ORCID Profile
0000-0002-1457-6137
Current Organisations
Aarhus Universitet Institut for Bioscience
,
University of Western Australia
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Publisher: Wiley
Date: 02-11-2020
DOI: 10.1111/PCMR.12831
Abstract: The combination of ipilimumab and nivolumab is a highly active systemic therapy for metastatic melanoma but can cause significant toxicity. We explore the safety and efficacy of this treatment in routine clinical practice, particularly in the setting of serine/threonine‐protein kinase B‐Raf (BRAF)‐targeted therapy. Consecutive patients with unresectable stage IIIC/IV melanoma commenced on ipilimumab and nivolumab across 10 tertiary melanoma institutions in Australia were identified retrospectively. Data collected included demographics, response and survival outcomes. A total of 152 patients were included for analysis, 39% were treatment‐naïve and 22% failed first‐line BRAF/MEK inhibitors. Treatment‐related adverse events occurred in 67% of patients, grade 3–5 in 38%. The overall objective response rate was 41%, 57% in treatment‐naïve and 21% in BRAF/MEK failure patients. Median progression‐free survival was 4.0 months (95% CI, 3.0–6.0) in the whole cohort, 11.0 months (95% CI, 6.0‐NR) in treatment‐naïve and 2.0 months (95% CI, 1.4–4.6) in BRAF/MEK failure patients. The combination of ipilimumab and nivolumab can be used safely and effectively in a real‐world population. While first‐line efficacy appears comparable to trial populations, BRAF‐mutant patients failing prior BRAF/MEK inhibitors show less response.
Publisher: Springer Science and Business Media LLC
Date: 28-07-2021
DOI: 10.1038/S41598-021-93479-Z
Abstract: Advances in cancer immunology have increased the use of immune checkpoint inhibitors in clinical practice, however not all patients respond, and treatment can have severe side-effects. Blood-based immunological biomarkers are an attractive method for predicting which patients will respond to therapy, however, reliable biomarkers for immune checkpoint blockade are lacking. This study aimed to identify patients before or early in treatment who would best respond to PD-1 inhibitors. We hypothesised that higher baseline PD-L1 and/or PD-1 on peripheral blood T cells could predict radiological response to PD-1 inhibitors. This pilot prospective cohort study assessed 26 patients with melanoma or non-small cell lung cancer, treated with pembrolizumab, nivolumab, or nivolumab/ipilimumab combined. Response was assessed by RECIST 1.1. Peripheral blood lymphocytes collected at baseline, after one cycle, 10 weeks and at discontinuation of therapy were analysed by flow cytometry. Patients with a higher proportion of PD-L1 + T cells at baseline had improved objective response to PD-1 inhibitor therapy, and patients with a lower proportion of regulatory T cells at baseline experienced more immune-related adverse events. These findings may prove useful to assist in clinical decision making. Further studies with larger cohorts are required to validate these findings.
Publisher: Elsevier BV
Date: 10-2022
Publisher: Impact Journals, LLC
Date: 04-01-2019
Publisher: Springer Science and Business Media LLC
Date: 13-02-2023
DOI: 10.1038/S41598-023-29416-Z
Abstract: Circulating tumour cells (CTCs) are heterogenous and contain genetic information from the tumour of origin. They bear specific intra- and extra-cellular protein markers aiding in their detection. However, since these markers may be shared with other rare cells in the blood, only genetic testing can confirm their malignancy. Herein, we analyse different CTC subsets using single cell whole genome DNA sequencing to validate their malignant origin. We randomly selected putative CTCs identified by immunostaining that were isolated from 4 patients with high grade serous ovarian cancer (HGSOC) and one with benign cystadenoma. We specifically targeted CTCs positive for epithelial (CK/EpCAM pos ), mesenchymal (vimentin pos ), and pseudoendothelial (CK/EpCAM pos plus CD31 pos ) markers. We isolated these cells and performed whole genome lification (WGA) and low-pass whole-genome sequencing (LP-WGS) for analysis of copy number alterations (CNA). Of the CK/EpCAM pos cells analysed from the HGSOC patients, 2 of 3 cells showed erse chromosomal CNAs. However, the 4 pseudoendothelial cells (CK/EpCAM pos plus CD31 pos ) observed in the HGSOC cases did not carry any CNA. Lastly, two of the clusters of vimentin positive cells sequenced from those found in the benign cystadenoma case had CNA. Despite the low number of cells analysed, our results underscore the importance of genetic analysis of putative CTCs to confirm their neoplastic origin. In particular, it highlights the presence of a population of CK/EpCAM pos cells that are not tumour cells in patients with HGSOC, which otherwise would be counted as CTCs.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-05-2021
DOI: 10.1200/JCO.2021.39.15_SUPPL.5584
Abstract: 5584 Background: Activity of durvalumab in patients with deficient mismatch repair (dMMR) advanced endometrial carcinoma (EC) was confirmed in the PHAEDRA trial (ANZGOG 1601). This study investigated the association between immune biomarkers and clinical outcomes in PHAEDRA. Methods: Formalin-fixed paraffin embedded sections immunohistochemically stained for PD-L1 using the Ventana platform, were with matched H& E slides scored independently by two pathologists according to the Ventana PD-L1 (SP263) algorithm for urothelial carcinoma (UC). Immune biomarkers assessed were PD-L1 staining of tumor cells (TCP) and immune cells (IC), and presence of tumor-associated immune cells (ICP). Results: Sixty-seven of the 71 patients had sufficient tumor for PD-L1 testing. AUC were 0.667, 0.726 and 0.644 for TCP, ICP and IC, respectively for predicting tumor response. Optimal cutpoints were TCP≥1%, ICP≥10% and IC≥35%. ICP≥10% achieved the highest sensitivity (53%) and specificity (82%) of the in idual cutpoints. The optimal cutpoint algorithm was able to identify patients who would not respond, (sensitivity 88%, negative predictive value 92%), but had low specificity (48%) and positive predictive value (37%). Differences in PFS were found using ICP≥10% (logrank p = 0.01), compared to TCP (p = 0.25), IC (p = 0.48) and the UC algorithm (p = 0.08) (Figure 1). PFS was shorter in patients with pMMR than dMMR after adjusting for ICP (HR 2.99, 95%CI: 1.61-5.57, p 0.001). Adjustment for MMR reduced the prognostic significance of ICP≥10% for PFS (HR 0.59, 95% CI: 0.28-1.23, p = 0.16). For OS, differences were seen for the UC algorithm (p = 0.02), but not ICP (p = 0.07), TCP (p = 0.18) or IC (p = 0.23). Similarly to PFS, adjustment for MMR reduced the prognostic significance of the UC algorithm for OS (HR: 0.53, 95% CI: 0.25-1.12, p = 0.10). Conclusions: In this exploratory analysis, ICP was more closely associated with tumor response and PFS than TCP or IC. ICP alone was better than the UC algorithm for predicting PFS. The optimum cutpoint algorithm was promising for identifying non-responders, but requires external validation. Clinical trial information: ACTRN12617000106336.
Publisher: Springer Science and Business Media LLC
Date: 27-08-2013
DOI: 10.1038/BJC.2013.504
Publisher: Elsevier BV
Date: 05-2020
Publisher: Elsevier BV
Date: 08-2023
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22477679.V1
Abstract: Tables S1-S8 and Figures S1-S4
Publisher: American Society of Clinical Oncology (ASCO)
Date: 03-2022
DOI: 10.1200/JCO.21.02067
Abstract: Balstilimab (antiprogrammed death-1) and zalifrelimab (anticytotoxic T-lymphocyte–associated antigen-4) are two new checkpoint inhibitors emerging as promising investigational agents for the treatment of advanced cervical cancer. This phase II trial (ClinicalTrials.gov identifier: NCT03495882 ) evaluated the combination of balstilimab plus zalifrelimab in patients with recurrent and/or metastatic cervical cancer who relapsed after prior platinum-based therapy. Patients were intravenously dosed with balstilimab 3 mg/kg once every 2 weeks and zalifrelimab 1 mg/kg once every 6 weeks, for up to 24 months. The primary end point was objective response rate (ORR, RECIST version 1.1, assessed by independent central review). Secondary end points included duration of response, safety and tolerability, and survival. In total, 155 women (median age, 50 years [range, 24-76 years]) were enrolled and treated with balstilimab plus zalifrelimab 125 patients had measurable disease at baseline and one prior line of platinum-based therapy in the advanced setting, and these patients constituted the efficacy-evaluable population. The median follow-up was 21 months. The confirmed ORR was 25.6% (95% CI, 18.8 to 33.9), including 10 complete responders and 22 partial responders, with median duration of response not reached (86.5%, 75.5%, and 64.2% at 6, 9, and 12 months, respectively). The ORRs were 32.8% and 9.1% in patients with programmed death ligand-1–positive and programmed death ligand-1–negative tumors, respectively. For patients with squamous cell carcinoma, the ORR was 32.6%. The overall disease control rate was 52% (95% CI, 43.3 to 60.6). Hypothyroidism (14.2%) and hyperthyroidism (7.1%) were the most common immune-mediated adverse events. Promising and durable clinical activity, with favorable tolerability, was seen in this largest trial to date evaluating dual programmed death-1/cytotoxic T-lymphocyte–associated antigen-4 blockade in patients with recurrent and/or metastatic cervical cancer. Further investigation of the balstilimab and zalifrelimab combination in this setting is continuing.
Publisher: Springer Science and Business Media LLC
Date: 22-08-2023
DOI: 10.1007/S00432-023-05271-3
Abstract: Approximately 50% of uveal melanoma (UM) patients will develop metastatic disease depending on the genetic features of the primary tumour. Patients need 3–12 monthly scans, depending on their prognosis, which is costly and often non-specific. Circulating tumour DNA (ctDNA) quantification could serve as a test to detect and monitor patients for early signs of metastasis and therapeutic response. We assessed ctDNA as a biomarker in three distinct UM cohorts using droplet-digital PCR: (A) a retrospective analysis of primary UM patients to predict metastases (B) a prospective analysis of UM patients after resolution of their primary tumour for early detection of metastases and (C) monitoring treatment response in metastatic UM patients. Cohort A: ctDNA levels were not associated with the development of metastases. Cohort B: ctDNA was detected in 17/25 (68%) with radiological diagnosis of metastases. ctDNA was the strongest predictor of overall survival in a multivariate analysis (HR = 15.8, 95% CI 1.7–151.2, p = 0.017). Cohort C: ctDNA monitoring of patients undergoing immunotherapy revealed a reduction in the levels of ctDNA in patients with combination immunotherapy. Our proof-of-concept study shows the biomarker feasibility potential of ctDNA monitoring in for the clinical management of uveal melanoma patients.
