Melbourne Medical School Collected Works - Research Publications
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Item5-Year Outcomes with Cobimetinib plus Vemurafenib in BRAFV600 Mutation-Positive Advanced Melanoma: Extended Follow-up of the coBRIM Study(AMER ASSOC CANCER RESEARCH, 2021-10-01)PURPOSE: The randomized phase III coBRIM study (NCT01689519) demonstrated improved progression-free survival (PFS) and overall survival (OS) with addition of cobimetinib to vemurafenib compared with vemurafenib in patients with previously untreated BRAFV600 mutation-positive advanced melanoma. We report long-term follow-up of coBRIM, with at least 5 years since the last patient was randomized. PATIENTS AND METHODS: Eligible patients were randomized 1:1 to receive either oral cobimetinib (60 mg once daily on days 1-21 in each 28-day cycle) or placebo in combination with oral vemurafenib (960 mg twice daily). RESULTS: 495 patients were randomized to cobimetinib plus vemurafenib (n = 247) or placebo plus vemurafenib (n = 248). Median follow-up was 21.2 months for cobimetinib plus vemurafenib and 16.6 months for placebo plus vemurafenib. Median OS was 22.5 months (95% CI, 20.3-28.8) with cobimetinib plus vemurafenib and 17.4 months (95% CI, 15.0-19.8) with placebo plus vemurafenib; 5-year OS rates were 31% and 26%, respectively. Median PFS was 12.6 months (95% CI, 9.5-14.8) with cobimetinib plus vemurafenib and 7.2 months (95% CI, 5.6-7.5) with placebo plus vemurafenib; 5-year PFS rates were 14% and 10%, respectively. OS and PFS were longest in patients with normal baseline lactate dehydrogenase levels and low tumor burden, and in those achieving complete response. The safety profile remained consistent with previously published reports. CONCLUSIONS: Extended follow-up of coBRIM confirms the long-term clinical benefit and safety profile of cobimetinib plus vemurafenib compared with vemurafenib monotherapy in patients with BRAFV600 mutation-positive advanced melanoma.
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ItemMetabolic Plasticity in Melanoma Progression and Response to Oncogene Targeted Therapies(MDPI, 2021-11)Resistance to therapy continues to be a barrier to curative treatments in melanoma. Recent insights from the clinic and experimental settings have highlighted a range of non-genetic adaptive mechanisms that contribute to therapy resistance and disease relapse, including transcriptional, post-transcriptional and metabolic reprogramming. A growing body of evidence highlights the inherent plasticity of melanoma metabolism, evidenced by reversible metabolome alterations and flexibility in fuel usage that occur during metastasis and response to anti-cancer therapies. Here, we discuss how the inherent metabolic plasticity of melanoma cells facilitates both disease progression and acquisition of anti-cancer therapy resistance. In particular, we discuss in detail the different metabolic changes that occur during the three major phases of the targeted therapy response-the early response, drug tolerance and acquired resistance. We also discuss how non-genetic programs, including transcription and translation, control this process. The prevalence and diverse array of these non-genetic resistance mechanisms poses a new challenge to the field that requires innovative strategies to monitor and counteract these adaptive processes in the quest to prevent therapy resistance.
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ItemEnhancing Adoptive Cell Transfer with Combination BRAF-MEK and CDK4/6 Inhibitors in Melanoma(MDPI, 2021-12)Despite the success of immune checkpoint inhibitors that target cytotoxic lymphocyte antigen-4 (CTLA-4) and programmed-cell-death-1 (PD-1) in the treatment of metastatic melanoma, there is still great need to develop robust options for patients who are refractory to first line immunotherapy. As such there has been a resurgence in interest of adoptive cell transfer (ACT) particularly derived from tumor infiltrating lymphocytes. Moreover, the addition of cyclin dependent kinase 4/6 inhibitors (CDK4/6i) have been shown to greatly extend duration of response in combination with BRAF-MEK inhibitors (BRAF-MEKi) in pre-clinical models of melanoma. We therefore investigated whether combinations of BRAF-MEK-CDK4/6i and ACT were efficacious in murine models of melanoma. Triplet targeted therapy of BRAF-MEK-CDK4/6i with OT-1 ACT led to sustained and robust anti-tumor responses in BRAFi sensitive YOVAL1.1. We also show that BRAF-MEKi but not CDK4/6i enhanced MHC Class I expression in melanoma cell lines in vitro. Paradoxically CDK4/6i in low concentrations of IFN-γ reduced expression of MHC Class I and PD-L1 in YOVAL1.1. Overall, this work provides additional pre-clinical evidence to pursue combination of BRAF-MEK-CDK4/6i and to combine this combination with ACT in the clinic.
