ORCID Profile
0000-0001-7068-4311
Current Organisations
The University of Auckland
,
Waikato District Health Board
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Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6529836.V1
Abstract: AbstractPurpose: Combination therapy with reduced-dose programmed death 1 inhibitor plus standard-dose cytotoxic T-lymphocyte–associated antigen 4 inhibitor demonstrated efficacy, but substantial toxicity, in melanoma. We present long-term results of part 1B of KEYNOTE-029, which assessed safety and efficacy of standard-dose pembrolizumab plus reduced-dose ipilimumab in advanced melanoma. Patients and Methods: Part 1B was an expansion cohort of the open-label, phase Ib portion of KEYNOTE-029. Eligible patients had advanced melanoma and no previous immune checkpoint inhibitor therapy. Patients received pembrolizumab 2 mg/kg (amended to 200 mg) every 3 weeks plus ipilimumab 1 mg/kg every 3 weeks (four cycles), then pembrolizumab alone for up to 2 years. Primary end point was safety secondary end points included objective response rate (ORR), progression-free survival (PFS), duration of response (DOR), and overall survival (OS). Results: A total of 153 patients received at least one dose of pembrolizumab plus ipilimumab. At a median follow-up of 36.8 months, 71.9% had received four doses of ipilimumab and 30.7% had completed 2 years of pembrolizumab 26.1% completed both treatments. Treatment-related adverse events occurred in 96.1% (47.1% grade 3/4 no deaths), leading to discontinuation of one or both study drugs in 35.9%. ORR was 62.1% with 42 (27.5%) complete and 53 (34.6%) partial responses. Median DOR was not reached 36-month ongoing response rate was 84.2%. Median PFS and OS were not reached 36-month rates were 59.1% and 73.4%, respectively. Conclusions: Standard-dose pembrolizumab plus reduced-dose ipilimumab demonstrated robust antitumor activity, durable response, and favorable long-term survival with manageable toxicity. /
Publisher: American Association for Cancer Research (AACR)
Date: 10-2020
DOI: 10.1158/1078-0432.CCR-20-0177
Abstract: Combination therapy with reduced-dose programmed death 1 inhibitor plus standard-dose cytotoxic T-lymphocyte–associated antigen 4 inhibitor demonstrated efficacy, but substantial toxicity, in melanoma. We present long-term results of part 1B of KEYNOTE-029, which assessed safety and efficacy of standard-dose pembrolizumab plus reduced-dose ipilimumab in advanced melanoma. Part 1B was an expansion cohort of the open-label, phase Ib portion of KEYNOTE-029. Eligible patients had advanced melanoma and no previous immune checkpoint inhibitor therapy. Patients received pembrolizumab 2 mg/kg (amended to 200 mg) every 3 weeks plus ipilimumab 1 mg/kg every 3 weeks (four cycles), then pembrolizumab alone for up to 2 years. Primary end point was safety secondary end points included objective response rate (ORR), progression-free survival (PFS), duration of response (DOR), and overall survival (OS). A total of 153 patients received at least one dose of pembrolizumab plus ipilimumab. At a median follow-up of 36.8 months, 71.9% had received four doses of ipilimumab and 30.7% had completed 2 years of pembrolizumab 26.1% completed both treatments. Treatment-related adverse events occurred in 96.1% (47.1% grade 3/4 no deaths), leading to discontinuation of one or both study drugs in 35.9%. ORR was 62.1% with 42 (27.5%) complete and 53 (34.6%) partial responses. Median DOR was not reached 36-month ongoing response rate was 84.2%. Median PFS and OS were not reached 36-month rates were 59.1% and 73.4%, respectively. Standard-dose pembrolizumab plus reduced-dose ipilimumab demonstrated robust antitumor activity, durable response, and favorable long-term survival with manageable toxicity.
Publisher: Wiley
Date: 21-06-2023
DOI: 10.1111/AJCO.13974
Abstract: Rectal cancer is a common malignancy. The management of rectal cancer has recently evolved and has undergone a paradigm shift with the advent of treatment approaches such as total neoadjuvant therapy and the watch‐and‐wait approach. However, despite the recently available evidence, there is no consensus on the optimal management approach in the setting of locally advanced rectal cancer. To address some of the controversies, a joint multidisciplinary panel discussion was conducted at the Australasian Gastro‐Intestinal Trials Group (AGITG) Annual Scientific Meeting in November 2022. Members from different subspecialties formed two panels and discussed three clinical cases in a debate format. Each case represented some of the complex issues faced by clinicians in this setting. The discussion is now presented in this manuscript, which depicts the different available management approaches and reiterates the importance of a multidisciplinary approach.