Publisher: Elsevier BV
Date: 09-2022
Publisher: Elsevier BV
Date: 10-2019
Publisher: Springer Science and Business Media LLC
Date: 02-11-2020
DOI: 10.1038/S41598-020-75837-5
Abstract: BRAF inhibitors revolutionised the management of melanoma patients and although resistance occurs, there is a subgroup of patients who maintain durable disease control. For those cases with durable complete response (CR) it is not clear whether it is safe to cease therapy. Here we identified 13 patients treated with BRAF +/− MEK inhibitors, who cease therapy after prolonged CR (median = 34 months, range 20–74). Recurrence was observed in 3/13 (23%) patients. In the remaining 10 patients with sustained CR off therapy, the median follow up after discontinuation was 19 months (range 8–36). We retrospectively measured ctDNA levels using droplet digital PCR (ddPCR) in longitudinal plasma s les. CtDNA levels were undetectable in 11/13 cases after cessation and remained undetectable in patients in CR (10/13). CtDNA eventually became detectable in 2/3 cases with disease recurrence, but remained undetectable in 1 patient with brain only progression. Our study suggests that consideration could be given to ceasing targeted therapy in the context of prolonged treatment, durable response and no evidence of residual disease as measured by ctDNA.
Publisher: Elsevier BV
Date: 09-2021
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-05-2016
Publisher: Elsevier BV
Date: 09-2020
Publisher: Springer Science and Business Media LLC
Date: 26-04-2023
DOI: 10.1007/S00520-023-07754-Y
Abstract: In ovarian cancer (OC), suboptimal muscle morphology (i.e., low muscle mass and density) is associated with poor clinical outcomes, yet little is known about the effect of interventions aimed at improving these measures. We investigated the effect of resistance exercise after first-line treatment on muscle mass and density, muscle strength and physical function, health-related quality of life (QoL), and pelvic-floor function in advanced-stage OC survivors. Fifteen OC survivors participated in supervised resistance exercise twice weekly for 12 weeks (in-clinic or by telehealth). Assessments included muscle mass and density (dual-energy X-ray absorptiometry, peripheral quantitative computed tomography), muscle strength (1-repetition maximum [1RM] chest press, 5RM leg press, handgrip strength), physical function (400-m walk, timed up-and-go [TUG]), QoL (QLQ-C30 questionnaire), and self-reported pelvic floor function (Australian Pelvic Floor Questionnaire). The median age was 64 (range 33–72) years, 10 women underwent neoadjuvant chemotherapy and five underwent adjuvant chemotherapy. All participants completed the intervention (median attendance = 92% range 79–100%). Post-intervention improvements were observed for whole-body lean mass (1.0 ± 1.4 kg, p = 0.015), appendicular lean mass (0.6 ± 0.9 kg, p = 0.013), muscle density ( p = 0.011), upper and lower body strength ( p ≤ 0.001), 400-m walk ( p = 0.001), TUG ( p = 0.005), and social and cognitive QoL domains ( p = 0.002 and 0.007), with no change to pelvic floor symptoms ( p 0.05). In this study, supervised resistance exercise effectively improved muscle mass and density, muscle strength, and physical functioning without deleterious effects on the pelvic floor. Considering the prognostic value of these outcomes, larger studies are needed to confirm the benefits of resistance exercise in OC supportive care.
Publisher: MDPI AG
Date: 10-12-2021
Abstract: Detection of ovarian cancer (OC) circulating tumour cells (CTCs) is primarily based on targeting epithelial markers, thus failing to detect mesenchymal tumour cells. More importantly, the immune checkpoint inhibitor marker PD-L1 has not been demonstrated on CTCs from OC patients. An antibody staining protocol was developed and tested using SKOV-3 and OVCA432 OC cell lines. We targeted epithelial (cytokeratin (CK) and EpCAM), mesenchymal (vimentin), and OC-specific (PAX8) markers for detection of CTCs, and CD45/16 and CD31 were used for the exclusion of white blood and vascular endothelial cells, respectively. PD-L1 was used for CTC characterisation. CTCs were enriched using the Parsortix™ system from 16 OC patients. Results revealed the presence of CTCs in 10 (63%) cases. CTCs were heterogeneous, with 113/157 (72%) cells positive for CK/EpCAM (epithelial marker), 58/157 (37%) positive for vimentin (mesenchymal marker), and 17/157 (11%) for both (hybrid). PAX8 was only found in 11/157 (7%) CTCs. In addition, 62/157 (39%) CTCs were positive for PD-L1. Positivity for PD-L1 was significantly associated with the hybrid phenotype when compared with the epithelial (p = 0.007) and mesenchymal (p = 0.0009) expressing CTCs. Characterisation of CTC phenotypes in relation to clinical outcomes is needed to provide insight into the role that epithelial to mesenchymal plasticity plays in OC and its relationship with PD-L1.
Publisher: Springer Science and Business Media LLC
Date: 10-02-2020
DOI: 10.1038/S41416-020-0750-9
Abstract: Circulating tumour cells (CTCs) can be assessed through a minimally invasive blood s le with potential utility as a predictive, prognostic and pharmacodynamic biomarker. The large heterogeneity of melanoma CTCs has hindered their detection and clinical application. Here we compared two microfluidic devices for the recovery of circulating melanoma cells. The presence of CTCs in 43 blood s les from patients with metastatic melanoma was evaluated using a combination of immunocytochemistry and transcript analyses of five genes by RT-PCR and 19 genes by droplet digital PCR (ddPCR), whereby a CTC score was calculated. Circulating tumour DNA (ctDNA) from the same patient blood s le, was assessed by ddPCR targeting tumour-specific mutations. Our analysis revealed an extraordinary heterogeneity amongst melanoma CTCs, with multiple non-overlapping subpopulations. CTC detection using our multimarker approach was associated with shorter overall and progression-free survival. Finally, we found that CTC scores correlated with plasma ctDNA concentrations and had similar pharmacodynamic changes upon treatment initiation. Despite the high phenotypic and molecular heterogeneity of melanoma CTCs, multimarker derived CTC scores could serve as viable tools for prognostication and treatment response monitoring in patients with metastatic melanoma.
Publisher: Springer Science and Business Media LLC
Date: 04-05-2023
DOI: 10.1186/S13046-023-02687-0
Abstract: Uterine leiomyosarcoma (uLMS) is a rare and aggressive gynaecological malignancy, with in iduals with advanced uLMS having a five-year survival of 10%. Mutations in the homologous recombination (HR) DNA repair pathway have been observed in ~ 10% of uLMS cases, with reports of some in iduals benefiting from poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi) therapy, which targets this DNA repair defect. In this report, we screened in iduals with uLMS, accrued nationally, for mutations in the HR repair pathway and explored new approaches to therapeutic targeting. A cohort of 58 in iduals with uLMS were screened for HR Deficiency (HRD) using whole genome sequencing (WGS), whole exome sequencing (WES) or NGS panel testing. In iduals identified to have HRD uLMS were offered PARPi therapy and clinical outcome details collected. Patient-derived xenografts (PDX) were generated for therapeutic targeting. All 13 uLMS s les analysed by WGS had a dominant COSMIC mutational signature 3 11 of these had high genome-wide loss of heterozygosity (LOH) ( 0.2) but only two s les had a CHORD score 50%, one of which had a homozygous pathogenic alteration in an HR gene (deletion in BRCA2 ). A further three s les harboured homozygous HRD alterations (all deletions in BRCA2), detected by WES or panel sequencing, with 5/58 (9%) in iduals having HRD uLMS. All five in iduals gained access to PARPi therapy. Two of three in iduals with mature clinical follow up achieved a complete response or durable partial response (PR) with the subsequent addition of platinum to PARPi upon minor progression during initial PR on PARPi. Corresponding PDX responses were most rapid, complete and sustained with the PARP1-specific PARPi, AZD5305, compared with either olaparib alone or olaparib plus cisplatin, even in a paired s le of a BRCA2 -deleted PDX, derived following PARPi therapy in the patient, which had developed PARPi-resistance mutations in PRKDC , encoding DNA-PKcs. Our work demonstrates the value of identifying HRD for therapeutic targeting by PARPi and platinum in in iduals with the aggressive rare malignancy, uLMS and suggests that in iduals with HRD uLMS should be included in trials of PARP1-specific PARPi.
Publisher: Elsevier BV
Date: 04-2016
DOI: 10.1016/J.JTHO.2015.12.108
Abstract: Malignant pleural mesothelioma (MPM) is a rare cancer with a heterogeneous prognosis. Prognostic models are not widely utilized clinically. Classification and regression tree (CART) analysis examines the interaction of multiple variables with a given outcome. Between 2005 and 2014, all cases with pathologically confirmed MPM had routinely available histological, clinical, and laboratory characteristics recorded. Classification and regression tree analysis was performed using 29 variables with 18-month survival as the dependent variable. Risk groups were refined according to survival and clinical characteristics. The model was then tested on an external international cohort. A total of 482 cases were included in the derivation cohort the median survival was 12.6 months, and the median age was 69 years. The model defined four risk groups with clear survival differences (p < 0.0001). The strongest predictive variable was the presence of weight loss. The group with the best survival at 18 months (86.7% alive, median survival 34.0 months, termed risk group 1) had no weight loss, a hemoglobin level greater than 153 g/L, and a serum albumin level greater than 43 g/L. The group with the worst survival (0% alive, median survival 7.5 months, termed risk group 4d) had weight loss, a performance score of 0 or 1, and sarcomatoid histological characteristics. The C-statistic for the model was 0.761, and the sensitivity was 94.5%. Validation on 174 external cases confirmed the model's ability to discriminate between risk groups in an alternative data set with fair performance (C-statistic 0.68). We have developed and validated a simple, clinically relevant model to reliably discriminate patients at high and lower risk of death using routinely available variables from the time of diagnosis in unselected populations of patients with MPM.
