ hybridization, and novel translocations were observed in EFT and DSCRT. No apparent relationship between tumor response and IGF-1 levels or EWS gene translocations was observed. Ganitumab was well tolerated and demonstrated antitumor activity in patients with advanced recurrent EFT or DSRCT.

First-in-man trial of 4-(N-(S-penicillaminylacetyl)amino) phenylarsonous acid (PENAO) as a continuous intravenous infusion (CIVI), in patients (pt) with advanced solid tumours

Publisher: American Society of Clinical Oncology (ASCO)

Date: 20-05-2016

DOI: 10.1200/JCO.2016.34.15_SUPPL.E14025

Patient Age and Comorbidity Are Major Determinants of Adjuvant Chemotherapy Use for Stage III Colon Cancer in Routine Clinical Practice

Publisher: American Society of Clinical Oncology (ASCO)

Date: 20-09-2008

DOI: 10.1200/JCO.2008.18.7443

Wither surgical oncology?

Publisher: Wiley

Date: 2019

DOI: 10.1111/ANS.14758

Tumor-Infiltrating Lymphocyte Function Predicts Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer

Publisher: American Society of Clinical Oncology (ASCO)

Date: 11-2018

DOI: 10.1200/PO.18.00075

Abstract: The presence of tumor-infiltrating lymphocytes (TILs) in tumors is superior to conventional pathologic staging in predicting patient outcome. However, their presence does not define TIL functionality. Here we developed an assay that tests TIL cytotoxicity in patients with locally advanced rectal cancer before definitive treatment, identifying those who will obtain a pathologic complete response (pCR). We also used the assay to demonstrate the rescue of TIL function after checkpoint inhibition blockade (CIB). Thirty-four consecutive patients were identified initially, with successful completion of the assay before surgery in those 17 patients who underwent full treatment. An in vitro cytotoxic assay of rectal cancer tumoroids cocultured with patient-matched TILs was established and validated. Newly diagnosed patients were recruited with pretreatment biopsy specimens processed within 1 month. Evaluation of TIL-mediated tumoroid lysis was performed by measuring the mean fluorescence intensity of cell death marker, propidium iodide. CIB (anti–programmed cell death protein 1 [anti–PD-1] antibody) response was also assessed in a subset of patient specimens. Six of the 17 patients achieved an objective pCR on final evaluation of the resected specimen after neoadjuvant chemoradiotherapy. Cytotoxic killing identified the pCR group with a higher mean fluorescence intensity (27,982 [95% CI, 25,340 to 30,625]) compared with the non-pCR cohort (12,428 [95% CI, 9,434 to 15,423] p .001). Assessment of the effectiveness of CIB revealed partial restoration of cytotoxicity in TILs with increased PD-1 expression with anti–PD-1 antibody exposure. Evaluating TIL function can be undertaken within weeks of the diagnostic biopsy, affording the potential to alter patient management decisions and refine selection for a watch-and-wait protocol. This cytotoxic assay also has the potential to serve as a platform to assist in the additional development of CIB.

Time to deterioration of patient-reported outcomes as a surrogate of overall survival: a meta-analysis

Publisher: Oxford University Press (OUP)

Date: 04-08-2023

DOI: 10.1093/JNCI/DJAD152

Abstract: Overall survival (OS) is the optimal marker of efficacy of treatments in randomized clinical trials (RCTs) but can take a considerable amount of time to mature. Progression free survival (PFS) has served as an early surrogate of OS however is imperfect. Time to deterioration (TTD) in quality of life (QoL) measures could be an alternative surrogate of OS. Phase 3 RCTs in solid malignancies that reported OS, PFS and TTD in QoL or physical function (PF) published between 1st of January 2010 and 30th of June 2022 were evaluated. Weighted regression analysis was utilised to assess the relationship between PFS, TTD QoL and TTD PF with OS. The coefficient of determination (R2) was used to quantify surrogacy. 138 phase 3 RCT were included. 47 trials evaluated immune checkpoint inhibitors (ICIs) and 91 investigated non-ICI agents. TTD QoL (137 RCTs) and TTD PF (75 RCTs) performed similarly to PFS as surrogates of OS (R2 0.18 vs 0.19 and R2 0.10 vs 0.09, respectively). For ICI studies, TTD PF had a higher association with OS compared to PFS (R2 0.38 vs 0.19) and PFS and TTD PF were not correlated with each other (R2=0). When used together, the coefficient of determination increased (R2 = 0.57). TTD of PF appears to be a OS surrogate measure of particular importance for ICI treatment efficacy. The combination of TTD PF with PFS may enable better prediction of OS treatment benefit in ICI RCTs than either PFS or TTD PF alone.

A phase I/II trial of combined BRAF and EGFR inhibition in patients (pts) with BRAF V600E mutated (BRAFm) metastatic colorectal (mCRC): The EViCT (Erlotinib and Vemurafenib in Combination Trial) study

Publisher: American Society of Clinical Oncology (ASCO)

Date: 20-05-2017

DOI: 10.1200/JCO.2017.35.15_SUPPL.3557

Abstract: 3557 Background: Pts with BRAFm mCRC have an exceedingly poor prognosis. Unlike melanoma, BRAF inhibitor monotherapy has limited activity in BRAFm mCRC. Preclinically, BRAF inhibition results in rapid feedback activation of EGFR and ongoing tumor proliferation, which can be readily overcome by combining BRAF and EGFR inhibition. EViCT examined the safety and efficacy of combining two oral agents targeting BRAF with Vemurafenib (Vem) and EGFR with Erlotinib (Erl), in BRAFm mCRC pts. Herein, we report safety and preliminary efficacy data. Methods: EViCT had 2 parts: a Phase I dose escalation of Erl (cohort 1: 100mg qd cohort 2: 150mg qd) together with Vem 960mg bd, to determine the maximum tolerated dose (MTD). The Phase II component involved dose expansion at MTD using a Simon 2-stage design to treat 9 pts in stage 1 and 15 pts in stage 2. Cycles were 28 days. Eligible pts had ECOG 1, 2 lines of systemic therapy for metastatic disease, and acceptable organ function. Staging CT scans were performed every 2 cycles, response assessed using RECIST 1.1. Primary endoint was clinical benefit rate (CR, PR and SD). A number of pharmacodynamics correlates were assessed including serial ctDNA, FDG-PET and optional tumour biopsies. Pts were treated until disease progression or toxicity requiring discontinuation. Results: Between Jul-2014 and Oct-2016, 30 BRAFm mCRC pts were enrolled. The Phase I Lead-in enrolled 4 pts in cohort 1 and 7 pts in cohort 2. There was 1 DLT (grade 3 hand-foot syndrome) in cohort 2. MTD/Recommended Phase 2 Dose was Erl 150mg qd and Vem 960mg bd, the full dose for each agent. The Phase II expansion enrolled 19 pts. Overall, 23 pts are evaluable for this interim analysis. Median age was 61 years, 11 (48%) pts were male. Most pts had 1(50%) or 2 (41%) lines of prior treatment. Overall response rate was 39% (95%CI = [20%, 61%]), including 5 (22%) confirmed PR, 4 (17%) unconfirmed PR, 3 (13%) stable disease and 11 (48%) progressive disease. Conclusions: Vem and Erl can both be given safely at their in idual full doses when used in combination. In BRAFm mCRC, this combination resulted in clear clinical activity. Clinical trial information: ACTRN12614000486628.

Criteria-based curation of a therapy-focused compendium to support treatment recommendations in precision oncology

Publisher: Springer Science and Business Media LLC

Date: 23-06-2021

DOI: 10.1038/S41698-021-00194-Z

Abstract: While several resources exist that interpret therapeutic significance of genomic alterations in cancer, many regional real-world issues limit access to drugs. There is a need for a pragmatic, evidence-based, context-adapted tool to guide clinical management based on molecular biomarkers. To this end, we have structured a compendium of approved and experimental therapies with associated biomarkers following a survey of drug regulatory databases, existing knowledge bases, and published literature. Each biomarker-disease-therapy triplet was categorised using a tiering system reflective of key therapeutic considerations: approved and reimbursed therapies with respect to a jurisdiction (Tier 1), evidence of efficacy or approval in another jurisdiction (Tier 2), evidence of antitumour activity (Tier 3), and plausible biological rationale (Tier 4). Two resistance categories were defined: lack of efficacy (Tier R1) or antitumor activity (Tier R2). Based on this framework, we curated a digital resource focused on drugs relevant in the Australian healthcare system (TOPOGRAPH: Therapy Oriented Precision Oncology Guidelines for Recommending Anticancer Pharmaceuticals). As of November 2020, TOPOGRAPH comprised 2810 biomarker-disease-therapy triplets in 989 expert-appraised entries, including 373 therapies, 199 biomarkers, and 106 cancer types. In the 345 therapies catalogued, 84 (24%) and 65 (19%) were designated Tiers 1 and 2, respectively, while 271 (79%) therapies were supported by preclinical studies, early clinical trials, retrospective studies, or case series (Tiers 3 and 4). A companion algorithm was also developed to support rational, context-appropriate treatment selection informed by molecular biomarkers. This framework can be readily adapted to build similar resources in other jurisdictions to support therapeutic decision-making.

Profound MEK inhibitor response in a cutaneous melanoma harboring a GOLGA4-RAF1 fusion

Publisher: American Society for Clinical Investigation

Date: 02-04-2019

DOI: 10.1172/JCI123089

Patterns of care according to treatment intent for metastatic colorectal cancer (mCRC): A two-year review of routine practice

Publisher: American Society of Clinical Oncology (ASCO)

Date: 02-2012

DOI: 10.1200/JCO.2012.30.4_SUPPL.682

Abstract: 682 Background: Cure is potentially achievable in select patients (pts) with mCRC with limited metastatic disease to liver and/or lung. To date the peri-operative strategies undertaken by oncologists in routine practice for such pts have not been well documented. Methods: A clinical database recording information on all pts diagnosed with mCRC since July 2009 from 5 hospitals was analysed. Management strategies where a curative-intent resection had occurred was planned or was a potential option were compared with those managed with palliative intent. Results: Status at the time of first review regarding systemic chemotherapy (CT) was documented for 280 pts. 11 (4%) had already undergone curative-intent resection 31 (11%) had a resection planned 27 (10%) were considered potentially resectable if their response to treatment was good and 207 (74%) were treated with palliative intent. No pts already resected or planned for resection were ECOG 1, compared with 11% (3/27) potentially resectable and 17% (36/207) palliative pts. CT was delivered in 9 (82%) already-resected, 26 (84%) planned for resection, 26 (96%) potentially-resectable and 159 (77%) palliative-intent pts. Combination CT was the dominant strategy, although 7 of 11 (66%) already-resected pts received single agent treatment. No already-resected pts received bevacizumab with CT, compared with 27% (n=14) of planned or potentially-curative pts and 55% (n=88) of those treated with palliative intent. At the time of analysis 13 pts (42%) with a planned resection and 8 (30%) considered potentially curative have had surgery, while 3 (1.4%) where treatment was initially considered palliative have had curative-intent surgery. Conclusions: Treatment strategies for pts with mCRC differ significantly based on the treatment intent, and may be affected by surgical preference and referral pattern. Bevacizumab was less likely to be used for already-resected pts and the use of single agent therapy in this group was also not uncommon. Many pts initially considered resectable do not ultimately undergo resection, whereas occasional ‘palliative’ pts may become resectable, confirming the importance of continued consideration of this option.

Thyrotoxicosis during sunitinib treatment for renal cell carcinoma

Publisher: Wiley

Date: 10-09-2008

DOI: 10.1111/J.1365-2265.2008.03253.X

Abstract: Sunitinib malate is an oral tyrosine kinase inhibitor used in the treatment of renal cell carcinoma (RCC) and gastrointestinal stromal tumours. Hypothyroidism has been observed in patients treated with sunitinib, but the mechanism whereby sunitinib induces hypothyroidism is unknown. To describe a series of six patients who developed thyrotoxicosis while on sunitinib for metastatic RCC. The study was conducted at Austin Health, a tertiary teaching hospital in Melbourne, Australia. Two patients developed severe thyrotoxicosis within 10 weeks after commencing sunitinib. In contrast, in the four patients who presented with later onset (16-30 weeks) thyrotoxicosis, the thyrotoxicosis was relatively mild, self-limiting and rapidly progressed to hypothyroidism. These patients experienced recurrent episodes of thyrotoxicosis in temporal relation to their cyclical sunitinib treatment. One patient had cytological evidence of lymphocytic thyroiditis. These findings suggest that sunitinib-induced hypothyroidism may be a consequence of preceding thyroiditis with associated transient thyrotoxicosis. As predictive factors are currently unknown, we suggest regular monitoring of thyroid function in all patients commenced on sunitinib. Clinicians treating patients with sunitinib or other similar kinase inhibitors should to be alerted to thyroid dysfunction as a potential toxicity of these agents.