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.
Publisher: Oxford University Press (OUP)
Date: 04-11-2010
DOI: 10.1111/J.1365-2133.2010.10010.X
Abstract: Teledermoscopy is a rapidly developing field of dermatology with studies demonstrating excellent agreement with face-to-face diagnosis. However, we are unaware of studies evaluating interobserver variability in diagnosis between dermatologists from different continents. This evaluation is important to determine the robustness of teledermoscopy and allow comparisons to be made between different studies. To assess the interobserver diagnostic variability between five independent experienced dermatologists (A-E) in New Zealand, Australia and the U.S.A. Images from 979 lesions from 206 patients were distributed to five dermatologists. The lesions were viewed and diagnoses recorded using MoleMap Diagnose (MoleMap, Auckland, New Zealand) software. The diagnoses were analysed for interobserver variability. There was excellent agreement between four of five dermatologists (A-D) for lesions that were agreed upon as melanoma (κ = 0·81-0·97) and benign naevus (κ = 0·77-0·82).The fifth dermatologist (E) made a more frequent diagnosis of atypical naevus and melanoma than the others. For nonmelanocytic lesions, there was moderate to very good agreement for seborrhoeic keratosis (κ = 0·64-0·80) and basal cell carcinoma (κ = 0·55-0·67), but poor agreement for invasive squamous cell carcinoma (SCC) (κ = 0·05-0·15). Agreement for actinic keratosis (κ = 0·32-0·67) and SCC in situ (κ = 0·15-0·32) was only moderate. When atypical and benign naevi were grouped together and actinic keratosis and SCC in situ grouped together, there was better agreement among all dermatologists. There was good ability to distinguish malignant from benign lesions (κ = 0·57-0·93). There was good agreement among dermatologists A-D but dermatologist E varied from the group with more frequent diagnosis of melanoma and atypical naevus. This difference could be due to different definition of terms with lack of consensus guidelines in definition of atypical naevus, lack of familiarity with the specific patient population and/or diagnostic drift.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 10-2022
DOI: 10.1200/CCI.22.00064
Abstract: Predicting short-term mortality in patients with advanced cancer remains challenging. Whether digitalized clinical text can be used to build models to enhance survival prediction in this population is unclear. We conducted a single-centered retrospective cohort study in patients with advanced solid tumors. Clinical correspondence authored by oncologists at the first patient encounter was extracted from the electronic medical records. Machine learning (ML) models were trained using narratives from the derivation cohort, before being tested on a temporal validation cohort at the same site. Performance was benchmarked against Eastern Cooperative Oncology Group performance status (PS), comparing ML models alone (comparison 1) or in combination with PS (comparison 2), assessed by areas under receiver operating characteristic curves (AUCs) for predicting vital status at 11 time points from 2 to 52 weeks. ML models were built on the derivation cohort (4,791 patients from 2001 to April 2017) and tested on the validation cohort of 726 patients (May 2017-June 2019). In 441 patients (61%) where clinical narratives were available and PS was documented, ML models outperformed the predictivity of PS (mean AUC improvement, 0.039, P .001, comparison 1). Inclusion of both clinical text and PS in ML models resulted in further improvement in prediction accuracy over PS with a mean AUC improvement of 0.050 ( P .001, comparison 2) the AUC was 0.80 at all assessed time points for models incorporating clinical text. Exploratory analysis of oncologist's narratives revealed recurring descriptors correlating with survival, including referral patterns, mobility, physical functions, and concomitant medications. Applying ML to oncologists' narratives with or without including patient's PS significantly improved survival prediction to 12 months, suggesting the utility of clinical text in building prognostic support tools.