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ItemReal-life data for first-line combination immune- checkpoint inhibition and targeted therapy in patients with melanoma brain metastases(ELSEVIER SCI LTD, 2021-10)BACKGROUND: Melanoma brain metastases (MBM) have a poor prognosis. Systemic treatments that have improved outcomes in advanced melanoma have been shown to have an intracranial (IC) effect. We studied the efficacy and outcomes of combined immune checkpoint inhibitor ipilimumab/nivolumab (Combi-ICI) or targeted therapy (Combi-TT) as first-line treatment in MBM. METHODS: MBM patients treated with Combi-ICI or Combi-TT within 3 months after MBM diagnosis. Endpoints were progression-free survival (PFS) and overall survival (OS). RESULTS: 53 patients received Combi-ICI, 32% had symptomatic MBM and 33.9% elevated LDH. 71.7% required local treatment. The disease control rate was 60.3%. IC response rate (RR) was 43.8% at 3-months with durable responses at 6- (46.5%) and 12-months (53.1%). Extracranial (EC) RR was 44.7% at 3-months and 50% at 12-months. Median PFS was 9.6 months (95% CI 3.6-NR) and median overall survival (mOS) 44.8 months (95% CI; 26.2-NR). 63 patients received Combi-TT, 55.6% of patients had symptomatic MBM, 57.2% of patients had elevated LDH and 68.3% of patients required local treatment. The disease control rate was 60.4%. ICRR was 50% at 3-months, but dropped at 6-months (20.9%). ECRR was 69.2% at 3-months and 17.6% at 12-months. Median PFS was 5.8 months (95% CI 4.2-7.6) and mOS 14.2 months (95% CI 8.99-26.8). In BRAFV600 patients, 26.7% of patients received Combi-ICI and 73.3% Combi-TT with OS (p = 0.0053) and mPFS (p = 0.03) in favour to Combi-ICI. CONCLUSION: Combi-ICI showed prolonged mOS with sustainable IC and EC responses. Despite the initially increased efficacy, Combi-TT responses at 12 months were low. Combi-ICI appeared superior to Combi-TT for OS and PFS in BRAFV600 patients. Other clinical factors are determinants for first-line treatment choice.
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ItemATEZOLIZUMAB PLUS VEMURAFENIB AND COBIMETINIB PROVIDES FAVORABLE SURVIVAL OUTCOMES IN PATIENTS WITH HIGH TUMOR MUTATION BURDEN AND PROINFLAMMATORY GENE SIGNATURE IN THE PHASE 3 IMSPIRE150 STUDY(BMJ PUBLISHING GROUP, 2020-11)Background The phase 3 IMspire150 study (NCT02908672) showed that first-line atezolizumab (A) combined with vemurafenib (V) + cobimetinib (C) improved progression-free survival (PFS) vs placebo (P) + V + C in patients with BRAFV600 mutation–positive advanced melanoma (15.1 vs 10.6 months; hazard ratio [HR] 0.78; 95% CI 0.63–0.97; P=0.0249). Insights into the clinical benefit of the A+V+C triple combination in prognostic molecular subgroups of patients can inform treatment selection and future clinical research. Methods 514 patients were randomized 1:1 to A+V+C (n=256) or P+V+C (n=258). The efficacy endpoints analyzed included PFS and duration of response (DOR) estimated using the Kaplan-Meier method. Outcomes were based on investigator-assessed best overall response per Response Evaluation Criteria in Solid Tumors v1.1. Patients were primarily categorized into binary subgroups defined by tumor mutation burden (TMB; low or high: <10 or ≥10 mutations/Mb, respectively) or by the < or ≥ median values of interferon (IFN)-gamma or CD8+ tumor cells. In addition, these subgroups were further broken down based on the proportion of programmed death-ligand 1 (PD-L1)-expressing tumor-infiltrating cells as PD-L1+ (≥1%) or PD-L1– (<1%). Results Patients treated with P+V+C with high and low TMB had similar PFS outcomes. However, the magnitude of the PFS benefit with A+V+C vs P+V+C was markedly higher in patients with high TMB (≥10 mutations/Mb) compared with patients with low TMB (<10 