Metastatic colorectal cancer and management in public versus private hospitals: Similarities and differences

Publisher: American Society of Clinical Oncology (ASCO)

Date: 02-2013

DOI: 10.1200/JCO.2013.31.4_SUPPL.497

Abstract: 497 Background: Potential differences between public and private cancer care in Australia include the degree of subspecialisation, multidisciplinary clinic review, access to clinical trials and continuity of care, all of which could impact treatment and outcomes. Here we compared demographics, tumour details, treatment and survival outcomes for patients (pts) with newly diagnosed metastatic colorectal cancer (mCRC) treated in the public versus private setting. Methods: This research was conducted using the TRACC (Treatment of Recurrent and Advanced Colorectal Cancer) mCRC clinical research database. Data collection began in June 2009 and is ongoing at 15 Australian centres. Here, data from four public and eight private hospitals are presented. Results: Of 671 pts, 253 (38%) were treated at public hospitals and 418 (62%) at private centres. For public versus private pts there was no significant difference in median age or percentage with good performance status. More private pts received first-line chemotherapy (89% vs 80%, p=0.002), but there were no significant difference in the use of bevacizumab (50% versus 43%, p=0.10). Similar proportions received combination therapy (72% private vs 68% public) but the use of single agent oral capecitabine was higher for private patients (9% vs 4%, p=0.03). More public pts were enrolled in a first-line clinical trial (17.3% vs 1.2%, p .0001). Preliminary analysis suggests improved overall survival for private pts (26 months versus 17 months, p .001). Conclusions: While public and private pts in this cohort were similar in age and performance status, significantly more private pts were given chemotherapy, but similar proportions were given bevacizumab and far less were enrolled on first-line clinical trials. This may relate to availability of first-line trials during this period. The superior survival outcomes achieved in private practice must be further explored, and might reflect a more intense approach to treatment, yet-to-be identified differences in patient characteristics, or differences in quality of care.

Response assessment in gastrointestinal stromal tumor

Publisher: Wiley

Date: 07-01-2011

DOI: 10.1002/IJC.25729

Abstract: Imatinib is standard first-line treatment for patients with advanced gastrointestinal stromal tumor (GIST). Initial responses are not always accompanied by reductions in tumor size consequently, other parameters should be considered in response assessments. Conventional size-based criteria such as Response Evaluation Criteria in Solid Tumors (RECIST) may underestimate responses to imatinib and have poor predictive value for outcome. Imatinib-responding tumors demonstrate decreased metabolic activity on positron emission tomography within the first weeks of treatment, often showing reduced density and greater homogeneity on computed tomography (CT) scans regardless of initial changes in tumor size. New criteria, based on reductions in tumor size or in tumor density on CT, seem more sensitive and specific for detecting early responses to imatinib, and more predictive of time to tumor progression and disease-specific survival. Compared with conventional size-based criteria, new CT-based criteria may potentially offer improved response assessment and be predictive of outcome in GIST. However, such emerging criteria should be further explored and validated in large, multicenter trials with imatinib and other kinase inhibitors in GIST and in other solid tumors.

Dose optimization of tyrosine kinase inhibitors to improve outcomes in GIST

Publisher: Wiley

Date: 20-02-2012

DOI: 10.1111/J.1743-7563.2011.01491.X

Abstract: Tyrosine kinase inhibitors such as imatinib and sunitinib have greatly improved clinical outcomes for patients with gastrointestinal stromal tumors (GIST). Dose optimization of these agents is critical and involves multiple considerations, including ensuring a durable response, monitoring drug blood levels to confirm adequate dosing, deciding whether to use high-dose imatinib or switch to second-line sunitinib in the event of disease progression and appropriately managing treatment-associated side effects. Imatinib is the standard first-line therapy for unresectable or metastatic GIST and is also an option for the adjuvant treatment of resected disease. Despite the efficacy and safety of imatinib in patients with advanced GIST, some in iduals develop primary or secondary resistance or intolerance to the drug. For patients with advanced disease, imatinib dose escalation to 800 mg/day is warranted in cases of disease progression on imatinib 400 mg/day. In addition, patients with documented KIT exon 9 mutations are likely to derive benefit from initial treatment with high-dose imatinib to improve clinical outcomes. For patients who fail imatinib, sunitinib is an effective treatment option. However, the decision to use either high-dose imatinib or sunitinib should be based on the underlying cause of failure on imatinib, KIT mutational status and on whether the patient is intolerant of or has developed a resistance to imatinib. In this article we review the existing literature supporting the use of imatinib and sunitinib in GIST to provide a current clinical perspective on how best to use these agents in the management of GIST to optimize patient outcomes.

Nivolumab in patients with DNA mismatch repair deficient/microsatellite instability high metastatic colorectal cancer: Update from CheckMate 142

Publisher: American Society of Clinical Oncology (ASCO)

Date: 02-2017

DOI: 10.1200/JCO.2017.35.4_SUPPL.519

Abstract: 519 Background: Approximately 4% of metastatic colorectal cancers (mCRCs) are associated with high microsatellite instability (MSI-H), indicating a deficient DNA mismatch repair (dMMR) system. dMMR/MSI-H CRC exhibits an increased tumor neoantigen load and immune cell infiltration and is hypothesized to be targetable by immune checkpoint inhibitors. CheckMate 142 (NCT02060188) evaluates the efficacy and safety of nivolumab (nivo) in patients (pts) with dMMR/MSI-H mCRC. Methods: Pts with dMMR/MSI-H mCRC who progressed on/were intolerant to ≥1 prior line of therapy received nivo 3 mg/kg (nivo 3) every 2 weeks (Q2W). The primary endpoint was objective response rate (ORR) per investigator (INV). The secondary endpoint was ORR per independent radiology review committee (IRRC) exploratory endpoints included safety, PFS, OS, and efficacy in biomarker-defined populations. Results: Among pts treated with nivo 3 Q2W (N = 74), 84% had received ≥2 prior lines of therapy. ORRs were 31% (INV) and 27% (IRRC) disease control rates were 69% (INV) and 62% (IRRC). The median time to response was ≈2.7 mo (INV/IRRC). PFS rates at 12 mo were 48.4% (INV) and 45.6% (IRRC). The duration of response and OS medians were not yet reached OS rates were 83.4% (6 mo) and 73.8% (12 mo). Responses were observed in pts regardless of tumor programmed death-1 ligand 1 (PD-L1) expression level or BRAF or KRAS mutation status and were observed in pts with or without a history of Lynch syndrome (Table). Grade 3–4 treatment-related adverse events (TRAEs) occurred in 20% of pts. TRAEs leading to discontinuation included acute kidney injury, increased ALT, colitis, and stomatitis (1 each). No treatment-related deaths occurred in this arm. Conclusions: Nivo showed durable responses and disease control in heavily pretreated pts with dMMR/MSI-H mCRC. Treatment was well tolerated, with no new safety signals. Clinical trial information: NCT02060188. [Table: see text]

CRESTONE: A Phase 2 study of seribantumab in adult patients with neuregulin-1 (NRG1) fusion positive locally advanced or metastatic solid tumors

Publisher: American Association for Cancer Research (AACR)

Date: 14-04-2023

DOI: 10.1158/1538-7445.AM2023-CT229

Abstract: Background: NRG1 fusions represent a rare and potentially actionable oncogenic alteration found in ~0.2% of solid tumors. Seribantumab is a fully human anti-HER3 IgG2 monoclonal antibody that blocks aberrant NRG1 fusion protein binding to HER3 thereby preventing ligand-dependent activation and dimerization resulting in complete inhibition of the PI3K/AKT and MAPK downstream signaling pathways. Seribantumab has shown significant anti-tumor activity in PDX models and in patients (pts) with solid tumors harboring NRG1 fusions. Methods: CRESTONE (NCT04383210) is a phase 2 study of seribantumab in adult pts with solid tumors harboring NRG1 fusions who received at least one prior therapy and were naïve to ERBB-targeted therapy (Cohort 1) pts previously treated with ERBB-targeted therapies (exploratory Cohort 2) and pts with tumors harboring additional molecular alterations (exploratory Cohort 3). Here, we present updated efficacy results for pts in Cohort 1 dosed at 3 g IV QW. Safety data are evaluated for pts enrolled in Cohort 1 and exploratory Cohorts 2 and 3. Results: As of Dec 2, 2022, 51 pts were enrolled across all cohorts with 30 pts in Cohort 1 dosed at 3 g IV QW. Median age was 62 years (range 19-84) median prior lines of therapy was 2 (range 1-7) tumor types included non-small cell lung cancer (NSCLC, n=30), pancreatic adenocarcinoma (PDAC, n=6), biliary tract/cholangiocarcinoma (CCA, n=6), breast (n=4), and others (n=5) 15 different NRG1 fusion partners were identified with CD74 (22%) and SLC3A2 (16%) as the most frequently reported. In the overall safety population, 41 pts (80%) reported at least one treatment-related adverse event (TRAE). The most common TRAEs (occurring in ≥20% of pts) were diarrhea (41%), fatigue (29%), rash (24%), and nausea (22%). Four pts (8%) experienced Gr 3/4 TRAEs no Gr 5 TRAEs. The safety profile for Cohort 1 was similar to the overall safety population. Among the 30 pts in Cohort 1, 22 were evaluable for investigator assessed (INV) response per RECIST v1.1 2 pts (9%) had confirmed complete response (CR), 6 pts (27%) had confirmed partial response (PR), and 13 pts (59%) had stable disease (SD) as their best overall response (BOR). The INV objective response rate (ORR, confirmed PR + CR) was 36% and disease control rate (DCR, confirmed PR+CR+SD) was 95%. The overall duration of response ranged from 1.4 to 17.2 months. In pts with NSCLC, the INV-ORR was 39% and DCR was 94%. Conclusions: Seribantumab has an acceptable safety and tolerability profile as a single agent in pts with solid tumors harboring NRG1 fusions. Updated efficacy data indicate seribantumab has robust and durable clinical activity, including CRs, across different tumor types harboring an NRG1 fusion and is a promising treatment option. Citation Format: Tejas Patil, Daniel R. Carrizosa, Mark E. Burkard, Karen L. Reck , Jayesh Desai, Young Kwang Chae, Stephen V. Liu, Kartik Konduri, Shirish M. Gadgeel, Jessica J. Lin, Parneet K. Cheema, David R. Spigel, Alison M. Schram, Valerie M. Jansen, Yasir Y. Elamin. CRESTONE: A Phase 2 study of seribantumab in adult patients with neuregulin-1 (NRG1) fusion positive locally advanced or metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023 Part 2 (Clinical Trials and Late-Breaking Research) 2023 Apr 14-19 Orlando, FL. Philadelphia (PA): AACR Cancer Res 2023 (8_Suppl):Abstract nr CT229.

The Management of Unresectable, Advanced Gastrointestinal Stromal Tumours.