Publisher: Springer Science and Business Media LLC
Date: 07-10-2011
Publisher: Springer Science and Business Media LLC
Date: 12-2019
DOI: 10.1186/S12885-019-6405-7
Abstract: Retrospective studies show improved outcomes in colorectal cancer patients if taking statins, including overall survival, pathological response of rectal cancer to preoperative chemoradiotherapy (pCRT), and reduced acute and late toxicities of pelvic radiation. Major tumour regression following pCRT has strong prognostic significance and can be assessed in vivo using MRI-based tumour regression grading (mrTRG) or after surgery using pathological TRG (pathTRG). A double-blind phase 2 trial will randomise 222 patients planned to receive long-course fluoropyrimidine-based pCRT for rectal adenocarcinoma at 18+ sites in New Zealand and Australia. Patients will receive simvastatin 40 mg or placebo daily for 90 days starting 1 week prior to standard pCRT. Pelvic MRI 6 weeks after pCRT will assess mrTRG grading prior to surgery. The primary objective is rates of favourable (grades 1–2) mrTRG following pCRT with simvastatin compared to placebo, considering mrTRG in 4 ordered categories (1, 2, 3, 4–5). Secondary objectives include comparison of: rates of favourable pathTRG in resected tumours incidence of toxicity compliance with intended pCRT and trial medication proportion of patients undergoing surgical resection cancer outcomes and pathological scores for radiation colitis. Tertiary objectives include: association between mrTRG and pathTRG grouping inter-observer agreement on mrTRG scoring and pathTRG scoring studies of T-cell infiltrates in diagnostic biopsies and irradiated resected normal and malignant tissue and the effect of simvastatin on markers of systemic inflammation (modified Glasgow prognostic score and the neutrophil-lymphocyte ratio). Trial recruitment commenced April 2018. When completed this study will be able to observe meaningful differences in measurable tumour outcome parameters and/or toxicity from simvastatin. A positive result will require a larger RCT to confirm and validate the merit of statins in the preoperative management of rectal cancer. Such a finding could also lead to studies of statins in conjunction with chemoradiation in a range of other malignancies, as well as further exploration of possible mechanisms of action and interaction of statins with both radiation and chemotherapy. The translational substudies undertaken with this trial will provisionally explore some of these possible mechanisms, and the tissue and data can be made available for further investigations. ANZ Clinical Trials Register ACTRN12617001087347 . ( www.anzctr.org.au , registered 26/7/2017) Protocol Version: 1.1 (June 2017).
Publisher: MDPI AG
Date: 20-11-2021
Abstract: We undertook a retrospective comparison of two teledermatology pathways that provide diagnostic and management advice for suspected skin cancers, to evaluate the time from referral to diagnosis and its concordance with histology. Primary Care doctors could refer patients to either the Virtual Lesion Clinic (VLC), a nurse-led community teledermoscopy clinic or, more recently, to the Suspected Skin Cancer (SSC) pathway, which requires them to attach regional, close-up, and dermoscopic images. The primary objective of this study was to determine the comparative time course between the SSC pathway and VLC. Secondary objectives included comparative diagnostic concordance, skin lesion classification, and evaluation of missed skin lesions during subsequent follow-up. VLC referrals from July to December 2016 and 2020 were compared to SSC referrals from July to December 2020. 408 patients with 682 lesions in the VLC cohort were compared with 480 patients with 548 lesions from the 2020 SSC cohort, matched for age, sex, and ethnicity, including histology where available. Median time (SD) from referral to receipt of teledermatology advice was four (2.8) days and 50 (43.0) days for the SSC and VLC cohorts, respectively (p 0.001). Diagnostic concordance between teledermatologist and histopathologist for benign versus malignant lesions was 70% for 114 lesions in the SSC cohort, comparable to the VLC cohort (71% of 122 lesions). Referrals from primary care, where skin lesions were imaged with variable devices and quality resulted in faster specialist advice with similar diagnostic performance compared to high-quality imaging at nurse-led specialist dermoscopy clinics.
Publisher: JMIR Publications Inc.