Publisher: Elsevier
Date: 2012
Publisher: BMJ
Date: 06-2021
Abstract: In this study, we assessed the activity of durvalumab, an antibody to programmed death ligand-1, in two cohorts of women with advanced endometrial cancers (AEC)—mismatch repair proficient (pMMR) and mismatch repair deficient (dMMR). A multicenter phase two study was performed in women with AEC with pMMR tumor progressing after one to three lines of chemotherapy and women with AEC with dMMR tumor progressing after zero to three lines of chemotherapy. Mismatch repair status was based on immunohistochemistry expression. All women received durvalumab 1500 mg given every 4 weeks until progression or unacceptable toxicity. The primary endpoint was objective tumor response by RECIST V.1.1 modified for immune-based therapeutics. Seventy-one women were recruited: 35 dMMR and 36 pMMR. Median follow-up was 19 vs 21 months in dMMR versus pMMR, respectively. Median age was 67 years. Histology in dMMR versus pMMR included endometrioid (94% vs 57%) and serous (0% vs 31%) and was high grade in 26% vs 74%. The objective tumor response rate (OTRR) in the dMMR cohort was 47% (17/36, 95% CI 32 to 63), including 6 complete responses and 11 partial responses (PRs)) vs 3% in the pMMR cohort (1/35, 95% CI 1 to 15, PR). In the dMMR cohort, durvalumab was the first-line therapy in 58% (OTRR 57%) and the second-line therapy in 39% (OTRR 38%). Median progression-free survival was 8.3 months in the dMMR cohort vs 1.8 months in the pMMR cohort. The 12-month overall survival (OS) rate was 71% in dMMR vs 51% in pMMR, with median OS not reached for dMMR vs 12 months for pMMR. Immune-related adverse events occurred in 14 women, mostly grades 1–2. Durvalumab monotherapy showed promising activity and acceptable safety in AEC with dMMR regardless of prior lines of chemotherapy, but activity was limited in AEC with pMMR. ANZGOG1601, ACTRN12617000106336, and NCT03015129 .
Publisher: Impact Journals, LLC
Date: 18-08-2017
Publisher: Asian Society of Gynecologic Oncology; Korean Society of Gynecologic Oncology and Colposcopy
Date: 2021
Publisher: MDPI AG
Date: 30-12-2022
Abstract: Women with advanced endometrial carcinoma (EC) with mismatch repair (MMR) deficiency have improved outcomes when treated with immune checkpoint inhibitors however, additional biomarkers are needed to identify women most likely to respond. Scores for programmed death ligand 1 (PD-L1), immunohistochemical staining of tumor (TC+), immune cells (IC+) and presence of tumor-associated immune cells (ICP) on MMR deficient (n = 34) and proficient (n = 33) EC from women treated with durvalumab in the PHAEDRA trial (ANZGOG1601/CTC0144) (trial registration number ACTRN12617000106336, prospectively registered 19 January 2017) are reported and correlated with outcome. Receiver operating characteristic (ROC) analyses and area under the ROC curve were used to determine optimal cutpoints. Performance was compared with median cutpoints and two algorithms a novel algorithm derived from optimal cutpoints (TC+ ≥ 1 or ICP ≥ 10 or IC+ ≥ 35) and the Ventana urothelial carcinoma (UC) algorithm (either TC+ ≥ 25, ICP 1 and IC+ ≥ 25 or ICP = 1 and IC+ = 100). The cutpoint ICP ≥ 10 had highest sensitivity (53%) and specificity (82%), being prognostic for progression-free survival (PFS) (p = 0.01), while the optimal cutpoints algorithm was associated with overall survival (p = 0.02) these results were not significant after adjusting for MMR status. The optimal cutpoints algorithm identified non-responders (p = 0.02) with high sensitivity (88%) and negative predictive value (92%), remaining significant after adjustment for MMR. Although MMR status had the strongest association with response, further work to determine the significance of ICP ≥ 10 and the novel optimal cutpoint algorithm is needed.
Publisher: BMJ
Date: 11-2021
DOI: 10.1136/JITC-2021-SITC2021.481
Abstract: THOR-707 (SAR444245) is a recombinant human IL-2 molecule irreversibly bound to a PEG chain to block alpha-binding while retaining near-native affinity for beta/gamma IL-2 receptor subunits. We report updated results from the ongoing HAMMER phase 1/2 trial. SAR444245 was given via IV infusion as monotherapy Q2W [A] or Q3W [B], with pembrolizumab 200mg IV Q3W [C], or Q3W with cetuximab 400mg/m2 IV on D1 then 250mg/m2 IV QW [D] after pre-medication and peri-infusion hydration. A 3+3 design was used to identify the MTD/RP2D in pts with advanced solid tumors. Key objectives included assessments of safety, efficacy, pharmacokinetics (PK) and pharmacodynamics (PD). 68 pts, median age 61.5 (37–78) yrs with median 3 (1–10) prior therapies enrolled. Most common tumors: melanoma (n=10), colorectal (n=11). Doses tested by cohort: [A]: 8–16 µg/kg (n=9) [B]: 8–40 µg/kg (n=29) [C]: 8–32 µg/kg (n=20) [D]: 16–24 µg/kg (n=10). The most common ( %) AEs included pyrexia (52.5%), nausea (50.0%), flu-like symptoms (44.1%), vomiting (36.8%), chills (32.4%), fatigue (32.4%), AST elevation (30.9%). AEs generally resolved promptly with supportive care. Grade(G) 3/4 ( %) related AEs included ALT/AST elevation (5.9%), and decreased lymphocyte count (26.5% within first 24 hrs, recovering by 48–72 hrs, this lymphocyte migration is mechanistically consistent with immune cell margination). G3/4 CRS was observed in 2 pts. Two DLTs occurred: G3 infusion reaction (32 µg/kg [B]) and G3 AST/ALT/G2 bilirubin elevation with G2 CRS (24 µg/kg [C]). No vascular leak syndrome, QTc prolongation, cardiac, or end organ toxicity was observed. Half-life was ~10 h. Sustained increases in CD8 T and NK cells were observed (fold relative to baseline): monotherapy (1–9.4x and 2–43.3x) with pembrolizumab (0.5–5.78x and 1.5–26.9x) with cetuximab (1.3–7.57x and 3.6–45.4x). Max CD4 and eosinophils increased to 136 cell/µL and 1078 cell/µL. No IL-5 elevation or ADAs were observed. Transient IL-6 increases in 4 pts (500, 627, 1000, 1100 pg/mL) were not associated with AEs. Four pts had confirmed PRs (1 PD1-treated SCC, unknown primary [B] 2 PD1-naïve BCC and 1 PD1-treated HNSCC [C]) 3 pts had minor responses -- prostate (-24%) and PD1-treated melanoma (-17%) [B] PD1-treated NSCLC (¬-29%) [C] -- after ≥2 scans. 23 pts completed ≥5 cycles. SAR444245 was well tolerated and demonstrated antitumor activity in heavily pretreated patients, including prior checkpoint inhibitor therapy. Clinical safety, efficacy and PD suggest a wide therapeutic window. Combination with pembrolizumab and cetuximab leveraged SAR44245’s effects on CD8 T and NK cells. NCT04009681 The clinical trial was approved by each institutions ethics’ and review board prior to beginning study enrollment.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-05-2021
DOI: 10.1200/JCO.2021.39.15_SUPPL.1050
Abstract: 1050 Background: Novel degraders and antagonists of ER are under evaluation in aBC, to overcome both ER mediated resistance and the bioavailability and dosing limitations of fulvestrant, the only approved SERD. ER is also overexpressed in ̃80% of EEC and endocrine therapy (ET) is utilized for these patients (pts). LY3484356, a novel, orally bioavailable SERD with pure antagonistic properties results in sustained inhibition of ER-dependent gene transcription and cell growth. Preclinically, LY3484356 shows favorable efficacy and pharmacokinetic (PK) properties, including antitumor activity in ESR1 mutants. Here we present the initial clinical data from EMBER, an ongoing first-in-human phase 1a/b trial of this novel agent. Methods: Phase 1a evaluated LY3484356 dose escalation (i3+3 design) in women with ER+, HER2- aBC (≤3 prior therapies for aBC following protocol amendment prior ET sensitivity) and ER+ EEC (prior platinum therapy). Premenopausal women received a concomitant GnRH agonist. Key endpoints included determination of the recommended phase 2 dose, safety and tolerability, PK, and objective response rate and clinical benefit rate per RECIST v1.1. Results: As of the data cut (November 9, 2020), 28 pts (n = 24 aBC, n = 4 EEC) were enrolled at doses ranging from 200-1200 mg QD. Median age was 59 years (range, 35-80). Median number of prior therapies for aBC was 2 (range, 1-8 6 pts enrolled prior to protocol amendment had received ≥4 prior therapies), including prior fulvestrant (46%), a CDK4/6 inhibitor (83%), and chemotherapy (33%). No dose-limiting toxicities were observed. Treatment-emergent adverse events (TEAEs) were mostly grade 1-2, including nausea (32%), fatigue (25%), and diarrhea (18%). The only grade 3 treatment-related AE was diarrhea (n = 1). TEAEs of bradycardia and QTc prolongation were not observed despite intensive central ECG monitoring. Dose-proportional increases in LY3484356 exposures were observed across all evaluated doses and t 1/2 was 25-30 hours. At the starting dose level (200 mg QD), unbound LY3484356 exposures exceeded those achieved with fulvestrant. 16 of 28 pts were efficacy evaluable, with the remaining 12 pts ongoing prior to first scan. Among 16 evaluable pts, 11 (8 aBC, 3 EEC) had stable disease (10 pts ongoing), and 5 had progressive disease. RECIST responses were observed after the data cut and will be detailed at the meeting. Plasma ctDNA analysis indicated decreases in mutant allele frequencies, including mutant ESR1 in 9/12 (75%) evaluable pts across all dose levels. Conclusions: LY3484356 QD dosing shows favorable safety and PK properties, along with preliminary efficacy in pts with heavily pretreated ER+ aBC and EEC. Updated data will be presented at the meeting. Clinical trial information: NCT04188548 .