Publisher: Springer Science and Business Media LLC

Date: 03-2022

DOI: 10.1007/S11523-022-00869-Y

Different APC genotypes in proximal and distal sporadic colorectal cancers suggest distinct WNT/β-catenin signalling thresholds for tumourigenesis

Publisher: Springer Science and Business Media LLC

Date: 22-10-2013

DOI: 10.1038/ONC.2012.486

Prospective evaluation of KRAS, NRAS, BRAF, and PI3KCA mutation screening for patient enrolment in AGITG ICECREAM (Irinotecan Cetaximab Evaluation and the Cetuximab Response Evaluation among Patients with G13D Mutation) trial in metastatic colorectal cancer (mCRC)

Publisher: American Society of Clinical Oncology (ASCO)

Date: 20-05-2014

DOI: 10.1200/JCO.2014.32.15_SUPPL.E14536

Characterising the immune microenvironment in liposarcoma, its impact on prognosis and the impact of radiotherapy

Publisher: Wiley

Date: 20-10-2020

DOI: 10.1002/JSO.26261

Circulating tumor DNA as an early marker of therapeutic response in patients with metastatic colorectal cancer

Publisher: Elsevier BV

Date: 08-2015

DOI: 10.1093/ANNONC/MDV177

Prospective real-time analysis of p-cadherin expression to select patients into a phase I oncology trial

Publisher: American Association for Cancer Research (AACR)

Date: 12-2009

DOI: 10.1158/1535-7163.TARG-09-C16

Abstract: Effectively personalizing medicine depends upon selecting patients (pts) amenable to targeted therapies. We report the development of a custom immunohistochemistry (IHC) assay to identify P-cadherin positive expression in the archival biopsy of pts with solid malignancies. Validated reagents including a mAB to P-cadherin were incorporated into a custom IHC kit standardized across three Phase I sites (Seoul National University, Royal Melbourne Hospital, and Fox Chase Cancer Center). Pts with a P-cadherin positive archival biopsy are being enrolled into an ongoing trial. Clinical results will be reported separately. P-cadherin positivity is defined by a scoring index (SI) [product of the Tumor Area Positive for P-cad x Staining Intensity]. Based on the literature, a SI ≥ 4 is associated with poor clinical outcome and was therefore required for pt entry into the trial. The IHC protocol was standardized across sites using positive and negative controls run in a masked fashion at each site and cross-examined and repeated by a central lab that had final decision-making authority (ApoCell, Inc., Houston, TX). Each site ran independent IHC assays and analyses by board-certified pathologists, and provided stained and unstained archival biopsy slides for independent, masked analysis by ApoCell. The turn-around time for central IHC analysis was ≤ 48 h. Forty-four of 67 pts (65.7%) were found to be P-cadherin positive and eligible for entry into the trial. The distribution of enrolled patients by site is as follows: Australia (SI ≥ 4, n = 20), Korea (SI ≥ 4, n = 15), and USA (SI ≥ 4, n = 9). Median and mean SI values for the P-cadherin SI were 6 and 5.3 ± 2.9 (SD), respectively, with a range of 0 – 9. Clinical sites produced a SI equal to ApoCell in 56 of 67 pts (85.6% concordance rate). Among solid malignancies tested, a majority of gastric, colon and rectal cancers have demonstrated P-cadherin SI values ≥ 4. Successful execution of this IHC study demonstrates the feasibility of prospectively selecting pts based on IHC expression of P-cadherin using a custom standardized scoring index analysis across multiple clinical sites. Citation Information: Mol Cancer Ther 2009 (12 Suppl):C16.

Comparing survival outcomes for advanced cancer patients who access comprehensive genomic sequencing using a registry-based synthetic control arm

Publisher: American Society of Clinical Oncology (ASCO)

Date: 20-05-2021

DOI: 10.1200/JCO.2021.39.15_SUPPL.E18851

Abstract: e18851 Background: Studies evaluating the clinical benefit from Comprehensive Genomic Sequencing (CGS) in cancer patients (pts) have been limited by heterogeneous populations in cancer types and treatment history, outcomes analysis focused on pts who received treatment, and single arm designs. This study evaluated the clinical utility of CGS in a unique real-world advanced cancer patient cohort by comparing a series of pts who received CGS to inform investigational treatment compared to those who did not. Methods: Two cohorts of advanced and refractory pts with erse cancer types seen for early phase trial consideration were identified from the Peter MacCallum Cancer Centre (PMCC) phase 1 trials clinic. The CGS group (N = 142) accessed an in-house assay on FFPE tissue and matched blood (PMCC Comprehensive Cancer Panel - 391 genes) through a research study between 2017-2018. A second cohort was defined as clinic pts in the following 12 months when profiling was unavailable (NoCGS, N = 133). Difference in overall survival (OS) from initial appointment between the two cohorts was analysed through Kaplan-Meier curves and Cox proportional hazard models. Potential confounding was analysed and adjusted for using stabilised weights based on propensity scores. Results: Within the CGS group, 25 (17.6%) pts received targeted treatment informed by CGS results via trials recruiting at that time (n = 16) or off label drug access (n = 9). This subgroup had improved survival compared with CGS pts in whom results did not alter treatment plan (unadjusted HR = 0.48, (0.27-0.88), p = 0.02). Comparing the CGS and NoCGS cohorts, there were proportional differences in clinical factors including ECOG, cancer types and previous lines of therapy, with standardised differences ranging from 0.23-0.63. Rates of trial participation were similar (CGS: n = 31 [22%], NoCGS: n = 34 [26%]) and CGS had improved unadjusted median OS of 14.5 mos (12.3-19.0) compared to 9.9 (8.6-13.4) for NoCGS (unadjusted HR = 0.71, (0.53-0.96), p = 0.03). In the adjusted analysis, weights ranged from 0.54-2.89 ensuring no in idual pts had excessive influence on analysis and resulted in well-balanced populations (range of standardised differences: 0.0-0.09). Adjusted median OS for CGS was 13.5 mos (9.9-17.8) compared to 11.0 (9.2-17.4) for NoCGS (adjusted HR = 0.88, 0.63-1.23, p = 0.50). Conclusions: We utilised real world data in a novel approach to comparative analysis of the clinical benefit of CGS in a heterogenous cancer cohort. Although the subset of CGS pts who went on to receive targeted treatments had improved outcomes, this was insufficient to drive an overall survival gain when considering the overall CGS vs NoCGS cohort. Therefore, translation into clinics requires strategies to ensure a greater proportion of tested pts obtain benefit to deliver on the value proposition of CGS in an advanced cancer population.

Data from Genotype-Tailored ERK/MAPK Pathway and HDAC Inhibition Rewires the Apoptotic Rheostat to Trigger Colorectal Cancer Cell Death

Publisher: American Association for Cancer Research (AACR)

Date: 03-04-2023

DOI: 10.1158/1535-7163.C.6543591

Abstract: Abstract The EGFR/RAS/MEK/ERK signaling pathway (ERK/MAPK) is hyperactivated in most colorectal cancers. A current limitation of inhibitors of this pathway is that they primarily induce cytostatic effects in colorectal cancer cells. Nevertheless, these drugs do induce expression of proapoptotic factors, suggesting they may prime colorectal cancer cells to undergo apoptosis. As histone deacetylase inhibitors (HDACis) induce expression of multiple proapoptotic proteins, we examined whether they could synergize with ERK/MAPK inhibitors to trigger colorectal cancer cell apoptosis. Combined MEK/ERK and HDAC inhibition synergistically induced apoptosis in colorectal cancer cell lines and patient-derived tumor organoids i in vitro /i , and attenuated i Apc /i -initiated adenoma formation i in vivo /i . Mechanistically, combined MAPK/HDAC inhibition enhanced expression of the BH3-only proapoptotic proteins BIM and BMF, and their knockdown significantly attenuated MAPK/HDAC inhibitor–induced apoptosis. Importantly, we demonstrate that the paradigm of combined MAPK/HDAC inhibitor treatment to induce apoptosis can be tailored to specific MAPK genotypes in colorectal cancers, by combining an HDAC inhibitor with either an EGFR, KRAS sup G12C /sup or BRAF sup V600 /sup inhibitor in i KRAS/BRAF sup WT /sup /i i KRAS sup G12C /sup /i , i BRAF sup V600E /sup /i colorectal cancer cell lines, respectively. These findings identify a series of ERK/MAPK genotype-tailored treatment strategies that can readily undergo clinical testing for the treatment of colorectal cancer. /

A Phase Ib Dose-Escalation and Expansion Study of the BCL2 Inhibitor Venetoclax Combined with Tamoxifen in ER and BCL2–Positive Metastatic Breast Cancer

Publisher: American Association for Cancer Research (AACR)

Date: 03-2019

DOI: 10.1158/2159-8290.CD-18-1151

Abstract: In the first clinical study to evaluate venetoclax in a solid tumor, we demonstrate that combining venetoclax with endocrine therapy has a tolerable safety profile and elicits notable activity in ER and BCL2-positive metastatic breast cancer. These findings support further investigation of combination therapy for patients with BCL2-positive tumors. See related commentary by Drago et al., p. 323. This article is highlighted in the In This Issue feature, p. 305

Systematic Screening Identifies Dual PI3K and mTOR Inhibition as a Conserved Therapeutic Vulnerability in Osteosarcoma

Publisher: American Association for Cancer Research (AACR)

Date: 14-07-2015

DOI: 10.1158/1078-0432.CCR-14-3026

Abstract: Purpose: Osteosarcoma is the most common cancer of bone occurring mostly in teenagers. Despite rapid advances in our knowledge of the genetics and cell biology of osteosarcoma, significant improvements in patient survival have not been observed. The identification of effective therapeutics has been largely empirically based. The identification of new therapies and therapeutic targets are urgently needed to enable improved outcomes for osteosarcoma patients. Experimental Design: We have used genetically engineered murine models of human osteosarcoma in a systematic, genome-wide screen to identify new candidate therapeutic targets. We performed a genome-wide siRNA screen, with or without doxorubicin. In parallel, a screen of therapeutically relevant small molecules was conducted on primary murine– and primary human osteosarcoma–derived cell cultures. All results were validated across independent cell cultures and across human and mouse osteosarcoma. Results: The results from the genetic and chemical screens significantly overlapped, with a profound enrichment of pathways regulated by PI3K and mTOR pathways. Drugs that concurrently target both PI3K and mTOR were effective at inducing apoptosis in primary osteosarcoma cell cultures in vitro in both human and mouse osteosarcoma, whereas specific PI3K or mTOR inhibitors were not effective. The results were confirmed with siRNA and small molecule approaches. Rationale combinations of specific PI3K and mTOR inhibitors could recapitulate the effect on osteosarcoma cell cultures. Conclusions: The approaches described here have identified dual inhibition of the PI3K–mTOR pathway as a sensitive, druggable target in osteosarcoma, and provide rationale for translational studies with these agents. Clin Cancer Res 21(14) 3216–29. ©2015 AACR.

Adverse Events Associated with Encorafenib Plus Cetuximab in Patients with BRAFV600E-mutant Metastatic Colorectal Cancer: An in-depth Analysis of the BEACON CRC Study

Publisher: Elsevier BV

Date: 03-2023

DOI: 10.1016/J.CLCC.2022.12.003

Genotype-Tailored ERK/MAPK Pathway and HDAC Inhibition Rewires the Apoptotic Rheostat to Trigger Colorectal Cancer Cell Death

Publisher: American Association for Cancer Research (AACR)

Date: 07-11-2023

DOI: 10.1158/1535-7163.MCT-22-0101

Abstract: The EGFR/RAS/MEK/ERK signaling pathway (ERK/MAPK) is hyperactivated in most colorectal cancers. A current limitation of inhibitors of this pathway is that they primarily induce cytostatic effects in colorectal cancer cells. Nevertheless, these drugs do induce expression of proapoptotic factors, suggesting they may prime colorectal cancer cells to undergo apoptosis. As histone deacetylase inhibitors (HDACis) induce expression of multiple proapoptotic proteins, we examined whether they could synergize with ERK/MAPK inhibitors to trigger colorectal cancer cell apoptosis. Combined MEK/ERK and HDAC inhibition synergistically induced apoptosis in colorectal cancer cell lines and patient-derived tumor organoids in vitro, and attenuated Apc-initiated adenoma formation in vivo. Mechanistically, combined MAPK/HDAC inhibition enhanced expression of the BH3-only proapoptotic proteins BIM and BMF, and their knockdown significantly attenuated MAPK/HDAC inhibitor–induced apoptosis. Importantly, we demonstrate that the paradigm of combined MAPK/HDAC inhibitor treatment to induce apoptosis can be tailored to specific MAPK genotypes in colorectal cancers, by combining an HDAC inhibitor with either an EGFR, KRASG12C or BRAFV600 inhibitor in KRAS/BRAFWT KRASG12C, BRAFV600E colorectal cancer cell lines, respectively. These findings identify a series of ERK/MAPK genotype-tailored treatment strategies that can readily undergo clinical testing for the treatment of colorectal cancer.