Date: 02-12-2021
Abstract: rimary care providers, dermatology specialists, and health care access are key components of primary prevention, early diagnosis, and treatment of skin cancer. Artificial intelligence (AI) offers the promise of diagnostic support for nonspecialists, but real-world clinical validation of AI in primary care is lacking. e aimed to (1) assess the reliability of an AI-based clinical triage algorithm in classifying benign and malignant skin lesions and (2) evaluate the quality of images obtained in primary care using the study camera (3Gen DermLite Cam v4 or similar). his was a single-center, prospective, double-blinded observational study with a predetermined study design. We recruited participants with suspected skin cancer in 20 primary care practices who were referred for assessment via teledermatology. A second set of photographs taken using a standardized camera was processed by the AI algorithm. We evaluated the image quality and compared two teledermatologists’ diagnoses by consensus (the “gold standard”) with AI and histology where applicable. ur primary outcome assessment stratified 391 skin lesions by management as benign, uncertain, or malignant. Uncertain lesions were not included in the sensitivity and specificity analyses. Uncertain lesions included lesions that had either diagnostic or management uncertainties. For the remaining 242 lesions, the sensitivity was 97.26% (95% CI 93.13%-99.25%) and the specificity was 97.92% (95% CI 92.68%-99.75%). The AI algorithm was compared with the histological diagnoses for 123 lesions. The sensitivity was 100% (95% CI 95.85%-100%) and the specificity was 72.22% (95% CI 54.81%-85.80%). he AI algorithm demonstrates encouraging results, with high sensitivity and specificity, concordant with previous AI studies. It shows potential as a triage tool in conjunction with teledermatology to augment health care and improve access to dermatology. Further real-life studies need to be conducted on a larger scale to assess the reliability, usability, and cost-effectiveness of the algorithm in primary care.
Publisher: Wiley
Date: 11-2020
DOI: 10.1111/IMJ.14681
Abstract: The testicular cancer incidence in New Zealand is rising. We evaluated if testicular cancer outcomes differed by ethnicity in NZ. To study if ethnic disparities existed among testicular cancer patients and their outcomes treated at Waikato Regional Cancer Centre. Retrospective review of testicular cancer cases in the Medical Oncology database, Waikato Hospital, between 2001 and 2013 inclusive. Three hundred and twenty-five patients were seen, with median follow up of survivors being 101 (range 13-230) months. 95 (29.2%) were Māori, 210 (64.6%) NZ European and 20 (6.1%) of other ethnicity. One hundred and eighty-two patients were diagnosed with seminoma and 143 with non-seminoma. Māori represented 27.5% of seminoma and 31.4% of non-seminoma patients. Median age at diagnosis was 39 years for seminoma and 30 years for non-seminoma Māori were significantly younger than non- Māori for both seminoma (median age 35 versus 42 years) and non-seminoma (median age 28 vs 34 years, respectively). While stage distribution of seminoma at diagnosis was similar for Māori and non-Māori (chi-squared P = 0.31), significantly more Māori had higher-stage non-seminoma than non-Māori (stage III in 44% and 22%, respectively, chi-squared P = 0.014). Survival for seminoma (logrank P = 0.19) and non-seminoma (logrank P = 0.89) patients did not differ significantly by ethnicity. Māori patients were younger at diagnosis of testicular cancer and presented with more advanced non-seminoma testicular tumours compared with non-Māori but survival was comparable.
Publisher: Cold Spring Harbor Laboratory
Date: 30-10-2020
DOI: 10.1101/2020.10.28.20214627
Abstract: Electronic medical records (EMR) represent a rich informatics resource that remains largely unexploited for improving healthcare outcomes. Here we report a systematic text mining analysis of EMR correspondence for 4791 cancer patients treated between 2001 and 2017. Meaningful groups of text descriptors correlating with poor survival outcomes were systematically identified, and applying machine learning analysis to clinical text accurately predicted cancer patient survival at selected timepoints up to 12 months. In a validation cohort of 726 patients, inclusion of EMR descriptors to machine learning models outperformed the predictivity of conventional clinical symptom scores by 4.9% ( p = 0.001). These results prove that labour-intensive EMR data collection can be repurposed to add clinical value. Extension of this approach to a broader spectrum of digital health data should transform the real-time utility of such latent informatics resources, enabling healthcare systems to be more adaptive and responsive to patient circumstances.