Publisher: BMJ
Date: 23-05-2023
Abstract: Our primary aim was to compare muscle morphology (skeletal muscle mass and density) between patients who underwent primary cytoreductive surgery versus interval cytoreductive surgery for advanced high-grade serous ovarian cancer. Secondarily, we explored the associations of muscle morphology with survival outcomes. We retrospectively analysed computed tomography (CT) images for 88 ovarian cancer patients (aged 38–89 years) to calculate skeletal muscle index (cm 2 /m 2 ) and skeletal muscle density (Hounsfield units (HU)). A skeletal muscle index of .5 cm 2 /m 2 and skeletal muscle density of .7 HU were classified as low. Analyses included repeated measures analysis of covariance and multivariable Cox proportional hazards regression. At baseline, 44.3% of patients had low skeletal muscle index and 50.6% had low skeletal muscle density, with interval surgery patients having significantly lower mean skeletal muscle density than primary surgery patients (32.2±8.9 vs 37.3±8.6 HU, p=0.014). Although both groups had similar reductions in skeletal muscle index following treatment (p=0.49), primary surgery patients had a greater reduction in skeletal muscle density compared with interval surgery patients (−2.4 HU, 95% CI −4.3 to −0.5, p=0.016). Patients who experienced skeletal muscle density loss % during treatment (HR 5.16, 95% CI 1.33 to 20.02) and had low skeletal muscle density post-treatment (HR 58.87, 95% CI 3.70 to 935.68) had significantly worse overall survival. Low skeletal muscle index and skeletal muscle density were prevalent at ovarian cancer diagnosis. While both groups experienced muscle mass loss, greater reductions in skeletal muscle density occurred in patients undergoing primary surgery. In addition, skeletal muscle density loss during treatment and low skeletal muscle density post-treatment were associated with poorer overall survival. Supportive care involving resistance exercise targeting muscle hypertrophic drive, and nutrition counseling during and after ovarian cancer treatment may help preserve/enhance muscle mass and density.
Publisher: Springer Netherlands
Date: 15-08-2013
Publisher: Informa UK Limited
Date: 09-02-2021
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-05-2021
DOI: 10.1200/JCO.2021.39.15_SUPPL.2583
Abstract: 2583 Background: Anti-programmed death 1 (PD-1) therapy has improved clinical outcomes for patients (pts) with advanced solid tumors but unmet needs remain. T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domains (TIGIT) is a co-inhibitory, immune checkpoint receptor. Ociperlimab (OCI BGB-A1217) is a novel, humanized, monoclonal antibody that binds to TIGIT with high affinity and specificity. OCI has demonstrated competent binding with C1q and all Fcγ receptors and induces antibody-dependent cellular cytotoxicity. Preclinical studies demonstrated dual targeting with OCI and tislelizumab (TIS), an anti-PD-1 antibody, produces synergistic immune cell activation and enhanced antitumor activity. Methods: AdvanTIG-105 is a phase 1, open label, multicenter, dose-escalation study (NCT04047862) that assessed the safety and preliminary antitumor activity of OCI plus TIS in pts with advanced, metastatic, unresectable solid tumors, for which standard therapy was ineffective or unavailable. Eligible pts had an Eastern Cooperative Oncology Group performance score ≤1 and no prior therapy targeting TIGIT. Pts received OCI intravenously (IV) on Day 1 of Cycle 1 and TIS 200 mg IV on Day 8. Pts were monitored for dose-limiting toxicities (DLTs) until Day 28. If tolerated, OCI and TIS were administered sequentially on Day 29 and every 3 weeks (Q3W) thereafter. Pts received escalating doses of OCI (50-900 mg) plus TIS 200 mg. The study objective was determination of recommended phase 2 dose (RP2D) of OCI plus TIS. Study endpoints included assessment of adverse events (AEs), pharmacokinetics and antitumor activity. Data cut-off was October 12 2020. Results: 24 pts with various advanced solid tumors received OCI plus TIS. At baseline, pts had undergone a median of 2 prior treatment regimens 9/24 (37.5%) pts had received prior immunotherapy. Median follow-up time was 17 weeks. No DLTs were observed. 20 pts had ≥1 treatment emergent AE (TEAE) and most TEAEs were grade ≤2 fatigue (6 pts) and diarrhea (4 pts) were most commonly reported. No pts had grade ≥4 TEAEs or TEAEs leading to death. There were 2 grade 3 immune related AEs (colitis and low cortisol). One pt on OCI 450 mg achieved partial response and 9 pts had stable disease. The longest duration of stable disease was 36 weeks (1 pt on OCI 150 mg). After administration, serum concentration of OCI decreased in a biphasic manner. Exposure to OCI increased proportionally with dose, and TIGIT receptor occupancy was sustained at ≥50 mg doses. Conclusions: OCI in combination with TIS was well tolerated across all doses in pts with advanced solid tumors. The RP2D was OCI 900 mg plus TIS 200 mg Q3W. Clinical trial information: NCT04047862.
Publisher: Elsevier BV
Date: 09-2019
Publisher: Elsevier BV
Date: 08-2019
DOI: 10.1016/J.YGYNO.2019.04.679
Abstract: There is a need to develop and validate biomarkers for treatment response and survival in tubo-ovarian high-grade serous carcinoma (HGSC). The chemotherapy response score (CRS) stratifies patients into complete/near-complete (CRS3), partial (CRS2), and no/minimal (CRS1) response after neoadjuvant chemotherapy (NACT). Our aim was to review current evidence to determine whether the CRS is prognostic in women with tubo-ovarian HGSC treated with NACT. We established an international collaboration to conduct a systematic review and meta-analysis, pooling in idual patient data from 16 sites in 11 countries. Patients had stage IIIC/IV HGSC, 3-4 NACT cycles and >6-months follow-up. Random effects models were used to derive combined odds ratios in the pooled population to investigate associations between CRS and progression free and overall survival (PFS and OS). 877 patients were included from published and unpublished studies. Median PFS and OS were 15 months (IQR 5-65) and 28 months (IQR 7-92) respectively. CRS3 was seen in 249 patients (28%). The pooled hazard ratios (HR) for PFS and OS for CRS3 versus CRS1/CRS2 were 0·55 (95% CI, 0·45-0·66 P < 0·001) and 0·65 (95% CI 0·50-0·85, P = 0·002) respectively no heterogeneity was identified (PFS: Q = 6·42, P = 0·698, I2 = 0·0% OS: Q = 6·89, P = 0·648, I2 = 0·0%). CRS was significantly associated with PFS and OS in multivariate models adjusting for age and stage. Of 306 patients with known germline BRCA1/2 status, those with BRCA1/2 mutations (n = 80) were more likely to achieve CRS3 (P = 0·027). CRS3 was significantly associated with improved PFS and OS compared to CRS1/2. This validation of CRS in a real-world setting demonstrates it to be a robust and reproducible biomarker with potential to be incorporated into therapeutic decision-making and clinical trial design.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 10-02-2018
DOI: 10.1200/JCO.2018.36.5_SUPPL.48
Abstract: 48 Background: The release of tumor-associated antigens may enhance the response to immunotherapy. BGB-A317, a humanized IgG4 variant monoclonal antibody engineered to have no Fc gamma receptor binding, targets the programmed cell death-1 (PD-1) receptor. It is being developed in solid and hematologic malignancies at a dose of 200 mg IV Q3W. BGB-290, a potent inhibitor of PARP 1/2, is hypothesized to promote neoantigen release that may potentially increase the efficacy of BGB-A317. A phase 1 study identified 60 mg BID as the recommended Phase 2 dose (RP2D) for BGB-290. This study consists of initial dose escalation to determine the maximum-tolerated dose (MTD), safety, pharmacokinetic (PK) profile, and preliminary antitumor activity of the combination, followed by expansion into ovarian, breast, prostate, gastric, bladder, pancreatic and small cell lung cancers. Methods: Cohorts of 6–12 patients with advanced solid tumors were treated in each of 5 planned dose levels (DLs). In DLs 1–3, BGB-290 doses ranged between 20–60 mg PO BID with BGB-A317 2 mg/kg IV Q3W. In DLs 4–5, BGB-290 doses were 40 or 60 mg BID A317 was given at 200 mg IV Q3W based on PK data from a single agent Phase 1 study. Results: As of 31 March 2017, 43 patients [median age 63 years (34–75)] were treated in DLs 1–5. Three patients experienced four dose-limiting toxicities: grade 2 nausea (DL4), grade 2 nausea and grade 2 vomiting (DL5), and grade 4 autoimmune hepatitis (DL5). MTD was identified as BGB-A317 200 mg IV Q3W + BGB-290 40 mg PO BID. The most common adverse event (AE) considered related to both study drugs was fatigue. Immune-related AEs of Grade ≥3 were elevated alanine aminotransferase/aspartate aminotransferase (n = 3), autoimmune hepatitis (n = 3), and hepatitis (n = 1). Complete or partial response was observed in 11 patients, 4 of whom had confirmed PR or CR. Plasma/serum exposure of BGB-290 and BGB-A317 were consistent with those in single-agent trials. Conclusions: The combination of BGB-A317 and BGB-290 was generally well tolerated in patients with advanced solid tumors. These results support the continuation of this trial with enrollment into the disease-specific cohorts. Clinical trial information: NCT02660034.
Publisher: Impact Journals, LLC
Date: 03-11-2020
Publisher: Wiley
Date: 28-06-2022
DOI: 10.1111/AJCO.13622
Abstract: Participation in early‐phase clinical trials has become a prominent part of medical oncology patient management. We examined the incidence and pattern of hospitalizations in early‐phase clinical trial patients and the associated clinical outcomes. We conducted a retrospective review of 194 patients with solid tumors treated on phase I clinical trials between July 2014 and October 2018 at a phase I trial unit. Unplanned hospitalizations occurring during the study period were characterized and correlated with treatment response and duration of trial participation. Among 194 patients, 104 hospitalizations were recorded involving 62 patients (31%). Nineteen percent of patients were hospitalized for cancer‐related complications and 8% for treatment toxicity. No significant correlation was seen between the hospitalization and age, sex, tumor type, or trial drug. Best response to trial therapy was complete response, partial response, stable disease, and progressive disease in 5%, 11%, 37%, and 47% of patients, respectively. Median duration on trial was 86 days (range 0–1,412). Twenty‐two patients (11%) remained on trial for more than 12 months. Overall, hospitalization did not impact treatment response or trial duration. However, cancer‐related hospitalization was associated with significantly lower response ( p 0.001) and early patient attrition ( p 0.001). Resolution of the hospitalization event was associated with improved response ( p = 0.002) and longer duration on trial ( p 0.001). The treatment related mortality was 0.5% ( n = 1). Approximately one third of patients required hospitalization, most commonly for cancer‐related complications which correlated with poorer clinical outcomes. Hospitalizations related to treatment toxicity were infrequent. A significant proportion of patients derived significant therapeutic benefit. Phase I clinical trials provide a valuable treatment option for patients with cancer.