Re: Residual Treatment Disparities After Oncology Referral for Rectal Cancer

Publisher: Oxford University Press (OUP)

Date: 03-12-2008

DOI: 10.1093/JNCI/DJN395

Updated results of the BEACON CRC safety lead-in: Encorafenib (ENCO) plus binimetinib (BIM) plus cetuximab (CETUX) for BRAFV600E-mutant metastatic colorectal cancer (mCRC)

Publisher: American Society of Clinical Oncology (ASCO)

Date: 02-2019

DOI: 10.1200/JCO.2019.37.4_SUPPL.688

Abstract: 688 Background: BRAF V600E mutation occurs in 10%-–15% of patients (pts) with mCRC and confers a poor prognosis. After first-line therapy, standard second-line therapies provide limited benefit, with objective response rates (ORRs) 10%, and overall survival (OS) of 4–6 months (mo). BEACON CRC (NCT02928224) is a 3-arm phase 3 trial of triplet therapy with the BRAF inhibitor ENCO + MEK inhibitor BINI + anti–EGFR antibody CETUX vs ENCO + CETUX vs a control arm (irinotecan/FOLFIRI + CETUX) in pts with BRAF V600E mCRC in the second or third-line setting. A safety lead-in (SLI) of the triplet therapy was conducted in 30 pts prior to initiation of the randomized part of the trial. Previously reported confirmed ORR in 29 pts with BRAF V600E mCRC was 48% and median progression-free survival (PFS) was 8.0 mo (Van Cutsem E, et al. Ann Oncol. 2018 :O-027). Here we present updated safety and efficacy results including mature OS. Methods: All pts in the SLI received ENCO 300 mg once daily + BINI 45 mg twice daily + CETUX standard weekly dose. Assessments included efficacy (ORR, duration of response, time to response, PFS, and OS), safety, and tolerability. Results: Among 30 pts treated, 1 had a BRAF non-V600E mutation and is not included in the efficacy analyses. At data cutoff, the median follow-up time for survival was 18.2 mo and median exposure was 7.8 mo (range 0.5–21.4 mo). The confirmed ORR and median PFS remain unchanged from the previous report (ORR, 48% [95%CI, 29.4–67.5] PFS, 8.0 mo [95% CI, 5.6–9.3 mo]). Mature median OS is 15.3 mo (95% CI, 9.6 mo–not reached). The triplet continues to be well-tolerated with no unexpected toxicities. The most common grade 3/4 toxicities were fatigue (13%), anemia, increases in creatine phosphokinase and/or aspartate aminotransferase, and urinary tract infections (each 10%). The rate of grade 3/4 skin toxicities continues to be lower than generally observed with CETUX in mCRC. Conclusions: With longer follow-up, triplet therapy with ENCO + BINI + CETUX continues to be well tolerated. Median PFS and now mature median OS are substantially improved over historical data for current standard-of-care options. Clinical trial information: NCT02928224.

Patient Comorbidities and Behaviour Once Diagnosed Are Major Contributors to Disparities in Cancer Health Outcomes

Publisher: American Society of Clinical Oncology (ASCO)

Date: 20-01-2010

DOI: 10.1200/JCO.2009.25.2007

Encorafenib, Binimetinib, and Cetuximab in BRAF V600E–Mutated Colorectal Cancer

Publisher: Massachusetts Medical Society

Date: 24-10-2019

DOI: 10.1056/NEJMOA1908075

Girdin (GIV) Expression as a Prognostic Marker of Recurrence in Mismatch Repair–Proficient Stage II Colon Cancer

Publisher: American Association for Cancer Research (AACR)

Date: 14-07-2016

DOI: 10.1158/1078-0432.CCR-15-2290

Abstract: Purpose: Prognostic markers that identify patients with stage II colon cancers who are at the risk of recurrence are essential to personalize therapy. We evaluated the potential of GIV/Girdin as a predictor of recurrence risk in such patients. Experimental Design: Expression of full-length GIV was evaluated by IHC using a newly developed mAb together with a mismatch repair (MMR)-specific antibody panel in three stage II colon cancer patient cohorts, that is, a training (n = 192), test (n = 317), and validation (n = 181) cohort, with clinical follow-up data. Recurrence risk stratification models were established in the training cohort of T3, proficient MMR (pMMR) patients without chemotherapy and subsequently validated. Results: For T3 pMMR tumors, GIV expression and the presence of lymphovascular invasion (LVI) were the only factors predicting recurrence in both training (GIV: HR, 2.78, P = 0.013 LVI: HR, 2.54, P = 0.025) and combined test and validation (pooled) cohorts (GIV: HR, 1.85, P = 0.019 LVI: HR, 2.52, P = 0.0004). A risk model based on GIV expression and LVI status classified patients into high- or low-risk groups 3-year recurrence-free survival was significantly lower in the high-risk versus low-risk group across all cohorts [Training: 52.3% vs. 84.8% HR, 3.74, 95% confidence interval (CI), 1.50–9.32 Test: 85.9% vs. 97.9%, HR, 7.83, 95% CI, 1.03–59.54 validation: 59.4% vs. 84.4%, HR, 3.71, 95% CI, 1.24–11.12]. Conclusions: GIV expression status predicts recurrence risk in patients with T3 pMMR stage II colon cancer. A risk model combining GIV expression and LVI status information further enhances prediction of recurrence. Further validation studies are warranted before GIV status can be routinely included in patient management algorithms. Clin Cancer Res 22(14) 3488–98. ©2016 AACR.

Safety and pharmacokinetics of motesanib in combination with gemcitabine and erlotinib for the treatment of solid tumors: a phase 1b study.

Publisher: Springer Science and Business Media LLC

Date: 26-07-2011

DOI: 10.1186/1471-2407-11-313

Clinical, Pharmacodynamic, and Pharmacokinetic Evaluation of BNC105P: A Phase I Trial of a Novel Vascular Disrupting Agent and Inhibitor of Cancer Cell Proliferation

Publisher: American Association for Cancer Research (AACR)

Date: 31-07-2011

DOI: 10.1158/1078-0432.CCR-11-0937

Abstract: Purpose: To determine the recommended phase II dose and evaluate the safety and toxicity profile and pharmacokinetic (PK) and pharmacodynamic (PD) effects of BNC105P, an inhibitor of tubulin polymerization that has vascular disrupting and antiproliferative effects. Experimental Design: BNC105P was administered as a 10-minute infusion on days 1 and 8 of a 21-day cycle in a first-in-human phase I study. A dynamic accelerated dose titration method was used for dose escalation. Plasma concentrations of BNC105P (phosphate prodrug) and BNC105 (active agent) were determined. PD assessments were carried out using dynamic contrast enhanced (DCE)-MRI and analysis of a blood-borne biomarker. Results: Twenty-one subjects with advanced solid tumors were enrolled on 6 dose levels (range: 2.1–18.9 mg/m2). The recommended dose level was 16 mg/m2 and was well tolerated. BNC105P (prodrug) rapidly converted to BNC105 with a half-life of 0.13 hours. Plasma concentrations of BNC105 generally increased in proportion to dose with a half-life of 0.57 hours. Pharmacodymanically active plasma levels were obtained with a dose dependant reduction in the levels of polymerized tubulin (on-target action) being observed in PBMCs. DCE-MRI also indicated blood flow changes in the tumor lesions of a number of subjects. Conclusions: BNC105P has a favorable toxicity profile at the recommended dose of 16 mg/m2 and is associated with PD changes consistent with its known mechanism of action. Phase II studies in renal cancer and mesothelioma have commenced. Clin Cancer Res 17(15) 5152–60. ©2011 AACR.

Response to “Disparities in the Use of Chemotherapy and Monoclonal Antibody Therapy for Elderly Advanced Colorectal Cancer Patients in the Community Oncology Setting”

Publisher: Oxford University Press (OUP)

Date: 2009

DOI: 10.1634/THEONCOLOGIST.2008-0222

Intra-patient dose escalation in Ewing's sarcoma treated with vincristine, doxorubicin, cyclophosphamide alternating with ifosfamide and etoposide: a retrospective review

Publisher: Springer Science and Business Media LLC

Date: 12-2013

DOI: 10.1186/2045-3329-3-15

Prescribing patterns for bevacizumab in first-line metastatic colorectal cancer: Exploring the introduction of a new drug into routine clinical practice

Publisher: American Society of Clinical Oncology (ASCO)

Date: 02-2012

DOI: 10.1200/JCO.2012.30.4_SUPPL.665

Abstract: 665 Background: Clinical trials support the addition of bevacizumab (Bev) to first line chemotherapy for metastatic colorectal cancer (mCRC). However, given that there are alternate biological agents that can be used with chemotherapy and rare but potentially serious toxicities with Bev, there has been variable use of the drug in routine care. The purpose of this study was to prospectively explore 1 st line use of Bev in routine clinical care. Methods: A multi-site data collection was initiated in July 2009 when Bev became publicly available in Australia. A particular focus was capturing information regarding clinician decision-making that is not routinely recorded or is often poorly documented. Comprehensive comorbidity data was collected, along with specific factors, both patient (pt) and disease-related, that may impact on treatment decisions. Major adverse events that may be related to Bev were also recorded. Results: For the 2-year period from July 2009-June 2011, a database search identified 278 pts diagnosed with mCRC at five participating hospitals. 240 pts (86%) had received 1 st line chemotherapy. 102 (43%) also received Bev, the majority in combination with oxaliplatin based chemotherapy (n = 81, 79%). Bev use increased significantly from 40.4% (34/84) of all pts receiving chemotherapy in July-December 2009, to 65.8% (25/38) in January-June 2011 (p=0.0114). Overall the most frequent reasons for clinicians advising against the use of Bev were a bleeding or asymptomatic primary in situ (n=28, 23%), known hypertension (n=14, 11%), clinical trial participation (n=14, 11%), poor performance status (n=9, 7%), and perceived risk of arterial ischemic event (n=8, 6.5%). There have been four episodes of gastro-intestinal perforation, 3 in pts receiving Bev (2.9% of Bev treated patients). Conclusions: Bev use in first line mCRC has significantly increased over time, presumably as further positive safety data emerges regarding safety in older and frailer pts, and clinician prescribing experience increases. The major grounds for not using Bev in the 1 st line mCRC setting were specific clinical contexts where the risk of adverse events may be increased.

SMAD2, SMAD3 and SMAD4 mutations in colorectal cancer

Publisher: American Association for Cancer Research (AACR)

Date: 15-01-2013

DOI: 10.1158/0008-5472.CAN-12-2706

Abstract: Activation of the canonical TGF-β signaling pathway provides growth inhibitory signals in the normal intestinal epithelium. Colorectal cancers (CRCs) frequently harbor somatic mutations in the pathway members TGFBR2 and SMAD4, but to what extent mutations in SMAD2 or SMAD3 contribute to tumorigenesis is unclear. A cohort of 744 primary CRCs and 36 CRC cell lines were sequenced for SMAD4, SMAD2, and SMAD3 and analyzed for allelic loss by single-nucleotide polymorphism (SNP) microarray analysis. Mutation spectra were compared between the genes, the pathogenicity of mutations was assessed, and relationships with clinicopathologic features were examined. The prevalence of SMAD4, SMAD2, and SMAD3 mutations in sporadic CRCs was 8.6% (64 of 744), 3.4% (25 of 744), and 4.3% (32 of 744), respectively. A significant overrepresentation of two genetic hits was detected for SMAD4 and SMAD3, consistent with these genes acting as tumor suppressors. SMAD4 mutations were associated with mucinous histology. The mutation spectra of SMAD2 and SMAD3 were highly similar to that of SMAD4, both in mutation type and location within the encoded proteins. In silico analyses suggested the majority of the mutations were pathogenic, with most missense changes predicted to reduce protein stability or hinder SMAD complex formation. The latter altered interface residues or disrupted the phosphorylation-regulated Ser-Ser-X-Ser motifs within SMAD2 and SMAD3. Functional analyses of selected mutations showed reductions in SMAD3 transcriptional activity and SMAD2–SMAD4 complex formation. Joint biallelic hits in SMAD2 and SMAD3 were overrepresented and mutually exclusive to SMAD4 mutation, underlining the critical roles of these three proteins within the TGF-β signaling pathway. Cancer Res 73(2) 725–35. ©2012 AACR.

Targeting BRAF mutant metastatic colorectal cancer: clinical implications and emerging therapeutic strategies

Publisher: Springer Science and Business Media LLC

Date: 15-08-2014

DOI: 10.1007/S11523-014-0330-0

Abstract: Increasing knowledge of the underlying signaling pathways and molecular defects involved in colorectal cancer growth or progression enabled the discovery of several prognostic and predictive biomarkers, leading to the development of novel molecularly targeted therapies. The mitogen-activated protein kinase (MAPK) signaling pathway plays a critical role in colorectal cancer progression. Mutations in BRAF, a principal effector of Ras in this signaling cascade, are found in 10 % of colorectal cancer and play a clear pathogenic role, particularly in patients with metastatic disease. Intense efforts have therefore focused on targeting BRAF as an oncogenic driver, with mixed early results. This article summarizes the molecular and clinical features of BRAF mutant colorectal cancer, the prognostic and predictive role of BRAFV600E mutation in colorectal cancer, initial clinical trial results in targeting BRAFV600E, and the more recent preclinical insights into potential mechanisms of resistance to BRAF inhibition that have now led to a number of rationale-driven combination therapeutic strategies.

Analysis of cellular phosphatidylinositol (3,4,5)-trisphosphate levels and distribution using confocal fluorescent microscopy.