Publisher: Oxford University Press (OUP)
Date: 05-03-2010
DOI: 10.1111/J.1365-2133.2010.09673.X
Abstract: Teledermatology is a rapidly growing field with studies showing high diagnostic accuracy when compared with face-to-face diagnosis. Teledermoscopy involves the use of epiluminescence microscopy to increase diagnostic accuracy. The utility of teledermoscopy as a triage tool has not been established. To assess teledermoscopy as a triage tool for a hospital skin lesion clinic. Patients referred to a dermatology skin lesion clinic were recruited. Digital and dermoscopic photographs were taken of skin lesions of concern and the patients were then seen independently face-to-face by two out of three dermatologists. The digital images were evaluated 4 weeks later, as a teledermoscopy consultation, by two of these dermatologists. The diagnosis and management from both types of consultation were compared. Two hundred patients with a total of 491 lesions were seen. There was excellent agreement between teledermoscopy and face-to-face diagnosis with only 12.3% of lesions having disparate diagnoses of clinical significance. Twelve of 491 (2.4%) lesions appeared to have been under-reported by teledermoscopy when compared with face-to-face diagnosis. However, when histopathology became available, only one malignant lesion had been missed (a basal cell carcinoma diagnosed as solar keratosis) by teledermoscopy. Teledermoscopy approximated 100% sensitivity and 90% specificity for detecting melanoma and nonmelanoma skin cancers. Importantly, 74% of all lesions were determined to be manageable by the general practitioner without needing to be seen face-to-face by a dermatologist. This use of teledermoscopy as a triage tool offers the potential to shorten waiting lists and thus improve healthcare access and delivery.
Publisher: BMJ
Date: 06-2020
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 .
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22478052
Abstract: Supplementary Materials
Publisher: Elsevier BV
Date: 09-2017
Publisher: JMIR Publications Inc.
Date: 10-12-2021
DOI: 10.2196/35395
Abstract: Primary care providers, dermatology specialists, and health care access are key components of primary prevention, early diagnosis, and treatment of skin cancer. Artificial intelligence (AI) offers the promise of diagnostic support for nonspecialists, but real-world clinical validation of AI in primary care is lacking. We aimed to (1) assess the reliability of an AI-based clinical triage algorithm in classifying benign and malignant skin lesions and (2) evaluate the quality of images obtained in primary care using the study camera (3Gen DermLite Cam v4 or similar). This was a single-center, prospective, double-blinded observational study with a predetermined study design. We recruited participants with suspected skin cancer in 20 primary care practices who were referred for assessment via teledermatology. A second set of photographs taken using a standardized camera was processed by the AI algorithm. We evaluated the image quality and compared two teledermatologists’ diagnoses by consensus (the “gold standard”) with AI and histology where applicable. Our primary outcome assessment stratified 391 skin lesions by management as benign, uncertain, or malignant. Uncertain lesions were not included in the sensitivity and specificity analyses. Uncertain lesions included lesions that had either diagnostic or management uncertainties. For the remaining 242 lesions, the sensitivity was 97.26% (95% CI 93.13%-99.25%) and the specificity was 97.92% (95% CI 92.68%-99.75%). The AI algorithm was compared with the histological diagnoses for 123 lesions. The sensitivity was 100% (95% CI 95.85%-100%) and the specificity was 72.22% (95% CI 54.81%-85.80%). The AI algorithm demonstrates encouraging results, with high sensitivity and specificity, concordant with previous AI studies. It shows potential as a triage tool in conjunction with teledermatology to augment health care and improve access to dermatology. Further real-life studies need to be conducted on a larger scale to assess the reliability, usability, and cost-effectiveness of the algorithm in primary care. MoleMap NZ, who developed the AI algorithm, provided some funding for this study. HT's salary was partially sponsored by MoleMap NZ, who developed the AI algorithm. AB is a shareholder and consultant to Molemap Ltd provider of the AI algorithm. None declared.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6529836