Publisher: Impact Journals, LLC
Date: 27-06-2017
Publisher: Elsevier BV
Date: 03-2016
DOI: 10.1016/J.LUNGCAN.2015.12.006
Abstract: The immune effects of EGFR tyrosine kinase inhibitors (EGFR-TKIs) are poorly understood. Identifying immune biomarkers could guide patient selection and optimisation of EGFR-TKI-immunotherapy combinations. 33 patients with NSCLC treated with an EGFR-TKI were prospectively enrolled. Peripheral blood mononuclear cells were collected pre-treatment, and after 1, 3 and 8 weeks. Flow cytometry was used to identify immune cell subsets, including PD-1 and PD-L1 expressing T cells. Immune parameters were correlated with clinical outcomes. Compared to healthy donors (n=10), patients had higher pre-treatment proportions of proliferating and PD-L1(+)CD3(+) T cells (p<0.001). Compared to patients with an EGFR mutation (n=12), patients without a known mutation (n=21) had higher proportions of proliferating CD4(+) and PD-L1(+)CD3(+) T cells (p=0.03). There was a significant increase in PD-L1(+) T cells after 1 week of EGFR-TKI in patients whose disease progressed compared to non-progressors. Patients with higher PD-L1(+)CD3(+) T cells at 1-week were more likely to progress (OR 30.3, p<0.01) and had shorter PFS (1.6 vs. 8.8m p<0.01) and OS (3.8 vs 23.2m p<0.001) than those with fewer PD-L1(+)CD3(+) T cells. On multivariate analysis, high PD-L1(+)CD3(+) T cells was the only independent predictor for PFS (HR 3.7, p=0.01), while for OS independent predictors were high PD-L1(+)CD3(+) T cells (HR 6.5, p<0.01) and EGFR-negative status (HR 3.3, p=0.04). There was a significant correlation between PD-L1 expression on peripheral T cells and clinical outcomes in EGFR-TKI-treated NSCLC. This warrants further validation as a blood-based biomarker that may identify candidates for PD-1 inhibitors or immunotherapy-EGFR-TKI combinations.
Publisher: Wiley
Date: 24-03-2014
DOI: 10.1111/RESP.12263_8
Publisher: Springer Netherlands
Date: 2013
Publisher: American Association for Cancer Research (AACR)
Date: 07-2021
DOI: 10.1158/1538-7445.AM2021-LB041
Abstract: THOR-707 (SAR444245) is a recombinant human IL-2 molecule that includes a PEG moiety irreversibly bound to a novel amino acid via click chemistry to block the alpha-binding domain while retaining near-native affinity for the beta/gamma subunits. In animal models, THOR-707 improved the anti-tumor benefits of aldesleukin, but without its severe side effects, both as single agent and combined with anti-PD1. Here we report safety, PK/PD, and preliminary anti-tumor activity for THOR-707 as monotherapy and combined with pembrolizumab in the ongoing HAMMER Phase 1/2 trial. THOR-707 was administered via IV infusion as monotherapy Q2W (Cohort A), Q3W (Cohort B), or combined with pembrolizumab 200 mg IV Q3W (Cohort C) escalation follows a 3 + 3 schema to identify the maximum tolerated dose and/or the recommended Phase 2 dose. As of 16 November 2020, 28 pts were enrolled: ECOG 0-1 median age 62 (37-76) yrs median lines of prior therapies were 3 (1-9 11 pts had prior anti-PD1). Most common tumor types: colorectal (n=5), melanoma (n=4). Cohort enrollment was A: 8 µg/kg (n=4) B: 8 µg/kg (n=4), 16 µg/kg (n=6), 24 µg/kg (n=7) C: 8 µg/kg (n=4), 16 µg/kg (n=3). No dose-limiting toxicity (DLT) or vascular leak syndrome (VLS) was observed. Most common treatment-emergent adverse events (TEAEs) were flu-like symptoms (46.4%), fever (46.4%), vomiting/nausea (35.7%), chills (32.1%), following the first dose and resolved with standard supportive care. No cumulative toxicity, end organ toxicity, QTc prolongation, or other cardiac toxicity was observed. Grade (G) 3-4 related toxicities in B: 1 G3 rash (8 µg/kg) 1 G4 AST increase, 2 G3 increase in AST/ALT & 1 G4 decrease in lymphocytes (16 µg/kg) 2 G4 decrease in lymphocytes, 1 G4 CRS with G3 hypertension (led to discontinuation), and 1 G3 acute kidney injury (24 µg/kg) C: 1 G3 & 1G4 decrease in lymphocytes (16 µg/kg). CD8 cells (effector & memory) and NK cells increased in Cycle 1 by a median (range) respectively of 3.1 (1.04 - 5.91) and 7.93 (1.71 - 26.85) fold and were sustained until next cycle. There was no meaningful increase in CD4 Tregs or eosinophil counts (a marker of potential VLS), 1.89 (0.86- 5.36) and 1.77 (0.47- 3.65) fold. No anti-drug antibodies (IL-2 or PEG) and no meaningful IL-5 elevations were found. One IL-6 increase at 24 hrs (to 1,000 pg/mL) was observed. Half-life is ~ 10 hours. Three pts have confirmed partial responses: 1 PD-1-naïve basal cell carcinoma 1 head & neck squamous cell carcinoma with progression after a prior anti-PD-1, ongoing for 9+ mos in C (8 µg/kg) 1 squamous cellular carcinoma of unknown origin, unresponsive to prior anti-PD-1, ongoing for 3+ mos in B (24 µg/kg). Two pts had stable disease for 9 and 6 mos, respectively, with pancreatic (in A, 8 µg/kg) and prostate cancer (in B, 16 µg/kg) 11 pts remained on treatment for ≥5 cycles. Preliminary encouraging results with THOR-707 monotherapy and in combination with pembrolizumab support IL-2 not-alpha preferential activity, validating preclinical models, with initial efficacy and a tolerable safety profile. Dose escalation continues. NCT04009681 Citation Format: Filip Janku, Raghad Abdul-Karim, Arun Azad, Johanna Bendell, Gerald Falchook, Hui K. Gan, Tira Tan, Judy S. Wang, Cheng Ean CHEE, Lina Ma, Jill Mooney, Neyssa Marina, Giovanni Abbadessa, Marcos Milla, Tarek Meniawy. THOR-707 (SAR444245), a novel not-alpha IL-2 as monotherapy and in combination with pembrolizumab in advanced/metastatic solid tumors: Interim results from HAMMER, an open-label, multicenter phase 1/2 Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR Cancer Res 2021 (13_Suppl):Abstract nr LB041.
Publisher: Elsevier BV
Date: 09-2021
Publisher: BMJ
Date: 18-07-2014
Publisher: American Association for Cancer Research (AACR)
Date: 13-11-2020
DOI: 10.1158/1078-0432.CCR-20-2251
Abstract: We evaluated the predictive value of pretreatment ctDNA to inform therapeutic outcomes in patients with metastatic melanoma relative to type and line of treatment. Plasma circulating tumor DNA (ctDNA) was quantified in 125 s les collected from 110 patients prior to commencing treatment with immune checkpoint inhibitors (ICIs), as first- (n = 32) or second-line (n = 27) regimens, or prior to commencing first-line BRAF/MEK inhibitor therapy (n = 66). An external validation cohort included 128 patients commencing ICI therapies in the first- (N = 77) or second-line (N = 51) settings. In the discovery cohort, low ctDNA (≤20 copies/mL) prior to commencing therapy predicted longer progression-free survival (PFS) in patients treated with first-line ICIs [HR, 0.20 95% confidence interval (CI) 0.07–0.53 P & 0.0001], but not in the second-line setting. An independent cohort validated that ctDNA is predictive of PFS in the first-line setting (HR, 0.42 95% CI, 0.22–0.83 P = 0.006), but not in the second-line ICI setting. Moreover, ctDNA prior to commencing ICI treatment was not predictive of PFS for patients pretreated with BRAF/MEK inhibitors in either the discovery or validation cohorts. Reduced PFS and overall survival were observed in patients with high ctDNA receiving anti–PD-1 monotherapy, relative to those treated with combination anti–CTLA-4/anti–PD-1 inhibitors. Pretreatment ctDNA is a reliable indicator of patient outcome in the first-line ICI treatment setting, but not in the second-line ICI setting, especially in patients pretreated with BRAF/MEK inhibitors. Preliminary evidence indicated that treatment-naïve patients with high ctDNA may preferentially benefit from combined ICIs.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 26-01-2018
Abstract: Until the past century or so, the movement of wild animals was relatively unrestricted, and their travels contributed substantially to ecological processes. As humans have increasingly altered natural habitats, natural animal movements have been restricted. Tucker et al. examined GPS locations for more than 50 species. In general, animal movements were shorter in areas with high human impact, likely owing to changed behaviors and physical limitations. Besides affecting the species themselves, such changes could have wider effects by limiting the movement of nutrients and altering ecological interactions. Science , this issue p. 466
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6529724
Abstract: AbstractPurpose: We evaluated the predictive value of pretreatment ctDNA to inform therapeutic outcomes in patients with metastatic melanoma relative to type and line of treatment. Experimental Design: Plasma circulating tumor DNA (ctDNA) was quantified in 125 s les collected from 110 patients prior to commencing treatment with immune checkpoint inhibitors (ICIs), as first- ( i n /i = 32) or second-line ( i n /i = 27) regimens, or prior to commencing first-line BRAF/MEK inhibitor therapy ( i n /i = 66). An external validation cohort included 128 patients commencing ICI therapies in the first- ( i N /i = 77) or second-line ( i N /i = 51) settings. Results: In the discovery cohort, low ctDNA (≤20 copies/mL) prior to commencing therapy predicted longer progression-free survival (PFS) in patients treated with first-line ICIs [HR, 0.20 95% confidence interval (CI) 0.07–0.53 i P /i 0.0001], but not in the second-line setting. An independent cohort validated that ctDNA is predictive of PFS in the first-line setting (HR, 0.42 95% CI, 0.22–0.83 i P /i = 0.006), but not in the second-line ICI setting. Moreover, ctDNA prior to commencing ICI treatment was not predictive of PFS for patients pretreated with BRAF/MEK inhibitors in either the discovery or validation cohorts. Reduced PFS and overall survival were observed in patients with high ctDNA receiving anti–PD-1 monotherapy, relative to those treated with combination anti–CTLA-4/anti–PD-1 inhibitors. Conclusions: Pretreatment ctDNA is a reliable indicator of patient outcome in the first-line ICI treatment setting, but not in the second-line ICI setting, especially in patients pretreated with BRAF/MEK inhibitors. Preliminary evidence indicated that treatment-naïve patients with high ctDNA may preferentially benefit from combined ICIs. /
Publisher: Elsevier BV
Date: 09-2022
Publisher: Elsevier BV
Date: 10-2018
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-05-2017
DOI: 10.1200/JCO.2017.35.15_SUPPL.3013
Abstract: 3013 Background: The release of tumor-associated antigens may enhance the response to immunotherapy. BGB-A317, a humanized IgG4 variant monoclonal antibody engineered to have no Fc gamma receptor binding, targets the programmed cell death-1 (PD-1) receptor. It is being developed in solid and hematologic malignancies at a dose of 200 mg IV Q3W. BGB-290, a potent inhibitor of PARP 1/2, is hypothesized to promote neoantigen release that will potentially increase the efficacy of BGB-A317. A phase 1 study identified 60mg BID as the recommended Phase 2 dose (RP2D) for BGB-290. This study consists of initial dose escalation to determine the maximum-tolerated dose (MTD), safety, PK profile, and preliminary anti-tumor activity of the combination, followed by expansion into ovarian, breast, prostate, gastric, bladder, pancreatic and small cell lung cancers. Methods: Cohorts of 6 -12 pts with advanced solid tumors were treated in each of 5 planned dose levels (DLs). In DLs 1-3, BGB-290 doses ranged between 20-60mg PO BID with BGB-A317 2mg/kg IV Q3W. In DLs 4 - 5, BGB-290 doses were 40 or 60 mg BID A317 was given at 200 mg IV Q3W based on PK data from a single agent Phase 1 study. Results: As of 16 Jan 2017, 38 pts [median age 59 years (34-75)] were treated in DLs 1-4 enrollment to DL5 is ongoing. One DLT of persistent Gr 2 nausea was reported in DL 4. The most common adverse event (AE) considered related to both study drugs was fatigue (10.5%). Immune-related AEs were Gr 3 hypophysitis (n = 1), Gr 3 or 4 autoimmune hepatitis(n = 2), and Gr 2 elevated AST/ALT (n = 1). Decreases in tumor burden have been observed in 16 pts 7 achieved a PR (5 with ovarian and one each with uterine and pancreatic cancer) and one CR was observed in ovarian cancer. Six pts had SD for 6 months including 2 pts with pancreatic cancer who received BGB-A317+BGB-290 for 189 and 281 days. Plasma/serum exposure of BGB-290 and BGB-A317 were consistent with those in single-agent trials. Conclusions: BGB290 and BGB-A317 can be combined. Dose expansion in multiple tumor types is planned to commence in 2017 once the RP2D is determined. Clinical trial information: NCT02660034.
