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Vemurafenib plus cobimetinib in unresectable stage IIIc or stage IV melanoma: response monitoring and resistance prediction with positron emission tomography and tumor characteristics (REPOSIT): study protocol of a phase II, open-label, multicenter study.

ABSTRACT: In patients with BRAFV600 mutated unresectable stage IIIc or metastatic melanoma, molecular targeted therapy with combined BRAF/MEK-inhibitor vemurafenib plus cobimetinib has shown a significantly improved progression-free survival and overall survival compared to treatment with vemurafenib alone. Nevertheless, the majority of BRAFV600 mutation-positive melanoma patients will eventually develop resistance to treatment. Molecular imaging with 18F-Fluorodeoxyglucose (18F-FDG) PET has been used to monitor response to vemurafenib in some BRAFV600 mutated metastatic melanoma patients, showing a rapid decline of 18F-FDG uptake within 2 weeks following treatment. Furthermore, preliminary results suggest that metabolic alterations might predict the development of resistance to treatment. 18F-Fluoro-3'-deoxy-3'L-fluorothymidine (18F-FLT), a PET-tracer visualizing proliferation, might be more suitable to predict response or resistance to therapy than 18F-FDG.This phase II, open-label, multicenter study evaluates whether metabolic response to treatment with vemurafenib plus cobimetinib in the first 7 weeks as assessed by 18F-FDG/18F-FLT PET can predict progression-free survival and whether early changes in 18F-FDG/18F-FLT can be used for early detection of treatment response compared to standard response assessment with RECISTv1.1 ceCT at 7 weeks. Ninety patients with BRAFV600E/K mutated unresectable stage IIIc/IV melanoma will be included. Prior to and during treatment all patients will undergo 18F-FDG PET/CT and in 25 patients additional 18F-FLT PET/CT is performed. Histopathological tumor characterization is assessed in a subset of 40 patients to unravel mechanisms of resistance. Furthermore, in all patients, blood samples are taken for pharmacokinetic analysis of vemurafenib/cobimetinib. Outcomes are correlated with PET/CT-imaging and therapy response.The results of this study will help in linking PET measured metabolic alterations induced by targeted therapy of BRAFV600 mutated melanoma to molecular changes within the tumor. We will be able to correlate both 18F-FDG and 18F-FLT PET to outcome and decide on the best modality to predict long-term remissions to combined BRAF/MEK-inhibitors. Results coming from this study may help in identifying responders from non-responders early after the initiation of therapy and reveal early development of resistance to vemurafenib/cobimetinib. Furthermore, we believe that the results can be fundamental for further optimizing individual patient treatment.Clinicaltrials.gov identifier: NCT02414750. Registered 10 April 2015, retrospectively registered.

SUBMITTER: van der Hiel B

PROVIDER: S-EPMC5603097 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Vemurafenib plus cobimetinib in unresectable stage IIIc or stage IV melanoma: response monitoring and resistance prediction with positron emission tomography and tumor characteristics (REPOSIT): study protocol of a phase II, open-label, multicenter study.

van der Hiel Bernies B Haanen John B A G JBAG Stokkel Marcel P M MPM Peeper Daniel S DS Jimenez Connie R CR Beijnen Jos H JH van de Wiel Bart A BA Boellaard Ronald R van den Eertwegh Alfons J M AJM

BMC cancer 20170915 1

<h4>Background</h4>In patients with BRAFV600 mutated unresectable stage IIIc or metastatic melanoma, molecular targeted therapy with combined BRAF/MEK-inhibitor vemurafenib plus cobimetinib has shown a significantly improved progression-free survival and overall survival compared to treatment with vemurafenib alone. Nevertheless, the majority of BRAFV600 mutation-positive melanoma patients will eventually develop resistance to treatment. Molecular imaging with <sup>18</sup>F-Fluorodeoxyglucose ( ...[more]