Publisher: Elsevier BV

Date: 11-2010

DOI: 10.1016/J.AB.2010.06.033

Abstract: We have developed an immunocytochemistry method for the semiquantitative detection of phosphatidylinositol (3,4,5)-trisphosphate (PI(3,4,5)P3) at the cell plasma membrane. This protocol combines the use of a glutathione S-transferase-tagged pleckstrin homology (PH) domain of the general phosphoinositides-1 receptor (GST-GRP1PH) with fluorescence confocal microscopy and image segmentation using cell mask software analysis. This methodology allows the analysis of PI(3,4,5)P3 subcellular distribution in resting and epidermal growth factor (EGF)-stimulated HEK293T cells and in LIM1215 (wild-type phosphoinositide 3-kinase (PI3K)) and LIM2550 (H1047R mutation in PI3K catalytic domain) colonic carcinoma cells. Formation of PI(3,4,5)P3 was observed 5min following EGF stimulation and resulted in an increase of the membrane/cytoplasm fluorescence ratio from 1.03 to 1.53 for HEK293T cells and from 2.2 to 3.3 for LIM1215 cells. Resting LIM2550 cells stained with GST-GRP1PH had an elevated membrane/cytoplasm fluorescence ratio of 9.8, suggesting constitutive PI3K activation. The increase in the membrane/cytoplasm fluorescent ratio was inhibited in a concentration-dependent manner by the PI3K inhibitor LY294002. This cellular confocal imaging assay can be used to directly assess the effects of PI3K mutations in cancer cell lines and to determine the potential specificity and effectiveness of PI3K inhibitors in cancer cells.

Figure S2 from Genotype-Tailored ERK/MAPK Pathway and HDAC Inhibition Rewires the Apoptotic Rheostat to Trigger Colorectal Cancer Cell Death

Publisher: American Association for Cancer Research (AACR)

Date: 03-04-2023

DOI: 10.1158/1535-7163.22523100.V1

Abstract: Supplementary figure 2 shows the effect of trametinib plus panobinostat on colony formation in HCT 116 cells

BRAFV600E Mutations Arising from a Left-Side Primary in Metastatic Colorectal Cancer: Are They a Distinct Subset?

Publisher: Springer Science and Business Media LLC

Date: 18-02-2021

DOI: 10.1007/S11523-021-00793-7

Utilization of systemic therapy options in the routine treatment of metastatic colorectal cancer

Publisher: American Society of Clinical Oncology (ASCO)

Date: 02-2017

DOI: 10.1200/JCO.2017.35.4_SUPPL.738

Abstract: 738 Background: In the treatment of metastatic colorectal cancer (mCRC), exposure to all three active cytotoxic agents 5-fluorouracil/capecitabine (FP), irinotecan (Ir) and oxaliplatin (Ox), and the biologic agents, bevacizumab (Bev) and cetuximab and panitumumab (EGFR-I) improves outcomes. The current uptake of systemic agents for mCRC in a community setting in Australia is poorly described. Methods: The ACCORD database was interrogated to determine demographics, treatments and outcomes for all patients diagnosed with mCRC between 1/01/2011 and 1/01/2015 at 6 Melbourne centres (3 public and 3 private). Results: 865 patients were identified: median age was 68 years. 68% were ECOG 0-1, 60% had de novo metastatic disease. RAS status was known in 59%, of whom 48% were RAS wild-type (WT). At the time of analysis 69% of all patients had received systemic treatment with 51% receiving treatment second line and beyond 65% RAS WT, 57% RASm, 16% RAS-Unk. See Table. Metastasectomy was performed in 29% of patients of whom 38% remain disease-free. With a median follow-up of 31.3 months 46% of patients remain alive. The median overall survival was 25 months for all patients(unresected .6 months, resected: not reached). Conclusions: A high proportion of patients receiving routine clinical care in the community setting do not receive any systemic therapy and few patients receive all available active agents. Despite this, the overall survival of patients with mCRC in this community-based cohort was 25 months and in-line with clinical trial data. [Table: see text]

Supplementary Table 1 from Genotype-Tailored ERK/MAPK Pathway and HDAC Inhibition Rewires the Apoptotic Rheostat to Trigger Colorectal Cancer Cell Death

Publisher: American Association for Cancer Research (AACR)

Date: 03-04-2023

DOI: 10.1158/1535-7163.22523085.V1

Abstract: Supplementary table 1

Survival Impact of Adjuvant Chemotherapy for Resected Locally Advanced Rectal Adenocarcinoma

Publisher: Elsevier BV

Date: 06-2017

DOI: 10.1016/J.CLCC.2016.09.011

Abstract: Recent data has created uncertainty regarding the benefit of adjuvant fluoropyrimidine-containing chemotherapy following preoperative chemoradiotherapy and surgical resection for locally advanced rectal cancer (LARC). In particular, patients with a pathologic complete response (pCR) may derive no benefit from adjuvant chemotherapy. This is a retrospective analysis of patients with LARC, diagnosed between January 1, 2003 and December 31, 2014 at 3 Melbourne health services. Patients were identified from the Australian Comprehensive Cancer Outcomes and Research Database, where a defined data set is prospectively collected on consecutive patients. Patient demographics, pCR rates, postoperative treatment, recurrence, and survival were analyzed. A total of 717 patients with LARC were identified, of whom 555 (77%) had received preoperative long-course chemoradiation followed by surgery. Four hundred fifty-two of 555 patients (81%) subsequently received adjuvant fluoropyrimidine-based chemotherapy. At a median follow-up of 45.9 months, 95 (21%) patients in the adjuvant chemotherapy group and 20 (19%) in the surveillance group had relapsed. Five-year relapse-free survival was 77% in the adjuvant chemotherapy group and 71% in the surveillance group with no significant difference on univariate analysis (hazard ratio [HR], 0.93 95% confidence interval [CI], 0.58-1.51 P = .780). No significant impact on relapse-free survival was seen for either pCR or non-pCR patients. Five-year overall survival (OS) was 85% in the adjuvant chemotherapy group and 74% in the surveillance group with a nonsignificant trend towards OS benefit (HR, 0.62 95% CI, 0.37-1.05 P = .074). A significant OS benefit favoring adjuvant chemotherapy was seen in the non-pCR subset of patients (HR, 0.49 95% CI, 0.28-0.86 P = .014). A high proportion of patients in this routine practice cohort received adjuvant chemotherapy following preoperative treatment and surgery for LARC. Adjuvant chemotherapy administration was associated with a significant improvement in 5-year OS only in the patients with a non-pCR.

Phase Ib/II open-label, randomized evaluation of efficacy and safety of atezolizumab plus isatuximab versus regorafenib in MORPHEUS-colorectal cancer

Publisher: American Society of Clinical Oncology (ASCO)

Date: 20-01-2021

DOI: 10.1200/JCO.2021.39.3_SUPPL.82

Abstract: 82 Background: The MORPHEUS platform consists of multiple, global, open-label, randomized Phase Ib/II trials designed to identify early efficacy signals and safety of treatment (tx) combinations across tumor types. Isatuximab (isa anti-CD38) targets CD38 receptors expressed on immunosuppressive cells in the tumor microenvironment. We hypothesized atezolizumab (atezo anti–PD-L1) + isa would induce an anti-tumor response beyond that of regorafenib (rego), a multi-kinase inhibitor, in patients (pts) with tx-refractory metastatic colorectal cancer (mCRC). Methods: This randomized Phase Ib/II trial (NCT03555149) enrolled pts with microsatellite stable/mismatched repair proficient mCRC who had received ≤ 2 prior tx lines (fluoropyrimidine-, oxaliplatin- or irinotecan-containing chemotherapy plus a biologic agent). Pts received atezo (1200 mg intravenously [IV] every 3 weeks [q3w]) + isa (10 mg/kg IV q3w) or control tx with rego (160 mg orally days 1–21 dose escalation to 160 mg during Cycle 1 allowed per institutional guidelines). The primary endpoint was objective response rate (ORR investigator-assessed RECIST 1.1) secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and safety. Results: Data cutoff date was March 3, 2020. Fifteen pts received atezo + isa and 13 pts received rego. Fourteen atezo + isa pts (93.3%) and 11 control arm pts (84.6%) had received 2 prior lines of tx 9 atezo + isa pts (60.0%) and 9 control pts (69.2%) had liver metastases at enrollment. No responses were seen in either arm 3 pts receiving atezo + isa (20.0%) and 8 control pts (61.5%) had stable disease as their best response. DCR (response and/or stable disease ≥ 12 weeks) was 6.7% with atezo + isa and 15.4% with control. One pt treated with atezo + isa beyond progression had prolonged disease stabilization. Median PFS was 1.4 mo (95% CI: 1.4, 1.8) with atezo + isa and 2.8 mo (95% CI: 1.6, 3.1) in the control arm median OS was 5.1 mo (95% CI: 3.1, 7.8) with atezo + isa and 10.2 mo (95% CI: 4.8, not reached) with control. Tx-related adverse events (AEs, Grade 1-4) occurred in 13 atezo + isa pts (86.7%), and 12 control pts (92.3%). The most common tx-related AEs with atezo + isa were infusion-related reaction (73.3%), nausea (26.7%) and fatigue (20.0%). No Grade 5 AEs occurred in the atezo + isa arm, 1 (7.7%) was reported in the control arm (sepsis, considered unrelated to study tx). No atezo + isa pts and 1 control-arm pt (7.7%) withdrew from treatment due to a tx-related AE. Biomarker analyses did not identify any significant trends related to efficacy. Conclusions: In this trial, superior efficacy of atezo + isa vs rego was not shown. However, the atezo + isa combination was well tolerated, with a manageable safety profile. Clinical trial information: NCT03555149.

A phase Ib/II translational study of sunitinib with neoadjuvant radiotherapy in soft-tissue sarcoma

Publisher: Springer Science and Business Media LLC

Date: 16-10-2014

DOI: 10.1038/BJC.2014.537

Abstract CT002: A Phase IB study of RAF dimer inhibitor BGB-283 in patients with B-RAF or K-RAS/N-RAS mutated solid tumors

Publisher: American Association for Cancer Research (AACR)

Date: 07-2017

DOI: 10.1158/1538-7445.AM2017-CT002

Abstract: Background: BGB-283 is a novel inhibitor of the RAF dimer with potent and reversible inhibitory activities against RAF family kinases including wild type A-RAF, B-RAF, C-RAF and B-RAF V600E, as well as EGFR. BGB-283 demonstrated acceptable safety and early clinical activity in its Phase 1A study. In this Phase IB dose expansion study, we further evaluated safety and tolerability of BGB-283 and investigated efficacy in pre-selected patients (pts) with B-RAF or K-RAS/N-RAS-mutated solid tumors. Methods: This Phase 1B study was a multicenter, open-label, multiple-arm, dose expansion study. Pts were treated at the RP2D of BGB-283 at 30 mg/day. There were 10 different expansion arms for: B-RAF V600-mutated melanoma (not previously treated with a B-RAF or MEK inhibitor, and B-RAF and/or MEK inhibitor-resistant pts), colorectal cancer (CRC), non-small cell lung cancer (NSCLC), papillary thyroid cancer (PTC) and other solid tumors with B-RAF mutations K-RAS/N-RAS-mutated endometrial cancer, NSCLC, CRC, and other solid tumors with K-RAS/N-RAS or NF-1 mutations. The primary end point was the response rate based on RECIST Version 1.1. Adverse events (AEs) are reported per CTCAE V4.03. Results: As of 19th Sep 2016, 96 pts were enrolled: median age was 63 years (range: 20 to 82 years) with all pts having baseline ECOG PS of 0 or 1. Forty-seven (49.0%) subjects had received ≥3 prior lines of treatment, 22 (22.9%) had received 2 prior lines of treatment, and 18 (18.8%) had received 1 prior line of treatment. BGB-283 was generally well-tolerated. Drug-related AEs were mostly Grade 1/2 in severity the most common were fatigue in 37 (38.5%) subjects, nausea in 16 (16.7%), decreased appetite in 21 (21.9%), and diarrhea in 17 (17.7%). A total of 34 (35.4%) subjects experienced study drug-related Grade 3/4 AEs, notably drug-related thrombocytopenia (6.3%), palmar-plantar erythrodysesthesia syndrome (1.0%) and hypertension (8.3%). In the cohorts with previously-untreated B-RAF V600-mutated melanoma (n=7), PTC with B-RAF mutation (n=3) and NSCLC with K-RAS mutation (n=6), the response rates were 42.9% (95% confidence interval [CI], 9.9, 81.6), 33.3% (95% CI, 0.8, 90.6) and 16.7% (95% [0.4, 64.1]), respectively. Confirmed PR was seen in the single case of ovarian cancer with B-RAF mutation enrolled and also in one of 4 melanoma subjects with a confirmed B-RAF V600 mutation, who had not responded to B-RAF and/or MEK inhibitor(s). One unconfirmed PR was found in two NSCLC subjects with a B-RAF mutation. Conclusions: BGB-283 was generally well-tolerated during the Phase 1B stage of the study. Antitumor activity was not only observed in subjects with B-RAF V600-mutated solid tumors including melanoma, PTC, and ovarian cancer, but also in subjects with K-RAS-mutated NSCLC. When added to the efficacy data in the Phase IA portion of this study, with objective responses noted in these tumor subtypes as well as in K-RAS-mutated endometrial carcinoma, BGB-283 demonstrated a desirable risk-benefit profile for further efficacy and safety investigation. Citation Format: Jayesh Desai, Hui Gan, Catherine Barrow, Michael B. Jameson, Ben Solomon, Victoria Atkinson, Andrew Haydon, Michael Millward, Stephen Begbie, Michael Brown, Benjamin Markman, William Patterson, Andrew Hill, Lisa Horvath, Adnan Nagrial, Gary Richardson, Christopher Jackson, Michael Friedlander, David Gibbs, Phillip Parente, Jason Yang, Lai Wang, Yunxin Chen, Lusong Luo. A Phase IB study of RAF dimer inhibitor BGB-283 in patients with B-RAF or K-RAS/N-RAS mutated solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017 2017 Apr 1-5 Washington, DC. Philadelphia (PA): AACR Cancer Res 2017 (13 Suppl):Abstract nr CT002. doi:10.1158/1538-7445.AM2017-CT002