Publisher: SAGE Publications
Date: 2021
DOI: 10.1177/15347354211040757
Abstract: Although exercise medicine is recommended to counter treatment-related side-effects and improve health-related outcomes of patients affected by different cancers, no specific recommendations exist for patients with melanoma. As a result, we systematically examined the current evidence regarding the effects of physical activity and exercise on objectively-measured and patient-reported outcomes among patients with melanoma. Searches were conducted in PubMed, CINAHL, EMBASE, SPORTDiscus, and Web of Science databases. This review included published data involving physical activity or exercise and objectively-measured or patient-reported outcomes of patients with cutaneous melanoma. The quality of included studies was assessed using the McMaster University Critical Appraisal Tool for Quantitative Studies. Six studies including 882 patients with melanoma were included. Studies presented heterogeneity of design with 2 cross-sectional surveys, 2 retrospective analyses, and 2 non-randomized intervention trials. No statistically significant change in quality of life, fatigue, physical function, cardiorespiratory fitness, body composition, psychological distress, cognitive function, or treatment-related side-effects were attributable to physical activity or exercise. Importantly, physical activity or exercise during melanoma treatment or into survivorship did not adversely impact patients/survivors. In summary, physical activity or exercise did not adversely impact quality of life, objectively-measured or patient-reported outcomes in patients with melanoma. In addition, there is a paucity of quality studies examining the effects of physical activity or exercise on patients with melanoma throughout the cancer care continuum.
Publisher: Springer Science and Business Media LLC
Date: 08-04-2014
DOI: 10.1038/BJC.2014.187
Publisher: BMJ
Date: 22-09-2022
Abstract: Physical symptoms, anxiety, depression, fear of recurrence, sexual dysfunction, and social withdrawal are common in women after treatment for ovarian cancer. Most patients would like and need help dealing with these symptoms. The traditional model of follow-up care is unstructured and largely focused on diagnosing recurrent disease, and most oncologists lack skills to identify and manage psychosocial issues. No high quality prospective clinical trials have been conducted to determine the optimal follow-up regimen or the cost effectiveness of ovarian cancer surveillance strategies. To assess emotional wellbeing, acceptability, safety, and cost effectiveness of nurse led follow-up via telehealth for women with ovarian cancer following completion of primary treatment. We hypothesize that compared with routine clinic based follow-up, nurse led follow-up via telehealth, including serum CA125 monitoring and completion of a patient reported outcome instrument, the Measure of Ovarian Symptoms and Treatment concerns-Surveillance (MOST-S26), will improve emotional wellbeing in women with ovarian cancer be feasible, safe, acceptable, and not delay the time to diagnosis of recurrent disease will result in greater patient satisfaction will identify more patients with psychological distress, lead to better care, and improved psychological outcomes and be cost-effective. Phase II multicenter randomized trial comparing 3 monthly nurse led telehealth consultations that include serum CA125 monitoring and completion of the MOST-S26, with routine clinic based follow-up. The allocation ratio will be 1:1. Eligible patients will be women with high grade epithelial ovarian cancer who have normalized serum CA125 (to kU/L) at completion of first line chemotherapy. Emotional wellbeing at 12 months. 150 patients. July 2023. Results expected in 2025, 24 months after the last participant is enrolled. ACTRN12620000332921
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22477679
Abstract: Tables S1-S8 and Figures S1-S4
Publisher: Wiley
Date: 07-12-2019
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-05-2017
DOI: 10.1200/JCO.2017.35.15_SUPPL.104
Abstract: 104 Background: BMS-986156 is a fully human IgG1 agonist mAb that binds GITR and promotes T effector cell activation and possible reduction/inactivation of T regulatory cells. Preclinical data show enhanced antitumor T-cell activity with anti-GITR + anti–programmed death-1 (PD-1). Here we describe preliminary dose escalation data from a phase I/IIa study of BMS-986156 ± nivolumab (anti–PD-1 mAb) in pts with advanced solid tumors (NCT02598960). Methods: During dose escalation, pts received BMS-986156 (10–800 mg) or BMS-986156 (30–800 mg) + nivolumab (240 mg) every 2 weeks. Objectives included safety (primary), immunogenicity, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy. Results: As of Dec 12, 2016, 66 pts were treated with BMS-986156 (n = 29) or BMS-986156 + nivolumab (n = 37).No dose-limiting toxicities (DLTs) were reported during dose escalation. The most common treatment-related adverse events reported with BMS-986156/BMS-986156 + nivolumab included pyrexia (21%/30%), chills (10%/16%), and fatigue (14%/14%) events were G1/2 in all pts except for 4 pts (6%) treated with the combination (G3 lipase [n = 1], G3 lung infection [n = 1], G3 fatigue [n = 1], and G3 aspartate aminotransferase with G4 creatine phosphokinase [n = 1 leading to discontinuation of treatment]). Preliminary data indicate that the incidence of immunogenicity to BMS-986156 was low when BMS-986156 ± nivolumab was administered. Preliminary data also indicate that BMS-986156 ± nivolumab exhibits linear PK with dose proportionality after a single dose, and BMS-986156 ± nivolumab is biologically active in PD analyses in peripheral blood. Initial antitumor activity has been observed in several pts treated with the combination these data will be reported. Conclusions: This is the first report of clinical data with an anti-GITR mAb ± a PD-1 inhibitor.BMS-986156 ± nivolumab was well tolerated, with no DLTs and low immunogenicity. Antitumor activity was observed with BMS-986156 + nivolumab at doses predicted to be biologically active. Further evaluation of this combination in pts with advanced solid tumors is ongoing. Clinical trial information: NCT02598960.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6529724.V1
Abstract: AbstractPurpose: We evaluated the predictive value of pretreatment ctDNA to inform therapeutic outcomes in patients with metastatic melanoma relative to type and line of treatment. Experimental Design: Plasma circulating tumor DNA (ctDNA) was quantified in 125 s les collected from 110 patients prior to commencing treatment with immune checkpoint inhibitors (ICIs), as first- ( i n /i = 32) or second-line ( i n /i = 27) regimens, or prior to commencing first-line BRAF/MEK inhibitor therapy ( i n /i = 66). An external validation cohort included 128 patients commencing ICI therapies in the first- ( i N /i = 77) or second-line ( i N /i = 51) settings. Results: In the discovery cohort, low ctDNA (≤20 copies/mL) prior to commencing therapy predicted longer progression-free survival (PFS) in patients treated with first-line ICIs [HR, 0.20 95% confidence interval (CI) 0.07–0.53 i P /i 0.0001], but not in the second-line setting. An independent cohort validated that ctDNA is predictive of PFS in the first-line setting (HR, 0.42 95% CI, 0.22–0.83 i P /i = 0.006), but not in the second-line ICI setting. Moreover, ctDNA prior to commencing ICI treatment was not predictive of PFS for patients pretreated with BRAF/MEK inhibitors in either the discovery or validation cohorts. Reduced PFS and overall survival were observed in patients with high ctDNA receiving anti–PD-1 monotherapy, relative to those treated with combination anti–CTLA-4/anti–PD-1 inhibitors. Conclusions: Pretreatment ctDNA is a reliable indicator of patient outcome in the first-line ICI treatment setting, but not in the second-line ICI setting, especially in patients pretreated with BRAF/MEK inhibitors. Preliminary evidence indicated that treatment-naïve patients with high ctDNA may preferentially benefit from combined ICIs. /
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-05-2021
DOI: 10.1200/JCO.2021.39.15_SUPPL.E21512
Abstract: e21512 Background: Anti-PD-1 therapy has improved the outcome of advanced melanoma patients with a 5-year survival rate of about 40-45%. However, biomarkers predictive of response to immune checkpoint blockade therapy are lacking. There is limited data on the utility of host germline human leucocyte antigen (HLA) genotype as a predictor of response to anti-PD-1 therapy in advanced melanoma. Here, we investigate the prognostic value of HLA in predicting survival outcomes of patients with unresectable locally advanced, metastatic melanoma on anti-PD-1 therapy. Methods: Blood was collected from 113 metastatic melanoma patients who were treated with anti-PD-1 therapy at two major oncology centres in Western Australia. High quality DNA was extracted from white blood cells and subsequently HLA-I and HLA-II typed using clinically validated assay. Univariate analyses were conducted using Cox regression model correlating homozygosity at HLA-I and HLA-II loci with overall survival (OS). HLA-A and HLA-B were classified into 12 supertypes and correlated with OS. Multivariate analyses were performed while controlling for age, gender, prior therapy, BRAF mutation status, ECOG performance status and presence of liver and brain metastases. Results: Homozygosity at HLA-I or HLA-II loci was not associated with OS. However, the absence of HLA-B62 supertype was associated with a trend towards improved OS (HR: 0.53 [95% CI:0.25-1.10] P = 0.09) as reported previously. Notably, the absence of HLA-B27 supertype was associated with improved OS which was statistically significant (HR: 0.45 [95% CI:0.24-0.85] P = 0.01). In multivariate analyses, the prognostic value of HLA-B27 supertype (HR: 0.38 [95% CI:0.19-0.76] P = 0.006) was maintained, whereas the prognostic value of HLA-B62 supertype significantly improved (HR: 0.42 [95% CI:0.19-0.94] P = 0.03). Conclusions: Our results suggest a limited role of HLA homozygosity in predicting survival of melanoma patients treated with anti-PD-1 therapy. However, we identified that the absence of HLA-B62 and HLA-B27 supertype is associated with improved survival benefit. Therefore, HLA-B27 and HLA-B62 supertype may be used as adjunct biomarkers of response to anti-PD-1 therapy in patients with melanoma in addition to PD-L1 status, pending validation in prospective randomised clinical trials.