Abstract: AbstractPurpose: Combination therapy with reduced-dose programmed death 1 inhibitor plus standard-dose cytotoxic T-lymphocyte–associated antigen 4 inhibitor demonstrated efficacy, but substantial toxicity, in melanoma. We present long-term results of part 1B of KEYNOTE-029, which assessed safety and efficacy of standard-dose pembrolizumab plus reduced-dose ipilimumab in advanced melanoma. Patients and Methods: Part 1B was an expansion cohort of the open-label, phase Ib portion of KEYNOTE-029. Eligible patients had advanced melanoma and no previous immune checkpoint inhibitor therapy. Patients received pembrolizumab 2 mg/kg (amended to 200 mg) every 3 weeks plus ipilimumab 1 mg/kg every 3 weeks (four cycles), then pembrolizumab alone for up to 2 years. Primary end point was safety secondary end points included objective response rate (ORR), progression-free survival (PFS), duration of response (DOR), and overall survival (OS). Results: A total of 153 patients received at least one dose of pembrolizumab plus ipilimumab. At a median follow-up of 36.8 months, 71.9% had received four doses of ipilimumab and 30.7% had completed 2 years of pembrolizumab 26.1% completed both treatments. Treatment-related adverse events occurred in 96.1% (47.1% grade 3/4 no deaths), leading to discontinuation of one or both study drugs in 35.9%. ORR was 62.1% with 42 (27.5%) complete and 53 (34.6%) partial responses. Median DOR was not reached 36-month ongoing response rate was 84.2%. Median PFS and OS were not reached 36-month rates were 59.1% and 73.4%, respectively. Conclusions: Standard-dose pembrolizumab plus reduced-dose ipilimumab demonstrated robust antitumor activity, durable response, and favorable long-term survival with manageable toxicity. /
Publisher: Elsevier BV
Date: 05-2021
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22478052.V1
Abstract: Supplementary Materials
Publisher: Wiley
Date: 26-10-2020
DOI: 10.1002/CNR2.1310
Publisher: Springer Science and Business Media LLC
Date: 25-10-2012
Publisher: Springer Science and Business Media LLC
Date: 29-11-2017
DOI: 10.1007/S11523-017-0543-0
Abstract: Delta-like ligand 4-Notch (DLL4-Notch) signaling contributes to the maintenance of chemotherapy-resistant cancer stem cells and tumor vasculature. This phase IB trial of demcizumab, an IgG2 humanized monoclonal antibody directed against DLL4, was undertaken to determine its maximum tolerated dose, safety, immunogenicity, preliminary efficacy, pharmacokinetics, and pharmacodynamics, combined with standard chemotherapy. Forty-six treatment-naive patients with metastatic non-squamous non-small cell lung cancer (NSCLC) were enrolled in this open-label, dose-escalation study using a standard 6 + 6 design. Demcizumab (2.5, 5.0, and 7.5 mg/kg) was given once every 3 weeks with standard doses of pemetrexed and carboplatin using a continuous (six cycles followed by demcizumab maintenance) or a truncated demcizumab regimen (four cycles followed by pemetrexed maintenance). Initially, continuous demcizumab was given until progression but two patients developed grade 3 pulmonary hypertension and congestive heart failure after eight or more infusions. Thereafter, 23 patients were treated with a truncated regimen of demcizumab, which was not associated with any grade 3 or greater cardiopulmonary toxicity. Common adverse events were hypertension, raised brain natriuretic peptide, and those expected from carboplatin and pemetrexed alone. Twenty of 40 evaluable patients (50%) had objective tumor responses. In peripheral blood, demcizumab treatment modulated the expression of genes regulating Notch signaling and angiogenesis, and achieved concentrations exceeding those saturating DLL4 binding. This study has identified a truncated dosing regimen and recommended phase II dose of demcizumab (5 mg/kg q3-weekly ×4) for subsequent clinical evaluation in combination with standard carboplatin and pemetrexed chemotherapy. NCT01189968.
Publisher: MDPI AG
Date: 18-04-0004
DOI: 10.3390/IJMS19103167
Abstract: Selenium, a trace element with anticancer properties, can reduce harmful toxicities of chemotherapy and radiotherapy without compromising efficacy. However, the dose-response relationship in normal versus malignant human cells is unclear. We evaluated how methylseleninic acid (MSA) modulates the toxicity and efficacy of chemotherapy and radiation on malignant and non-malignant human mononuclear blood cells in vitro. We specifically investigated its effects on endoplasmic reticulum stress induction, intracellular glutathione concentration, DNA damage and viability of peripheral blood mononuclear cells and THP1 monocytic leukaemia cells in response to radiation, cytosine arabinoside or doxorubicin chemotherapy. MSA, at lower concentrations, induced protective responses in normal cells but cytotoxic effects in malignant cells, alone and in conjunction with chemotherapy or radiation. However, in normal cells higher concentrations of MSA were directly toxic and increased the cytotoxicity of radiation but not chemotherapy. In malignant cells higher MSA concentrations were generally more effective in combination with cancer treatments. Thus, optimal MSA concentrations differed between normal and malignant cells and treatments. This work supports clinical reports that selenium can significantly reduce dose-limiting toxicities of anticancer therapies and potentially improve efficacy of anticancer treatments. The optimal selenium compound and dose is not yet determined.
No related grants have been discovered for Michael Jameson.