Treatment of patients with primary retroperitoneal sarcoma: predictors of outcome from an Australian specialist sarcoma centre

Publisher: Wiley

Date: 04-10-2018

DOI: 10.1111/ANS.14842

Abstract: Several unanswered questions surround the management of retroperitoneal sarcoma (RPS). Guidelines recommend treatment by a multidisciplinary team at a specialized referral centre. The objective of this study was to describe the management of RPS at an Australian specialist sarcoma centre, comparing outcomes to international standards and analysing for predictors of local failure. A retrospective review of a prospectively maintained database was performed on patients with RPS treated between 2008 and 2016. A 5-year outcome analyses focussed on patients undergoing curative-intent surgery for primary, non-metastatic RPS. Eighty-eight patients underwent surgery for primary RPS. Five-year overall survival was 66%, 5-year freedom from local recurrence was 65% and 5-year freedom from distant metastasis was 71%. Overall survival was associated with tumour grade (hazard ratio (HR) 6.1, P < 0.001) and histologic organ invasion (HR 5.7, P < 0.001). Variables associated with improved freedom from local recurrence were macroscopically complete resection (HR 0.14, P < 0.001) and neoadjuvant radiotherapy (HR 0.33, P = 0.014). Treatment at a specialist sarcoma centre was associated with a higher rate of preoperative biopsy and neoadjuvant radiotherapy (both with P < 0.001). There was a trend towards improved local control for patients undergoing surgery at a specialist centre (P = 0.055). This is the largest Australian series of RPS and outcomes are comparable to major international sarcoma centres. Patients treated at a specialist centre had higher rates of preoperative diagnosis and tailored therapy which was associated with improved outcomes. Patients with suspected RPS should be referred to a specialist centre for optimal preoperative evaluation and multidisciplinary management.

Prognostic impact of clinicopathologic features in metastatic rectal versus colon cancer

Publisher: American Society of Clinical Oncology (ASCO)

Date: 20-05-2014

DOI: 10.1200/JCO.2014.32.15_SUPPL.E14518

Optimising the management of soft tissue tumours

Publisher: Elsevier BV

Date: 06-2011

DOI: 10.1097/PAT.0B013E3283464427

Mechanistic Insights of an Immunological Adverse Event Induced by an Anti-KIT Antibody Drug Conjugate and Mitigation Strategies

Publisher: American Association for Cancer Research (AACR)

Date: 15-07-2018

DOI: 10.1158/1078-0432.CCR-17-3786

Abstract: Purpose: Hypersensitivity reactions (HSRs) were observed in three patients dosed in a phase I clinical trial treated with LOP628, a KIT targeted antibody drug conjugate. Mast cell degranulation was implicated as the root cause for the HSR. Underlying mechanism of this reported HSR was investigated with an aim to identifying potential mitigation strategies. Experimental Design: Biomarkers for mast cell degranulation were evaluated in patient s les and in human peripheral blood cell-derived mast cell (PBC-MC) cultures treated with LOP628. Mitigation strategies interrogated include pretreatment of mast cells with small molecule inhibitors that target KIT or signaling pathways downstream of FcϵR1, FcγR, and treatment with Fc silencing antibody formats. Results: Transient elevation of serum tryptase was observed in patients 1-hour posttreatment of LOP628. In agreement with the clinical observation, LOP628 and its parental antibody LMJ729 induced degranulation of human PBC-MCs. Unexpectedly, KIT small molecule inhibitors did not abrogate mast cell degranulation. By contrast, small molecule inhibitors that targeted pathways downstream of Fc receptors blunted degranulation. Furthermore, interference of the KIT antibody to engage Fc receptors by pre-incubation with IgG or using engineered Fc silencing mutations reduced or prevented degranulation. Characterization of Fcγ receptors revealed human PBC-MCs expressed both FcγRII and low levels of FcγRI. Interestingly, increasing the level of FcγRI upon addition of IFNγ, significantly enhanced LOP628-mediated mast cell degranulation. Conclusions: Our data suggest LOP628-mediated mast cell degranulation is the likely cause of HSR observed in the clinic due to co-engagement of the FcγR and KIT, resulting in mast cell activation. Clin Cancer Res 24(14) 3465–74. ©2018 AACR.

Figure S4 from Genotype-Tailored ERK/MAPK Pathway and HDAC Inhibition Rewires the Apoptotic Rheostat to Trigger Colorectal Cancer Cell Death

Publisher: American Association for Cancer Research (AACR)

Date: 04-2023

DOI: 10.1158/1535-7163.22523091.V1

Abstract: Supplementary figure 4 shows phosphorylated ERK staining in an adenoma from a ACDX2 mouse

Binimetinib, Encorafenib, and Cetuximab Triplet Therapy for Patients With BRAF V600E–Mutant Metastatic Colorectal Cancer: Safety Lead-In Results From the Phase III BEACON Colorectal Cancer Stud

Publisher: American Society of Clinical Oncology (ASCO)

Date: 10-06-2019

DOI: 10.1200/JCO.18.02459

Abstract: To determine the safety and preliminary efficacy of selective combination targeted therapy for BRAF V600E–mutant metastatic colorectal cancer (mCRC) in the safety lead-in phase of the open-label, randomized, three-arm, phase III BEACON Colorectal Cancer trial ( ClinicalTrials.gov identifier: NCT02928224 European Union Clinical Trials Register identifier: EudraCT2015-005805-35). Before initiation of the randomized portion of the BEACON Colorectal Cancer trial, 30 patients with BRAF V600E–mutant mCRC who had experienced treatment failure with one or two prior regimens were to be recruited to a safety lead-in of encorafenib 300 mg daily, binimetinib 45 mg twice daily, plus standard weekly cetuximab. The primary end point was safety, including the incidence of dose-limiting toxicities. Efficacy end points included overall response rate, progression-free survival, and overall survival. Among the 30 treated patients, dose-limiting toxicities occurred in five patients and included serous retinopathy (n = 2), reversible decreased left ventricular ejection fraction (n = 1), and cetuximab-related infusion reactions (n = 2). The most common grade 3 or 4 adverse events were fatigue (13%), anemia (10%), increased creatine phosphokinase (10%), increased AST (10%), and urinary tract infections (10%). In 29 patients with BRAF V600E–mutant tumors (one patient had a non– BRAF V600E–mutant tumor and was not included in the efficacy analysis), the confirmed overall response rate was 48% (95% CI, 29.4% to 67.5%), median progression-free survival was 8.0 months (95% CI, 5.6 to 9.3 months), and median overall survival was 15.3 months (95% CI, 9.6 months to not reached), with median duration of follow-up of 18.2 months (range, 16.6 to 19.8 months). In the safety lead-in, the safety and tolerability of the encorafenib, binimetinib, and cetuximab regimen is manageable and acceptable for initiation of the randomized portion of the study. The observed efficacy is promising compared with available therapies and, if confirmed in the randomized portion of the trial, could establish this regimen as a new standard of care for previously treated BRAF V600E–mutant mCRC.

First-in-human study of oleclumab, a potent, selective anti-CD73 monoclonal antibody, alone or in combination with durvalumab in patients with advanced solid tumors

Publisher: Springer Science and Business Media LLC

Date: 05-04-2023

DOI: 10.1007/S00262-023-03430-6

Abstract: CD73 upregulation in tumors leads to local immunosuppression. This phase I, first-in-human study evaluated oleclumab (MEDI9447), an anti-CD73 human IgG1λ monoclonal antibody, alone or with durvalumab in patients with advanced colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), or epidermal growth factor receptor-mutant non-small-cell lung cancer (NSCLC). Patients received oleclumab 5–40 mg/kg (dose-escalation) or 40 mg/kg (dose-expansion) intravenously every 2 weeks (Q2W), alone (escalation only) or with durvalumab 10 mg/kg intravenously Q2W. 192 patients were enrolled, 66 during escalation and 126 (42 CRC, 42 PDAC, 42 NSCLC) during expansion. No dose-limiting toxicities occurred during escalation. In the monotherapy and combination therapy escalation cohorts, treatment-related adverse events (TRAEs) occurred in 55 and 54%, respectively, the most common being fatigue (17 and 25%). In the CRC, PDAC, and NSCLC expansion cohorts, 60, 57, and 45% of patients had TRAEs, respectively the most common were fatigue (15%), diarrhea (9%), and rash (7%). Free soluble CD73 and CD73 expression on peripheral T cells and tumor cells showed sustained decreases, accompanied by reduced CD73 enzymatic activity in tumor cells. Objective response rate during escalation was 0%. Response rates in the CRC, PDAC, and NSCLC expansion cohorts were 2.4% (1 complete response [CR]), 4.8% (1 CR, 1 partial response [PR]), and 9.5% (4 PRs), respectively 6-month progression-free survival rates were 5.4, 13.2, and 16.0%. Oleclumab ± durvalumab had a manageable safety profile, with pharmacodynamic activity reflecting oleclumab’s mechanism of action. Evidence of antitumor activity was observed in tumor types that are generally immunotherapy resistant. Clinicaltrials.gov, NCT02503774 date of registration, July 17, 2015.

KRAS Mutation Is Associated with Lung Metastasis in Patients with Curatively Resected Colorectal Cancer

Publisher: American Association for Cancer Research (AACR)

Date: 03-2011

DOI: 10.1158/1078-0432.CCR-10-1720

Abstract: Purpose: Oncogene mutations contribute to colorectal cancer development. We searched for differences in oncogene mutation profiles between colorectal cancer metastases from different sites and evaluated these as markers for site of relapse. Experimental Design: One hundred colorectal cancer metastases were screened for mutations in 19 oncogenes, and further 61 metastases and 87 matched primary cancers were analyzed for genes with identified mutations. Mutation prevalence was compared between (a) metastases from liver (n = 65), lung (n = 50), and brain (n = 46), (b) metastases and matched primary cancers, and (c) metastases and an independent cohort of primary cancers (n = 604). Mutations differing between metastasis sites were evaluated as markers for site of relapse in 859 patients from the VICTOR trial. Results: In colorectal cancer metastases, mutations were detected in 4 of 19 oncogenes: BRAF (3.1%), KRAS (48.4%), NRAS (6.2%), and PIK3CA (16.1%). KRAS mutation prevalence was significantly higher in lung (62.0%) and brain (56.5%) than in liver metastases (32.3% P = 0.003). Mutation status was highly concordant between primary cancer and metastasis from the same in idual. Compared with independent primary cancers, KRAS mutations were more common in lung and brain metastases (P & 0.005), but similar in liver metastases. Correspondingly, KRAS mutation was associated with lung relapse (HR = 2.1 95% CI, 1.2 to 3.5, P = 0.007) but not liver relapse in patients from the VICTOR trial. Conclusions: KRAS mutation seems to be associated with metastasis in specific sites, lung and brain, in colorectal cancer patients. Our data highlight the potential of somatic mutations for informing surveillance strategies. Clin Cancer Res 17(5) 1122–30. ©2011 AACR.