PMID: 28915798

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Project description:BackgroundMelanoma in people of Asian descent presents primarily in non-sun-exposed areas, such as acral and mucosal melanoma. Compared with the predominant sun-exposed area melanomas in Caucasians, acral and mucosal melanomas do not respond as well to immunotherapy and are associated with a worse prognosis. Hence, there is an urgent need for improved treatment for melanoma in Asians. This phase Ib trial evaluated the safety and efficacy of the modified herpes simplex virus-1 oncolytic virus OrienX010 in Chinese patients with unresectable stage IIIC-IV melanoma.MethodsPatients were treated in two different cohorts. In cohort 08 (n=12), patients received up to 5 mL of 8×107 pfu/mL OrienX010 intratumoral injections every 2 weeks until disease progression and responses were evaluated every 6 weeks. In cohort 09 (n=14), patients received up to 10 mL of 8×107 pfu/mL OrienX010 intratumoral injections and responses were evaluated every 8 weeks.ResultsBetween June 2014 and May 2017, 26 patients were enrolled, including 18 (69.2%) patients with acral melanoma. Fever and injection site reaction were the most frequent adverse events. Only one patient experienced a grade ≥3 adverse event and no dose-limiting toxicities were observed. The objective response rate was 19.2% and the disease control rate was 53.8%. The median duration of response was 6.0 months. Antitumor effects were observed in 54.6% of injected lesions and 48.8% of non-injected lesions, including one (16.7%) of six evaluable distant lung metastases. The median progression-free survival was 2.9 months and overall survival was 19.2 months. Compared with patients treated in cohort 08, patients treated in cohort 09 had an improved objective response rate (28.6% vs 8.3%) and a median progression-free survival of 3.0 months vs 2.8 months.ConclusionsOrienX010 oncolytic virotherapy has a tolerable safety profile with antitumor effects in both injected and non-injected metastases and warrants further evaluation in patients with melanoma. Based on these results, the higher cohort 09 dose (up to 10 mL of 8×107 pfu/mL every 2 weeks) was selected as the recommended phase II dose for ongoing trials.Trial registration numberCTR20140631 (cohort 08), CTR20150881 (cohort 09).

Project description:BackgroundStudies carried out in vitro and in a mouse model have shown that BRAF inhibitors enhance the effects of IFN-? on BRAFV600E melanoma cells through the inhibition of ERK. Therefore, the combination of vemurafenib and IFN-? in patients with BRAFV600E melanoma may provide therapeutic benefits; MEK inhibition may prevent the reactivation of the MAPK pathway induced by BRAF inhibitor resistance.Patients and methodsIn a phase I study, adult patients with advanced BRAFV600-mutated melanoma were treated with vemurafenib?+?PEG-IFN-?-2b or vemurafenib?+?cobimetinib?+?PEG-IFN-?-2b, to assess the safety of the combination and the upregulation of IFN-?/? receptor-1 (IFNAR1).ResultsEight patients were treated; 59 adverse events with four serious ones (three related to study treatments) were reported. Patients with a pre-treatment IFNAR1 expression on???35% melanoma cells had a median progression-free survival of 12.0 months (range: 5.6-18.4 months) and a median overall survival of 31.0 months (range: 19.8-42.2 months), while patients with a pre-treatment IFNAR1 expression on?>?35% of melanoma cells had a median progression-free survival of 4.0 months (range: 0-8.8; p?=?0.03), and a median overall survival of 5 months (p?=?0.02). Following treatment, responders had higher levels of growth-suppressor genes, including GAS1 and DUSP1, and genes involved in a metabolically robust immune response, including FAP.ConclusionOur study supports the overall safety of the vemurafenib?+?PEG-IFN-?-2b?+?cobimetinib combination. IFNAR1 expression levels correlated with response to treatment, including survival. Vemurafenib?+?PEG-IFN-?-2b?+?cobimetinib would have difficulty finding a niche in the current treatment scenario for advanced melanoma, but we speculate that our findings may contribute to identify subjects particularly responsive to treatment.Trial registrationThe study was registered at clinicaltrials.gov (NCT01959633). Registered 10 October 2013, https://clinicaltrials.gov/ct2/show/NCT01959633.