mutations/Mb) in whom the benefit between treatment arms was comparable (figure 1A). The magnitude of the PFS benefit with A+V+C was further enhanced in patients with high TMB and PD-L1– compared with patients with high TMB and PD-L1+. Overall, patients with potential for increased antitumor immunity (IFN-gamma ≥ median or CD8+ ≥ median) who received A+V+C had more favorable outcomes compared with their counterparts with IFN-gamma < median or CD8+ < median. In general, the PFS benefit with A+V+C vs P+V+C was more readily apparent in PD-L1– subgroups. Similar trends were seen with DOR (figure 1B). Abstract 307 Figure 1Forest plot of PFS (A) and DOR (B). mo, months; NE, not evaluable; Neg, negative; NE, not estimable; Pos, positive. Conclusions There was a trend of larger magnitude of PFS benefit with A+V+C vs P+V+C in PD-L1– patient subgroups, who benefit less with single-agent immunotherapy. The PFS and DOR benefits were more evident in patients with high IFN-gamma or TMB >10 mutations/Mb. Additional multivariate analyses are ongoing to delineate the PFS trends observed. Trial Registration ClinicalTrials. gov, identifier NCT02908672
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ItemASSOCIATION OF RESPONSE WITH SURVIVAL OUTCOMES WITH ATEZOLIZUMAB IN COMBINATION WITH VEMURAFENIB AND COBIMETINIB IN THE PHASE 3 IMSPIRE150 STUDY(BMJ PUBLISHING GROUP, 2020-11)Background The phase 3 IMspire150 study (NCT02908672) demonstrated improved progression-free survival (PFS) with first-line atezolizumab (A) vs placebo (P) combined with vemurafenib (V) + cobimetinib (C) in patients with BRAFV600 mutation–positive advanced melanoma (15.1 vs 10.6 months; hazard ratio [HR] 0.78; 95% confidence interval [CI] 0.63–0.97; P=0.0249). Objective response has been associated with increased survival with chemotherapy and targeted therapies, but it is unclear whether the association holds for immunotherapy. In this exploratory analysis, we evaluated the impact of response on survival outcomes in patients treated with A+V+C or P+V+C in the IMspire150 study. Methods 514 patients were randomized 1:1 to A+V+C (n=256) or P+V+C (n=258). Patients received V+C in cycle 1; A or P was added on days 1+15 from cycle 2 onward. The primary endpoints for this exploratory analysis were PFS and overall survival (OS), estimated using the Kaplan-Meier method. Outcomes were analyzed by investigator-assessed best overall response (BOR) per RECIST v1.1 (complete response [CR] vs partial response [PR] vs stable disease [SD]). Results Median follow-up was 18.9 mo. In the A+V+C arm, BOR was CR (n=41), PR (n=129), and SD (n=58); in the P+V+C arm, BOR was CR (n=46), PR (n=122), and SD (n=58). An imbalance in baseline prognostic factors (eg, lactate dehydrogenase, tumor burden measures) was noted across response categories in both treatment arms, with favorable factors more prevalent in patients with CR and unfavorable factors more prevalent in patients with PR/SD. Improvement in PFS and OS was observed with A+V+C vs P+V+C in patients with PR, with 2-year PFS rates of 42.1% vs 24.6% and 2-year OS rates of 69.1% vs 56.1% with A+V+C vs P+V+C (table 1). In patients with CR, median PFS and OS were not yet reached in either arm, with 2-year PFS rates of 64.6% vs 59.8% and 2-year OS rates of 82.6% vs 82.8% with A+V+C vs P+V+C. PFS and OS outcomes were poor in both treatment arms in patients with SD, with 2-year PFS rates of 10.7% vs not estimable (NE) and 2-year OS rates of 36.6% vs 29.3% with A+V+C vs P+V+C. Abstract 301 Table 1PFS and OS outcomes with A+V+C vs P+V+C by BOR per RECIST v1.1 Conclusions PFS and OS improvement was observed for A+V+C vs P+V+C for patients who achieved PR. CR is associated with improved PFS and OS with both A+V+C and P+V+C. Further follow-up is required to determine the impact of A+C+V vs P+C+V on survival outcomes. Trial Registration ClinicalTrials. gov, NCT02908672