Final results of ENLIVEN: A global, double-blind, randomized, placebo-controlled, phase 3 study of pexidartinib in advanced tenosynovial giant cell tumor (TGCT)

Publisher: American Society of Clinical Oncology (ASCO)

Date: 20-05-2018

DOI: 10.1200/JCO.2018.36.15_SUPPL.11502

Novel quality indicators for metastatic colorectal cancer management identify significant variations in these measures across treatment centers in Australia

Publisher: Wiley

Date: 14-04-2015

DOI: 10.1111/AJCO.12355

Abstract: Defining multidisciplinary quality of care indicators (QCIs) for metastatic colorectal cancer (mCRC) could improve understanding of variations in routine practice care. This may identify areas of below-average performance, which could then be addressed by clinicians to improve the quality of care delivered. This study aimed to define a panel of QCIs in mCRC and, based on these QCIs, to evaluate quality of care across multiple Australian sites. A panel of clinicians with expertise in colorectal cancer defined evidence-based or best practice-based QCIs relevant to the routine multidisciplinary management of mCRC patients through structured consensus discussion. Related data were extracted from the Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) registry, a prospectively maintained database recording comprehensive details on consecutive mCRC patients across multiple Australian hospitals. Variations in QCIs across sites were explored. Of 13 QCIs defined, data related to 10 were reliably extracted from TRACC. Analysis of data on 1276 patients across 10 sites demonstrated low rates of screening for hereditary nonpolyposis colorectal cancer in young patients and significant variation in surveillance-detected recurrences, lung resection rates and palliative chemotherapy use. Exploratory analyses suggested correlation between liver resection rates and survival. We have defined a novel set of mCRC QCIs and have demonstrated wide variation in the quality of care of mCRC across multiple Australian sites. With further validation to confirm a direct correlation between QCI and patient outcomes, these QCIs could be applied to improve the quality of care received by all mCRC patients.

Real world outcomes in KRAS G12C mutation positive non-small cell lung cancer

Publisher: Elsevier BV

Date: 08-2020

DOI: 10.1016/J.LUNGCAN.2020.06.030

BMS-986205, an optimized indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor, is well tolerated with potent pharmacodynamic (PD) activity, alone and in combination with nivolumab (nivo) in advanced cancers in a phase 1/2a trial

Publisher: American Association for Cancer Research (AACR)

Date: 07-2017

DOI: 10.1158/1538-7445.AM2017-CT116

Abstract: Background: IDO1 is highly expressed in multiple cancers and may be an immunosuppressive mechanism for tumor escape via its production of metabolites that inhibit T-cell function. Nivo, a mAb that targets PD-1, causes IDO1 upregulation, supporting a rationale for combining it with an IDO1 inhibitor. Our preclinical program aimed to identify a best in class IDO1 inhibitor with favorable pharmacokinetic (PK) characteristics (Hunt J, et al. AACR 2017 [abst 6774]). Here we present BMS-986205, a selective IDO1 inhibitor validated in a novel phase 1/2a trial alone and in combination with nivo. Methods: During dose escalation, patients (pts) with advanced cancers were treated in escalating cohorts with BMS-986205 (25-200 mg as of Jan 5, 2017) orally once daily (QD) for 2 wk, followed by BMS-986205 + nivo 240 mg IV every 2 wk. Objectives included safety (primary), PK, and PD. Preclinical analyses included measurement of enzyme inhibition in HEK293 cells overexpressing human IDO1 or tryptophan 2,3-dioxygenase (TDO) and IFNγ-stimulated HeLa cells. Results: In support of clinical testing, BMS-986205 was evaluated preclinically. In vitro characteristics included potent inhibition of kynurenine (kyn) production in IDO1-HEK293 cells (IC50 = 1.1 nM) but not in TDO-HEK293 cells, sustained inhibition in IDO1 cell-based assays after washout, and single-digit nM potency in human tolerogenic MLR assays. Based on preclinical data, a 150 mg QD human dose was projected to maximally inhibit IDO1. In the ongoing clinical study, 42 pts have been treated. All treatment-related adverse events were grade 1/2 except three grade 3 toxicities (autoimmune hepatitis [dose limiting BMS-986205 100 mg/nivo 240 mg], rash, and asymptomatic hypophosphatemia). Day 14 in idual trough concentrations began exceeding the human whole blood IC50 starting with 25 mg QD, and the IC90 starting with 50 mg QD all pts treated at 200 mg QD exceeded the IC90. Serum kyn was substantially reduced at all doses (& 45% mean reduction at each dose), with & 60% mean reduction at the 100 and 200 mg QD doses. Importantly, intratumoral kyn was reduced up to 90% in evaluable paired pre- and on-treatment s les. Conclusions: BMS-986205 is an optimized, once-daily, selective and potent oral IDO1 inhibitor at clinically relevant concentrations. It is well tolerated up to at least 200 mg in combination with nivo in this novel trial. Evidence of substantial serum kyn reduction was observed at doses as low as 25 mg QD inhibition at 100 and 200 mg QD appears greater than that reported for other in-class compounds. In addition, we have presented the first evidence of intratumoral kyn reduction by an IDO1 inhibitor. These data suggest the potential of BMS-986205 as an IDO1 inhibitor with superior PD properties and support further evaluation in combination with nivo. Citation Format: Lillian L. Siu, Karen Gelmon, Quincy Chu, Russell Pachynski, Olatunji Alese, Paul Basciano, Justine Walker, Priyam Mitra, Li Zhu, Penny Phillips, John Hunt, Jayesh Desai. BMS-986205, an optimized indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor, is well tolerated with potent pharmacodynamic (PD) activity, alone and in combination with nivolumab (nivo) in advanced cancers in a phase 1/2a trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017 2017 Apr 1-5 Washington, DC. Philadelphia (PA): AACR Cancer Res 2017 (13 Suppl):Abstract nr CT116. doi:10.1158/1538-7445.AM2017-CT116

Data from A Phase Ib/II Trial of Combined BRAF and EGFR Inhibition in <i>BRAF</i> V600E Positive Metastatic Colorectal Cancer and Other Cancers: The EVICT (Erlotinib and Vemurafenib In Com

Publisher: American Association for Cancer Research (AACR)

Date: 04-2023

DOI: 10.1158/1078-0432.C.6533113

Abstract: AbstractPurpose: BRAF V600E mutant metastatic colorectal cancer represents a significant clinical problem, with combination approaches being developed clinically with oral BRAF inhibitors combined with EGFR-targeting antibodies. While compelling preclinical data have highlighted the effectiveness of combination therapy with vemurafenib and small-molecule EGFR inhibitors, gefitinib or erlotinib, in colorectal cancer, this therapeutic strategy has not been investigated in clinical studies. Patients and Methods: We conducted a phase Ib/II dose-escalation/expansion trial investigating the safety/efficacy of the BRAF inhibitor vemurafenib and EGFR inhibitor erlotinib. Results: Thirty-two patients with i BRAF /i V600E positive metastatic colorectal cancer (mCRC) and 7 patients with other cancers were enrolled. No dose-limiting toxicities were observed in escalation, with vemurafenib 960 mg twice daily with erlotinib 150 mg daily selected as the recommended phase II dose. Among 31 evaluable patients with mCRC and 7 with other cancers, overall response rates were 32% [10/31, 16% (5/31) confirmed] and 43% (3/7), respectively, with clinical benefit rates of 65% and 100%. Early ctDNA dynamics were predictive of treatment efficacy, and serial ctDNA monitoring revealed distinct patterns of convergent genomic evolution associated with acquired treatment resistance, with frequent emergence of MAPK pathway alterations, including polyclonal i KRAS /i , i NRAS /i , and i MAP2K1 /i mutations, and i MET /i lification. Conclusions: The Erlotinib and Vemurafenib In Combination Trial study demonstrated a safe and novel combination of two oral inhibitors targeting BRAF and EGFR. The dynamic assessment of serial ctDNA was a useful measure of underlying genomic changes in response to this combination and in understanding potential mechanisms of resistance. /

Phase II Pilot Study of Vemurafenib in Patients With Metastatic BRAF-Mutated Colorectal Cancer

Publisher: American Society of Clinical Oncology (ASCO)

Date: 12-2015

DOI: 10.1200/JCO.2015.63.2497

Abstract: BRAF V600E mutation is seen in 5% to 8% of patients with metastatic colorectal cancer (CRC) and is associated with poor prognosis. Vemurafenib, an oral BRAF V600 inhibitor, has pronounced activity in patients with metastatic melanoma, but its activity in patients with BRAF V600E–positive metastatic CRC was unknown. In this multi-institutional, open-label study, patients with metastatic CRC with BRAF V600 mutations were recruited to an expansion cohort at the previously determined maximum-tolerated dose of 960 mg orally twice a day. Twenty-one patients were enrolled, of whom 20 had received at least one prior metastatic chemotherapy regimen. Grade 3 toxicities included keratoacanthomas, rash, fatigue, and arthralgia. Of the 21 patients treated, one patient had a confirmed partial response (5% 95% CI, 1% to 24%) and seven other patients had stable disease by RECIST criteria. Median progression-free survival was 2.1 months. Patterns of concurrent mutations, microsatellite instability status, CpG island methylation status, PTEN loss, EGFR expression, and copy number alterations were not associated with clinical benefit. In contrast to prior expectations, concurrent KRAS and NRAS mutations were detected at low allele frequency in a subset of the patients' tumors (median, 0.21% allele frequency) and were apparent mechanisms of acquired resistance in vemurafenib-sensitive patient-derived xenograft models. In marked contrast to the results seen in patients with BRAF V600E–mutant melanoma, single-agent vemurafenib did not show meaningful clinical activity in patients with BRAF V600E mutant CRC. Combination strategies are now under development and may be informed by the presence of intratumor heterogeneity of KRAS and NRAS mutations.

Are the survival benefits associated with primary resection in de novo metastatic colorectal cancer (mCRC) mediated by reversal of systemic inflammation?

Publisher: American Society of Clinical Oncology (ASCO)

Date: 20-01-2014

DOI: 10.1200/JCO.2014.32.3_SUPPL.464

Abstract: 464 Background: Despite reported survival benefits for primary tumor resection in de novo mCRC, its use remains controversial, particularly as the biological explanation remains unclear. We explored whether reversal of systemic inflammation, a marker of a tumor-promoting immune response and poor prognosis, is associated with improved survival in pts undergoing primary resection. Methods: We identified pts who underwent primary resection for de novo mCRC from a prospective CRC database, excluding pts who had metastatectomy. Neutrophil-lymphocyte ratio (NLR) was used to represent systemic inflammation. Survival differences associated with reversal of systemic inflammation, as defined by NLR falling from an elevated level ( 5) at diagnosis to ≤ 5 postoperatively, were examined. Associations between falling NLR and primary tumor bulk (maximal length assessed by pathologist) as well as metastatic burden (maximal axial diameter of largest metastasis assessed by radiologist) were explored. Results: Baseline and postoperative NLR were examined in 156 pts with median age 69y and median overall survival (OS) 18.3 mo. Baseline NLR was elevated in 66 (42%) pts primary resection resulted in falling NLR in 37 of these pts (56%). Compared to pts with persistent NLR , a falling NLR was significantly associated with improved OS (HR 0.53, p = 0.012). Falling NLR was also associated with larger primary tumors, although this was not significant (median length 55mm vs. 45mm, p = 0.059). In a preliminary analysis of 26 pts with retrievable radiology, falling NLR was associated with lower metastatic burden compared to an unchanged NLR (median diameter 29mm vs. 41mm, p = 0.046). Conclusions: Our data demonstrates improved OS in pts who have reversal of systemic inflammation following primary resection in de novo mCRC. The possible associations between reversed systemic inflammation with larger primary tumors or a lower metastatic burden suggest an immune mediated response to reduced tumour bulk as an explanation for the reported survival advantage associated with primary resection. If confirmed, this might define a subgroup of pts who might benefit most from primary resection.