Project description:ImportanceIn the IMspire150 trial, triplet treatment with atezolizumab and vemurafenib plus cobimetinib significantly improved progression-free survival (PFS) compared with vemurafenib plus cobimetinib alone for treatment of BRAF V600 variation metastatic melanoma. However, considering high cost of this combination, it is unclear if the incremental cost is worth the additional survival benefit.ObjectiveTo evaluate the cost-effectiveness of atezolizumab and vemurafenib plus cobimetinib vs vemurafenib plus cobimetinib alone in patients with newly diagnosed unresectable BRAF V600 variation metastatic melanoma from the US health care perspective.Design, setting, and participantsThis economic evaluation study used a 3-state partitioned survival model to assess the cost-effectiveness of the combination of atezolizumab with vemurafenib plus cobimetinib vs vemurafenib plus cobimetinib alone. The observed Kaplan-Meier curves for overall survival and PFS were digitized from the IMspire150 trial (January 2017-April 2018) and the long-term survivals (over a lifetime horizon) beyond the end of the trial were extrapolated using 7 different survival models. The cost and health preference data were collected from a literature review. This study was performed from March 2021 through June 2021.Main outcomes and measuresThe outcomes of interest were expected life-years (LYs) gained and quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness ratio (ICER), expressed as cost per LYs and per QALYs saved.ResultsAdding atezolizumab to vemurafenib and cobimetinib provided an additional 3.267 QALYs compared with the doublet regimen of vemurafenib plus cobimetinib, at an ICER of $271 669 per QALY, which is not considered cost-effective at the willingness-to-pay threshold of $150 000 per QALY. However, the scenario analyses found that atezolizumab combined with vemurafenib plus cobimetinib could be cost-effective at 20-year (ICER, $121 432 per QALY) and 30-year ($98 092 per QALY) time horizons when both strategies were stopped after 2 years of treatments, and over a lifetime horizon ($122 220 per QALY) when only immunotherapy with atezolizumab was stopped after 2 years of treatment.Conclusions and relevanceThese findings suggest that the atezolizumab and vemurafenib plus cobimetinib regimen provides significant survival benefits over vemurafenib plus cobimetinib alone, and a price reduction would be encouraged to maximize the value of its survival gain.

Project description:Since 2001, there has been a rapid adoption of positron emission tomography (PET) for diagnosis and American Joint Committee on Cancer (AJCC) staging of head and neck cancer (HNC) without data describing improved clinical outcomes.To determine the association between increased use of PET and stage and/or survival for patients with HNC in the managed care environment.Adult patients diagnosed as having HNC (n = 958) from 2000 to 2008 at 4 integrated health systems were identified via tumor registries linked to administrative data. The AJCC stage distribution, patient and treatment characteristics, and survival between pre-PET era (2000-2004) vs PET era (2005-2008) and use of PET vs no use of PET during the PET era were compared. The AJCC stages were categorized to represent localized (stage I or II), locally advanced (stage III, IVA, or IVB), and metastatic (stage IVC) disease.Treatments were determined by billing codes for surgery, radiation treatment, and chemotherapy.The primary outcome for this study was the use of PET. Secondary outcomes included treatment received and 2-year survival. A logit model estimated the effects of PET on diagnosis of locally advanced disease. Kaplan-Meier estimates described overall survival differences between PET and non-PET. Cox regression evaluated the association of PET on survival in patients with locally advanced disease.An association between PET and locally advanced disease was found (odds ratio, 2.86 [95% CI, 1.90-4.29) (P < .001). Two-year overall survival for patients with locally advanced disease with and without PET was 52% and 32%, respectively (P = .004), but there was no difference for all stages (P = .69). On Cox proportional hazard regression, PET had no association with survival in patients with locally advanced disease (hazard ratio, 1.208 [95% CI, 0.778-1.877]) (P = .40).The increasing use of PET among patients with HNC is associated with a greater number of patients with higher-stage disease and a dilution of the population with higher-stage disease with patients who have a better prognosis. Thus, the improved survival in patients with locally advanced disease likely reflects selection bias and stage migration. Further research on PET use among patients with HNC is necessary to determine if it results in improved treatment for individual patients.

Dataset Information

Vemurafenib plus cobimetinib in unresectable stage IIIc or stage IV melanoma: response monitoring and resistance prediction with positron emission tomography and tumor characteristics (REPOSIT): study protocol of a phase II, open-label, multicenter study.

Publications

Vemurafenib plus cobimetinib in unresectable stage IIIc or stage IV melanoma: response monitoring and resistance prediction with positron emission tomography and tumor characteristics (REPOSIT): study protocol of a phase II, open-label, multicenter study.

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