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ItemCDK4/6 Inhibition Reprograms Mitochondrial Metabolism in BRAFV600 Melanoma via a p53 Dependent Pathway(MDPI, 2021-02)Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are being tested in numerous clinical trials and are currently employed successfully in the clinic for the treatment of breast cancers. Understanding their mechanism of action and interaction with other therapies is vital in their clinical development. CDK4/6 regulate the cell cycle via phosphorylation and inhibition of the tumour suppressor RB, and in addition can phosphorylate many cellular proteins and modulate numerous cellular functions including cell metabolism. Metabolic reprogramming is observed in melanoma following standard-of-care BRAF/MEK inhibition and is involved in both therapeutic response and resistance. In preclinical models, CDK4/6 inhibitors overcome BRAF/MEK inhibitor resistance, leading to sustained tumour regression; however, the metabolic response to this combination has not been explored. Here, we investigate how CDK4/6 inhibition reprograms metabolism and if this alters metabolic reprogramming observed upon BRAF/MEK inhibition. Although CDK4/6 inhibition has no substantial effect on the metabolic phenotype following BRAF/MEK targeted therapy in melanoma, CDK4/6 inhibition alone significantly enhances mitochondrial metabolism. The increase in mitochondrial metabolism in melanoma cells following CDK4/6 inhibition is fuelled in part by both glutamine metabolism and fatty acid oxidation pathways and is partially dependent on p53. Collectively, our findings identify new p53-dependent metabolic vulnerabilities that may be targeted to improve response to CDK4/6 inhibitors.
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ItemNo Preview AvailableTowards new models of cancer care in Australia: lessons from Victoria's response to theCOVID-19 pandemic(WILEY, 2020-10)In response to the COVID‐19 pandemic, the Department of Health and Human Services Victoria (DHHS), the Monash Partners Comprehensive Cancer Consortium (MPCCC) and Victorian Comprehensive Cancer Centre (VCCC) pooled their combined infrastructure to establish the Victorian COVID‐19 Cancer Network (VCCN) backed by a Taskforce of expert members. In a few short months, this state‐wide clinical network implemented a number of new models of care including clinics to manage acutely presenting cancer patients away from emergency departments, chemotherapy in the home, telehealth models and addressing sustainability of clinical trials.
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ItemGenome-wide RNAi screen for genes regulating glycolytic response to vemurafenib in BRAFV600 melanoma cells(NATURE RESEARCH, 2020-10-12)Identification of mechanisms underlying sensitivity and response to targeted therapies, such as the BRAF inhibitor vemurafenib, is critical in order to improve efficacy of these therapies in the clinic and delay onset of resistance. Glycolysis has emerged as a key feature of the BRAF inhibitor response in melanoma cells, and importantly, the metabolic response to vemurafenib in melanoma patients can predict patient outcome. Here, we present a multiparameter genome-wide siRNA screening dataset of genes that when depleted improve the viability and glycolytic response to vemurafenib in BRAFV600 mutated melanoma cells. These datasets are suitable for analysis of genes involved in cell viability and glycolysis in steady state conditions and following treatment with vemurafenib, as well as computational approaches to identify gene regulatory networks that mediate response to BRAF inhibition in melanoma.