Therapeutic strategies to remodel immunologically cold tumors

Publisher: Wiley

Date: 2020

DOI: 10.1002/CTI2.1226

Natural convection heat transfer utilizing nanofluid in a cavity with a periodic side-wall temperature in the presence of a magnetic field

Publisher: Elsevier BV

Date: 05-2019

DOI: 10.1016/J.ICHEATMASSTRANSFER.2019.02.018

Surgical management of advanced gastrointestinal stromal tumors after treatment with targeted systemic therapy using kinase inhibitors

Publisher: American Society of Clinical Oncology (ASCO)

Date: 20-05-2006

DOI: 10.1200/JCO.2005.05.3439

Abstract: While targeted inhibitors of tyrosine kinase activity demonstrate dramatic efficacy in the majority of patients with advanced gastrointestinal stromal tumors (GISTs), cure remains elusive and resistance to systemic therapy is a challenge. To assess the role of surgery in multimodality management of GISTs, we studied postoperative outcomes in patients treated with targeted kinase inhibitors for advanced GIST. We evaluated outcomes in a single institution series of 69 consecutive patients who underwent surgery for advanced GISTs while receiving kinase inhibitors. Patients were categorized based on extent of disease before surgery (stable disease, limited disease progression, generalized disease progression) and surgical result (no evidence of disease, minimal residual disease, bulky residual disease). Disease status before surgery was associated with surgical result (P .0001 median follow-up, 14.6 months). After surgery, there was no evidence of disease in 78%, 25%, and 7% of patients with stable disease, limited progression, and generalized progression, respectively. Bulky residual disease remained after surgery in 4%, 16%, and 43% of the patients with stable disease, limited progression, and generalized progression. Twelve-month progression-free survival was 80%, 33%, and 0% for patients with stable disease, limited progression, and generalized progression (P .0001). Twelve-month overall survival was 95%, 86%, and 0% for patients with stable disease, limited progression, and generalized progression (P .0001). Patients with advanced GISTs exhibiting stable disease or limited progression on kinase inhibitor therapy have prolonged overall survival after debulking procedures. Surgery has little to offer in the setting of generalized progression.

ASO Author Reflections: Immunotherapy for Solid Tumors: A Review

Publisher: Springer Science and Business Media LLC

Date: 30-10-2018

DOI: 10.1245/S10434-018-6966-8

Abstract CT005: Phase I study of RAF dimer inhibitor BGB-283 in patients with B-RAF or K-RAS/N-RAS mutated solid tumors

Publisher: American Association for Cancer Research (AACR)

Date: 15-07-2016

DOI: 10.1158/1538-7445.AM2016-CT005

Abstract: Background: BGB-283 is a novel inhibitor of the RAF dimer with potent and reversible inhibitory activities against RAF family kinases including wild type ARAF, BRAF, CRAF and BRAF V600E, as well as EGFR. We report here the initial findings of the dose escalation component of an ongoing phase I first-in-human, dose escalation and expansion trial of BGB-283. Methods: Safety, tolerability, pharmacokinetics, recommended phase 2 dose and antitumor activity of BGB-283 were evaluated in patients (pts) with advanced BRAF, N- or KRAS mutant solid tumors. The phase Ia dose escalation study utilized a modified 3+3 dose escalation design. Adverse events (AEs) are reported per CTCAE V4.03 and responses per RECIST V1.1. Results: As of 31st Oct 2015, 31 pts (mutations: 18 KRAS 3 NRAS 7 BRAF V600E 2 BRAF non-V600 and 1 NRAS/BRAF non-V600) enrolled in 7 cohorts received BGB-283 from 5 mg QD to 60 mg QD. BGB-283 was well tolerated. MTD was determined to be 40 mg/QD and dose-limiting toxicity (DLT) was thrombocytopenia. Most frequent treatment-related AEs were fatigue (68%), anorexia (48%), constipation (42%), thrombocytopenia (39%), nausea (39%), vomiting (39%), dermatitis acneiform (39%), hand-foot syndrome (35%), hypertension (35%) and dysphonia (32%). Frequent treatment-related Grade 3/4 AEs included thrombocytopenia (13%), fatigue (10%) and ALT increase (10%). Cutaneous malignancies associated with the approved first-generation BRAF inhibitors have not been observed in pts treated with BGB-283, with a mean follow-up of 6 months. The plasma concentrations of BGB-283 increased proportionally from 5 mg QD through 50 mg QD. The mean t½ of BGB-283 was around 110 hours. Among 29 evaluable pts, one of the only two melanoma pts with a BRAF V600E mutation had a partial response (PR) (on treatment over 249 days). In addition, there were two confirmed PRs including 1 pt with KRAS mutated endometrial cancer (on treatment over 456 days) and 1 thyroid cancer pt with BRAF V600E mutation (on treatment over 481 days) and one unconfirmed PR for 1 pt with KRAS mutated NSCLC (stable disease with transient PR and on treatment for over 572 days). Except for the K-RAS mutated endometrial cancer patient, all other three responders are still on study treatment at the cutoff date. Furthermore, 14 of the 29 evaluable pts achieved prolonged stable disease (3 pts have been on treatment for over 300 days), with the disease control rate at 62%. Finally, 18F-FDG uptake was measured at baseline and at the end of cycle 1 to evaluate BGB-283 pharmacodynamic activity. Partial metabolic responses were observed in 13/30 (43%) pts. Conclusions: BGB-283 was well tolerated and the MTD on a continuous once daily dosing was determined at 40 mg/day. Promising clinical activity was observed at multiple dose levels in pts with BRAF or KRAS mutated tumors. BGB-283 activity and safety are being further investigated in a number of molecularly-defined tumors in an ongoing phase Ib expansion study. Citation Format: Jayesh Desai, Hui Gan, Catherine Barrow, Michael B. Jameson, Grant Mcarthur, Ben Tran, Michael Lam, Laird Cameron, Andrew Weickhardt, Jason Yang, Lai Wang, Zhen Qin, Lusong Luo, Ben Solomon. Phase I study of RAF dimer inhibitor BGB-283 in patients with B-RAF or K-RAS/N-RAS mutated solid tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research 2016 Apr 16-20 New Orleans, LA. Philadelphia (PA): AACR Cancer Res 2016 (14 Suppl):Abstract nr CT005.

KRAS^G12C Inhibition with Sotorasib in Advanced Solid Tumors

Publisher: Massachusetts Medical Society

Date: 24-09-2020

DOI: 10.1056/NEJMOA1917239

BREAKWATER: Randomized phase 3 study of encorafenib (enco) plus cetuximab (cetux) +/- chemotherapy for first-line (1L) treatment (tx) of BRAF V600E-mutant (BRAF(V600E)) metastatic colorectal cancer (mCRC)

Publisher: American Society of Clinical Oncology (ASCO)

Date: 20-05-2021

DOI: 10.1200/JCO.2021.39.15_SUPPL.TPS3619

Abstract: TPS3619 Background: Approximately 10% of patients (pts) with mCRC have BRAF mutations (mostly V600E). 1L tx options for BRAF V600E mCRC are limited to cytotoxic chemotherapy ± anti-VEGF or anti-EGFR, or immune checkpoint inhibitors in pts with MSI-H tumors. In Europe, Japan, and USA, the combination of BRAF inhibitor enco + EGFR inhibitor cetux is approved for tx of BRAF V600E mCRC after prior therapy. In BEACON CRC, enco + cetux resulted in a median overall survival (OS) of 9.3 months (95% confidence interval [CI]: 8.0–11.3) and an objective response rate (ORR) of 19.5% (95% CI: 14.5%–25.4%) in previously treated pts with BRAF V600E mCRC (median follow-up: 12.8 months) 57.4% of pts had grade 3/4 adverse events (AEs) 9% discontinued due to AEs. Given the poor prognosis of pts with BRAF V600E mCRC and based on the efficacy and tolerability of enco + cetux from BEACON CRC, BREAKWATER will evaluate efficacy and safety of enco + cetux ± chemotherapy in tx-naive pts with BRAF V600E mCRC. Methods: BREAKWATER is an open-label, global, multicenter, randomized, phase 3 study with a safety lead-in (SLI). Approximately 60 and 870 pts will be enrolled in the SLI and phase 3 parts of the study, respectively. Pts must have BRAF V600E mCRC (determined using tumor tissue or blood) ECOG performance status 0/1 and adequate bone marrow, hepatic, and renal function. Pts in the SLI must have evaluable disease (RECIST v1.1) and have received ≤ 1 prior tx regimen those previously treated with a BRAF or EGFR inhibitor, or both oxaliplatin and irinotecan, will be excluded. Pts in the phase 3 study must have measurable disease and be tx naive for metastatic disease. Study tx and endpoints are shown in the table. Enrollment began on 6 January 2021. Clinical trial information: NCT04607421. [Table: see text]

Figure S3 from Genotype-Tailored ERK/MAPK Pathway and HDAC Inhibition Rewires the Apoptotic Rheostat to Trigger Colorectal Cancer Cell Death

Publisher: American Association for Cancer Research (AACR)

Date: 03-04-2023

DOI: 10.1158/1535-7163.22523094

Abstract: Supplementary figure 3 shows combining trametinib with different classes of HDAC inhibitors in COLO 201 cells

Royal Melbourne Hospital

Location: Australia

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Victorian Comprehensive Cancer Centre Project

Location: Australia

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Victorian Medical Oncology Training Program

Location: Australia

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Monash Medical Centre

Location: Australia

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Walter And Eliza Hall Institute Of Medical Research

Location: Australia

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Victorian Comprehensive Cancer Centre

Location: Australia

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Monash University

Location: Australia

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Austin Hospital

Location: Australia

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Austin & Repatriation Medical Centre

Location: Australia

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Peter MacCallum Cancer Institute

Location: Australia

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Royal Australian College Of Physicians (FRACP)

Location: Australia

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Western Hospital

Location: Australia

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Australian Cancer Trials

Location: Australia

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Educational Commission For Foreign Medical Graduates

Location: United States of America

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Harvard Medical School

Location: United States of America

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Providing Equitable, Convenient And Efficient Access To Novel Cancer Therapies: A Phase I Outreach Program

Start Date: 2017

End Date: 2020

Funder: Cancer Council Victoria

A Phase II Study Of Continuous, Low-dose LBH 589 (Panobinostat) In Patients With Refractory Solid Tumors, Including CNS Tumors

Start Date: 2017

End Date: 2020

Funder: National Health and Medical Research Council

Mechanisms Of Resistance To Immunological Targeting Of Primary And Metastatic Colorectal Cancers

Start Date: 2018

End Date: 2021

Funder: National Health and Medical Research Council

Targeting BCL-2 In Estrogen Receptor Positive Breast Cancer.

Start Date: 2019

End Date: 2021

Funder: Cancer Australia

The Role Of Glucose In Response To Cancer

Start Date: 2010

End Date: 2012

Funder: Cancer Council Victoria

LCCI/NIBR Collaborative Project To Investigate Molecular Targets In Colorectal Cancer

Start Date: 2010

End Date: 2012

Funder: Novartis Pharmaceuticals UK Limited

Australasian Sarcoma Study Group: Co-operative Oncology Group Funds

Start Date: 2008

End Date: 2010

Funder: Cancer Australia

Centre For Translational Pathology Research And Training

Start Date: 2011

End Date: 2016

Funder: National Health and Medical Research Council

Translating The Human Cancer Genome Project Into Better Outcomes For Patients With Cancer

Start Date: 2011

End Date: 2013

Funder: Victorian Cancer Agency

Targeting The BCL-2 Pro-survival Pathway In Breast Cancer – Translating Discovery To The Clinic

Start Date: 2013

End Date: 2017

Funder: National Breast Cancer Foundation

Australasian Sarcoma Study Group: Co-operative Oncology Group Funds

Start Date: 2013

End Date: 2015

Funder: Cancer Australia

Identifying New Indications For Targeted Therapies By Enabling Innovative, Molecularly-directed, Signal-seeking, Phase II Oncology Clinical Trials

Start Date: 2012

End Date: 2013

Funder: Victorian Cancer Agency

Centre Of Research Excellence For Translational Breast Cancer Research: From Discovery To Better Health Outcomes

Start Date: 2012

End Date: 2017

Funder: National Health and Medical Research Council

Discovery Of Synergistic Drug Combinations For Colorectal Cancer

Start Date: 2015

End Date: 2019

Funder: National Health and Medical Research Council

Vaccination Against Adenoid Cystic And Colorectal Carcinoma Using MYB CDNA - VACCUMeD Clinical Trial - Immune Modulatory Therapy In Colorectal And Adenoid Cystic Carcinoma.

Start Date: 2016

End Date: 2019

Funder: Victorian Cancer Agency

Overcoming Resistance To Anti-EGFR Antibody Therapy In Colorectal Cancer Using Novel Targeted PI3K And MEK Inhibitors

Start Date: 2013

End Date: 2015

Funder: National Health and Medical Research Council

Role Of MACROD2 Loss In DNA Repair, Chromosomal Instability And Development Of Colorectal Cancer: Clinical And Therapeutic Implications

Start Date: 2015

End Date: 2017

Funder: National Health and Medical Research Council