Publisher: MDPI AG
Date: 16-12-2020
Abstract: In this study, we evaluated the predictive value of circulating tumour DNA (ctDNA) to inform therapeutic outcomes in metastatic melanoma patients receiving systemic therapies. We analysed 142 plasma s les from metastatic melanoma patients prior to commencement of systemic therapy: 70 were treated with BRAF/MEK inhibitors and 72 with immunotherapies. Patient-specific droplet digital polymerase chain reaction assays were designed for ctDNA detection. Plasma ctDNA was detected in 56% of patients prior to first-line anti-PD1 and/or anti-CTLA-4 treatment. The detection rate in the immunotherapy cohort was comparably lower than those with BRAF inhibitors (76%, p = 0.0149). Decreasing ctDNA levels within 12 weeks of treatment was strongly concordant with treatment response (Cohen’s k = 0.798, p 0.001) and predictive of longer progression free survival. Notably, a slower kinetic of ctDNA decline was observed in patients treated with immunotherapy compared to those on BRAF/MEK inhibitors. Whole exome sequencing of ctDNA was also conducted in 9 patients commencing anti-PD-1 therapy to derive tumour mutational burden (TMB) and neoepitope load measurements. The results showed a trend of high TMB and neoepitope load in responders compared to non-responders. Overall, our data suggest that changes in ctDNA can serve as an early indicator of outcomes in metastatic melanoma patients treated with systemic therapies and therefore may serve as a tool to guide treatment decisions.
Publisher: Springer Science and Business Media LLC
Date: 09-08-2021
DOI: 10.1038/S41416-021-01507-6
Abstract: The validity of circulating tumour DNA (ctDNA) as an indicator of disease progression compared to medical imaging in patients with metastatic melanoma requires detailed evaluation. Here, we carried out a retrospective ctDNA analysis of 108 plasma s les collected at the time of disease progression. We also analysed a validation cohort of 66 metastatic melanoma patients monitored prospectively after response to systemic therapy. ctDNA was detected in 62% of patients at the time of disease progression. For 67 patients that responded to treatment, the mean ctDNA level at progressive disease was significantly higher than at the time of response ( P 0.0001). However, only 30 of these 67 (45%) patients had a statistically significant increase in ctDNA by Poisson test. A validation cohort of 66 metastatic melanoma patients monitored prospectively indicated a 56% detection rate of ctDNA at progression, with only two cases showing increased ctDNA prior to radiological progression. Finally, a correlation between ctDNA levels and metabolic tumour burden was only observed in treatment naïve patients but not at the time of progression in a subgroup of patients failing BRAF inhibition ( N = 15). These results highlight the low efficacy of ctDNA to detect disease progression in melanoma when compared mainly to standard positron emission tomography imaging.
Publisher: Wiley
Date: 15-05-2023
DOI: 10.1002/CAM4.6091
Abstract: To determine the feasibility, safety and preliminary efficacy of a telehealth supervised exercise programme in patients with advanced melanoma receiving checkpoint inhibitor therapy. A 8‐week non‐randomised feasibility pilot trial utilising a telehealth delivered multimodal exercise programme undertaken thrice weekly with assessments at baseline and post‐intervention. The study was considered feasible if there were no severe or life‐threatening adverse events as a result of exercise, and three or more of the following criteria were met: the recruitment rate was %, completion rate was %, median programme attendance was %, median exercise compliance %, and average tolerance was %. Preliminary efficacy was assessed for objective measures of physical function (2‐min step test, repeated chair stand test, 30‐s push‐up test, and a modified static balance test) and quality of life (QoL), fatigue and other patient‐reported outcomes were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30. Eleven patients (32–80 years) were included in the study (6 female, 5 male). The recruitment rate was 48%, completion rate 91%, programme attendance 88%, median exercise compliance 82.1% and 84.9% for resistance and aerobic exercise, respectively, and tolerance 88%, with no severe or life‐threatening adverse events as a result of exercise. In terms of preliminary efficacy, physical function significantly improved while QoL was maintained following the intervention. An 8‐week telehealth exercise intervention is feasible and safe for patients with advanced melanoma and appears to improve physical function while preserving QoL during checkpoint inhibitor therapy.
Publisher: Springer Science and Business Media LLC
Date: 20-07-2023
DOI: 10.1038/S41416-023-02349-0
Abstract: The aim of this study was to investigate the antitumour activity, safety, and tolerability of pamiparib plus tislelizumab in patients with previously treated advanced solid tumours. In this study, patients were enrolled into eight arms by tumour type. All received pamiparib 40 mg orally twice daily plus tislelizumab 200 mg intravenously every 3 weeks. The primary endpoint was objective response rate (ORR), assessed by the investigator per Response Evaluation Criteria in Solid Tumours v1.1. Secondary endpoints included duration of response (DoR), safety, and tolerability. Overall, 180 patients were enrolled. In the overall population, the ORR was 20.0% (range: 0–47.4 across study arms), with median DoR of 17.1 months (95% confidence interval [CI]: 6.2, not estimable [NE]). The highest ORR was observed in the triple-negative breast cancer (TNBC) arm (patients with BRCA 1/2 mutations and/or homologous recombination deficiency) (ORR: 47.4% median DoR: 17.1 months [95% CI: 3.0, NE]). Treatment-emergent adverse events (TEAEs) of ≥Grade 3 occurred in 61.7% of patients. Serious TEAEs occurred in 50.0% of patients. Pamiparib plus tislelizumab showed a variable level of antitumour activity in patients with advanced solid tumours, with the highest ORR in TNBC and was associated with a manageable safety profile. ClinicalTrial.gov: NCT02660034.
Publisher: BMJ
Date: 05-2017
DOI: 10.1097/IGC.0000000000000945
Abstract: Our objective was to validate the prognostic role of the chemotherapy response score (CRS), which has been proposed for measuring tumor response to neoadjuvant chemotherapy in patients with high-grade serous tubo-ovarian carcinoma, in predicting progression-free survival (PFS) and overall survival (OS). A retrospective cohort study was conducted of patients with advanced high-grade serous tubo-ovarian carcinoma diagnosed between January 1, 2010, and December 31, 2014, and treated with neoadjuvant chemotherapy. Treatment-related tumor regression was determined according to the 3-tier CRS, and results were compared with standard clinicopathological variables. Survival analysis was performed using Cox proportional hazards models and the log-rank test. Seventy-one patients were eligible for analysis. Median OS was 25.5 months. Fifty-eight patients (82%) had disease recurrence and 32 (45%) had died at study census. Of the 71 patients, 19, 29, and 23 patients had a CRS of 1, 2, and 3, respectively. On univariate analysis, the CRS significantly predicted PFS (hazard ratio [HR], 3.77 95% confidence interval [CI], 1.83–7.78 P = 0.000) and OS (HR, 2.81 95% CI, 1.16–6.79 P = 0.022). In a multivariate model, the CRS was significantly associated with PFS (HR, 2.81 95% CI, 1.16–6.79 P = 0.022) but not with OS (HR, 2.39 95% CI, 0.47–3.08 P = 0.079). Patients with CRS of 1 and 2 combined were twice as likely to progress during the study period compared with patients with a CRS of 3 (HR, 2.0 95% CI, 1.06–3.78 P = 0.032 median PFS, 16 vs 26 months). No significant association was observed for OS (CRS 1/2 vs 3 HR, 1.57 95% CI, 0.68–3.65 P = 0.291). In this study, the CRS showed independent prognostic significance for PFS but not for OS.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-05-2016
Publisher: BMJ
Date: 09-2018
Publisher: Wiley
Date: 09-05-2022
DOI: 10.1111/GEB.13523
Abstract: Macroecological studies that require habitat suitability data for many species often derive this information from expert opinion. However, expert‐based information is inherently subjective and thus prone to errors. The increasing availability of GPS tracking data offers opportunities to evaluate and supplement expert‐based information with detailed empirical evidence. Here, we compared expert‐based habitat suitability information from the International Union for Conservation of Nature (IUCN) with habitat suitability information derived from GPS‐tracking data of 1,498 in iduals from 49 mammal species. Worldwide. 1998–2021. Forty‐nine terrestrial mammal species. Using GPS data, we estimated two measures of habitat suitability for each in idual animal: proportional habitat use (proportion of GPS locations within a habitat type), and selection ratio (habitat use relative to its availability). For each in idual we then evaluated whether the GPS‐based habitat suitability measures were in agreement with the IUCN data. To that end, we calculated the probability that the ranking of empirical habitat suitability measures was in agreement with IUCN's classification into suitable, marginal and unsuitable habitat types. IUCN habitat suitability data were in accordance with the GPS data ( 95% probability of agreement) for 33 out of 49 species based on proportional habitat use estimates and for 25 out of 49 species based on selection ratios. In addition, 37 and 34 species had a 50% probability of agreement based on proportional habitat use and selection ratios, respectively. We show how GPS‐tracking data can be used to evaluate IUCN habitat suitability data. Our findings indicate that for the majority of species included in this study, it is appropriate to use IUCN habitat suitability data in macroecological studies. Furthermore, we show that GPS‐tracking data can be used to identify and prioritize species and habitat types for re‐evaluation of IUCN habitat suitability data.
Publisher: Elsevier BV
Date: 09-2020
Publisher: BMJ
Date: 11-2016
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-05-2016
Publisher: Elsevier BV
Date: 04-2021
Publisher: Springer Science and Business Media LLC
Date: 09-07-2018
Publisher: Oxford University Press (OUP)
Date: 05-12-2019
DOI: 10.1634/THEONCOLOGIST.2019-0557
Abstract: PD-1 inhibitors are routinely used for the treatment of advanced melanoma. This study sought to determine whether PD-L1 expression on circulating tumor cells (CTCs) can serve as a predictive biomarker of clinical benefit and response to treatment with the PD-1 inhibitor pembrolizumab. Blood s les were collected from patients with metastatic melanoma receiving pembrolizumab, prior to treatment and 6–12 weeks after initiation of therapy. Multiparametric flow cytometry was used to identify CTCs and evaluate the expression of PD-L1. CTCs were detected in 25 of 40 patients (63%). Patients with detectable PD-L1+ CTCs (14/25, 64%) had significantly longer progression-free survival (PFS) compared with patients with PD-L1− CTCs (26.6 months vs. 5.5 months p = .018). The 12-month PFS rates were 76% versus 22% in the PD-L1+ versus PD-L1− CTCs groups (p = .012), respectively. A multivariate linear regression analysis confirmed that PD-L1+ CTC is an independent predictive biomarker of PFS (hazard ratio, 0.229 95% confidence interval, 0.052–1.012 p = .026). Our results reveal the potential of CTCs as a noninvasive real-time biopsy to evaluate PD-L1 expression in patients with melanoma. PD-L1 expression on CTCs may be predictive of response to pembrolizumab and longer PFS.
Publisher: Impact Journals, LLC
Date: 22-09-2015
Publisher: Elsevier BV
Date: 2020
DOI: 10.1016/J.CANLET.2019.10.014
Abstract: Liquid biopsies hold the potential to inform cancer patient prognosis and to guide treatment decisions at the time when direct tumor biopsy may be impractical due to its invasive nature, inaccessibility and associated complications. Specifically, circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) have shown promising results as companion diagnostic biomarkers for screening, prognostication and/or patient surveillance in many cancer types. In ovarian cancer (OC), CTC and ctDNA analysis allow comprehensive molecular profiling of the primary, metastatic and recurrent tumors. These biomarkers also correlate with overall tumor burden and thus, they provide minimally-invasive means for patient monitoring during clinical course to ascertain therapy response and timely treatment modification in the context of disease relapse. Here, we review recent reports of the potential clinical value of CTC and ctDNA in OC, expatiating on their use in diagnosis and prognosis. We critically appraise the current evidence, and discuss the issues that still need to be addressed before liquid biopsies can be implemented in routine clinical practice for OC management.
Publisher: Elsevier BV
Date: 11-2014
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.
Publisher: Wiley
Date: 12-11-2021
DOI: 10.1111/ANS.16440
Publisher: Elsevier BV
Date: 05-2020
Publisher: Springer Science and Business Media LLC
Date: 06-01-2023
DOI: 10.1038/S41598-023-27445-2
Abstract: Plasma circulating tumour DNA (ctDNA) has been suggested to be a viable biomarker of response to treatment in patients with high grade serous ovarian carcinoma (HGSOC). TP53 mutations are present in more than 90% of HGSOCs but somatic variants are distributed across all exonic regions of the gene, requiring next generation sequencing (NGS) technologies for mutational analysis. In this study, we compared the suitability of the Accel (Swift) and Oncomine (ThermoFisher) panels for identification of TP53 mutations in ctDNA of HGSOC patients (N = 10). Only 6 patients (60%) were found to have TP53 mutations using the ACCEL panel but the addition of molecular tags in the Oncomine panel improved ctDNA detection with at least one mutation detected in all cases (100%). Orthogonal validation of the 14 somatic variants found by Oncomine, using droplet digital PCR, confirmed 79% (11/14) of the identified mutations. Overall, the Oncomine panel with unique molecular identifiers (UMI) appears more useful for ctDNA analysis in HGSOC.
Publisher: Elsevier BV
Date: 2018
DOI: 10.2139/SSRN.3292601
Publisher: American Medical Association (AMA)
Date: 2020
Publisher: Elsevier BV
Date: 09-2021
Publisher: Elsevier BV
Date: 06-2018
Publisher: Elsevier BV
Date: 10-2020
Publisher: American Association for Cancer Research (AACR)
Date: 03-2019
DOI: 10.1158/1078-0432.CCR-18-2277
Abstract: Preclinically, AKT kinase inhibition restores drug sensitivity in platinum-resistant tumors. Here the pan-AKT kinase inhibitor afuresertib was given in combination with paclitaxel and carboplatin (PC) in patients with recurrent platinum-resistant epithelial ovarian cancer (PROC) and primary platinum-refractory ovarian cancer (PPROC). Part I was a combination 3+3 dose escalation study for recurrent ovarian cancer. Patients received daily continuous oral afuresertib at 50–150 mg/day with intravenous paclitaxel (175 mg/m2) and carboplatin (AUC5) every 3 weeks for six cycles followed by maintenance afuresertib at 125 mg/day until progression or toxicity. Part II was a single-arm evaluation of the clinical activity of this combination in recurrent PROC (Cohort A) or PPROC (Cohort B). Patients received oral afuresertib at the MTD defined in Part I in combination with PC for six cycles, followed by maintenance afuresertib. Primary endpoints were safety and tolerability of afuresertib in combination with PC (Part I, dose escalation), and investigator-assessed overall response rate (ORR) as per RECIST version 1.1 (Part II). Twenty-nine patients enrolled into Part I, and 30 into Part II. Three dose-limiting toxicities of grade 3 rash were observed, one at 125 mg and two at 150 mg afuresertib. The MTD of afuresertib in combination with PC was therefore identified as 125 mg/day. The most common (≥50%) drug-related adverse events observed in Part I of the study were nausea, diarrhea, vomiting, alopecia, fatigue, and neutropenia and, in Part II, were diarrhea, fatigue, nausea, and alopecia. The Part II ORR in the intention to treat patients was 32% [95% confidence interval (CI), 15.9–52.4] by RECIST 1.1 and 52% (95% CI, 31.3–72.2) by GCIG CA125 criteria. Median progression-free survival was 7.1 months (95% CI, 6.3–9.0 months). Afuresertib plus PC demonstrated efficacy in recurrent PROC with the MTD of afuresertib defined as 125 mg/day.
Publisher: Springer Science and Business Media LLC
Date: 16-10-2023
Publisher: Informa UK Limited
Date: 03-2020
DOI: 10.2147/DDDT.S243787
Publisher: Future Medicine Ltd
Date: 10-2022
Abstract: Despite improvements made with checkpoint inhibitor (CPI) therapy, a need for new approaches to improve outcomes for patients with unresectable or metastatic melanoma remains. EVX-01, a personalized neoepitope vaccine, combined with pembrolizumab treatment, holds the potential to fulfill this need. Here we present the rationale and novel design behind the KEYNOTE – D36 trial: an open label, single arm, phase II trial aiming to establish the clinical proof of concept and evaluate the safety of EVX-01 in combination with pembrolizumab in CPI naive patients with unresectable or metastatic melanoma. The primary objective is to evaluate if EVX-01 improves best overall response after initial stable disease or partial response to pembrolizumab treatment, in patients with advanced melanoma. The novel end points ensure a decisive readout which may prove helpful before making major investments in phase III trials with limited phase I data. Clinical Trial Registration: NCT05309421 ( ClinicalTrials.gov )
Publisher: Elsevier BV
Date: 09-2015
Publisher: Elsevier BV
Date: 10-2018
Publisher: Elsevier BV
Date: 09-2021
Publisher: American Society of Clinical Oncology (ASCO)
Date: 10-08-2023
DOI: 10.1200/JCO.22.02199
Abstract: To address the paucity of data in patients with historically poor outcomes, we conducted the single-arm phase IIIb CheckMate 401 study to evaluate the safety and efficacy of nivolumab plus ipilimumab followed by nivolumab monotherapy in clinically erse patient populations with advanced melanoma. Treatment-naive patients with unresectable stage III-IV melanoma received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks (four doses) followed by nivolumab 3 mg/kg (240 mg following a protocol amendment) once every 2 weeks for ≤24 months. The primary end point was the incidence of grade 3-5 select treatment-related adverse events (TRAEs). Overall survival (OS) was a secondary end point. Outcomes were evaluated in subgroups defined by Eastern Cooperative Oncology Group performance status (ECOG PS), brain metastasis status, and melanoma subtype. In total, 533 patients received at least one dose of study drug. Grade 3-5 select TRAEs affecting the GI (16%), hepatic (15%), endocrine (11%), skin (7%), renal (2%), and pulmonary (1%) systems occurred in the all-treated population similar incidence rates were observed across all subgroups. At 21.6 months' median follow-up, 24-month OS rates were 63% in the all-treated population, 44% in the ECOG PS 2 subgroup (including patients with cutaneous melanoma only), 71% in the brain metastasis subgroup, 36% in the ocular/uveal melanoma subgroup, and 38% in the mucosal melanoma subgroup. Nivolumab plus ipilimumab followed by nivolumab monotherapy was tolerable in patients with advanced melanoma and poor prognostic characteristics. Efficacy was similar between the all-treated population and patients with brain metastases. Reduced efficacy was observed in patients with ECOG PS 2, ocular/uveal melanoma, and/or mucosal melanoma, highlighting the continued need for novel treatment options for these difficult-to-treat patients.
Location: Norway
Location: Netherlands
Location: Canada
No related grants have been discovered for Tarek Meniawy.