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Vemurafenib in patients with BRAFV600 mutation-positive metastatic melanoma: final overall survival results of the randomized BRIM-3 study.

ABSTRACT: Background:The BRIM-3 trial showed improved progression-free survival (PFS) and overall survival (OS) for vemurafenib compared with dacarbazine in treatment-naive patients with BRAFV600 mutation-positive metastatic melanoma. We present final OS data from BRIM-3. Patients and methods:Patients were randomly assigned in a 1 : 1 ratio to receive vemurafenib (960?mg twice daily) or dacarbazine (1000?mg/m2 every 3?weeks). OS and PFS were co-primary end points. OS was assessed in the intention-to-treat population, with and without censoring of data for dacarbazine patients who crossed over to vemurafenib. Results:Between 4 January 2010 and 16 December 2010, a total of 675 patients were randomized to vemurafenib (n?=?337) or dacarbazine (n?=?338, of whom 84 crossed over to vemurafenib). At the time of database lock (14 August 2015), median OS, censored at crossover, was significantly longer for vemurafenib than for dacarbazine {13.6?months [95% confidence interval (CI) 12.0-15.4] versus 9.7?months [95% CI 7.9-12.8; hazard ratio (HR) 0.81 [95% CI 0.67-0.98]; P?=?0.03}, as was median OS without censoring at crossover [13.6?months (95% CI 12.0-15.4) versus 10.3?months (95% CI 9.1-12.8); HR 0.81 (95% CI 0.68-0.96); P?=?0.01]. Kaplan-Meier estimates of OS rates for vemurafenib versus dacarbazine were 56% versus 46%, 30% versus 24%, 21% versus 19% and 17% versus 16% at 1, 2, 3 and 4?years, respectively. Overall, 173 of the 338 patients (51%) in the dacarbazine arm and 175 of the 337 (52%) of those in the vemurafenib arm received subsequent anticancer therapies, most commonly ipilimumab. Safety data were consistent with the primary analysis. Conclusions:Vemurafenib continues to be associated with improved median OS in the BRIM-3 trial after extended follow-up. OS curves converged after??3?years, likely as a result of crossover from dacarbazine to vemurafenib and receipt of subsequent anticancer therapies. ClinicalTrials.gov:NCT01006980.

SUBMITTER: Chapman PB

PROVIDER: S-EPMC5834156 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Vemurafenib in patients with BRAFV600 mutation-positive metastatic melanoma: final overall survival results of the randomized BRIM-3 study.

Chapman P B PB Robert C C Larkin J J Haanen J B JB Ribas A A Hogg D D Hamid O O Ascierto P A PA Testori A A Lorigan P C PC Dummer R R Sosman J A JA Flaherty K T KT Chang I I Coleman S S Caro I I Hauschild A A McArthur G A GA

Annals of oncology : official journal of the European Society for Medical Oncology 20171001 10

<h4>Background</h4>The BRIM-3 trial showed improved progression-free survival (PFS) and overall survival (OS) for vemurafenib compared with dacarbazine in treatment-naive patients with BRAFV600 mutation-positive metastatic melanoma. We present final OS data from BRIM-3.<h4>Patients and methods</h4>Patients were randomly assigned in a 1 : 1 ratio to receive vemurafenib (960 mg twice daily) or dacarbazine (1000 mg/m2 every 3 weeks). OS and PFS were co-primary end points. OS was assessed in the int ...[more]

PMID: 28961848

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Project description:BackgroundIn the OlympiAD study, olaparib was shown to improve progression-free survival compared with chemotherapy treatment of physician's choice (TPC) in patients with a germline BRCA1 and/or BRCA2 mutation (BRCAm) and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (mBC). We now report the planned final overall survival (OS) results, and describe the most common adverse events (AEs) to better understand olaparib tolerability in this population.Patients and methodsOlympiAD, a Phase III, randomized, controlled, open-label study (NCT02000622), enrolled patients with a germline BRCAm and HER2-negative mBC who had received ≤2 lines of chemotherapy for mBC. Patients were randomized to olaparib tablets (300 mg bid) or predeclared TPC (capecitabine, vinorelbine, or eribulin). OS and safety were secondary end points.ResultsA total of 205 patients were randomized to olaparib and 97 to TPC. At 64% data maturity, median OS was 19.3 months with olaparib versus 17.1 months with TPC (HR 0.90, 95% CI 0.66-1.23; P = 0.513); median follow-up was 25.3 and 26.3 months, respectively. HR for OS with olaparib versus TPC in prespecified subgroups were: prior chemotherapy for mBC [no (first-line setting): 0.51, 95% CI 0.29-0.90; yes (second/third-line): 1.13, 0.79-1.64]; receptor status (triple negative: 0.93, 0.62-1.43; hormone receptor positive: 0.86, 0.55-1.36); prior platinum (yes: 0.83, 0.49-1.45; no: 0.91, 0.64-1.33). Adverse events during olaparib treatment were generally low grade and manageable by supportive treatment or dose modification. There was a low rate of treatment discontinuation (4.9%), and the risk of developing anemia did not increase with extended olaparib exposure.ConclusionsWhile there was no statistically significant improvement in OS with olaparib compared to TPC, there was the possibility of meaningful OS benefit among patients who had not received chemotherapy for metastatic disease. Olaparib was generally well-tolerated, with no evidence of cumulative toxicity during extended exposure. Please see the article online for additional video content.

Project description:On November 6, 2017, the U.S. Food and Drug Administration (FDA) granted regular approval to vemurafenib for the treatment of adult patients with Erdheim-Chester disease (ECD) with BRAFV600 mutation. ECD is a type of histiocytosis, a rare disorder characterized by an abnormal accumulation and behavior of cells of the mononuclear phagocytic system, which includes antigen-processing cells, dendritic cells, monocytes, or macrophages. Recently published data confirm a frequency of 54% of BRAFV600E mutations in patients with ECD.Approval was based on a cohort of 22 patients who received 960 mg of vemurafenib twice daily within the VE Basket Trial (MO28072), a single-arm, multicenter, multiple cohort study. Patients in the ECD cohort had histologically confirmed ECD with BRAFV600 mutations that were refractory to standard therapy. The ECD cohort achieved an overall response rate of 54.5% (95% confidence interval: 32.2-75.6), with a complete response rate of 4.5%. With a median duration of follow-up of 26.6 months, the median duration of response has not been reached. The most frequently reported adverse reactions (>50%) in the ECD cohort were arthralgia, rash maculo-papular, alopecia, fatigue, electrocardiogram QT interval prolonged, and skin papilloma. The median treatment duration for ECD patients in this study was 14.2 months. This article describes the FDA review of the vemurafenib efficacy supplement for patients with ECD with BRAFV600 mutations. IMPLICATIONS FOR PRACTICE: Vemurafenib, an oral monotherapy targeting a mutation in BRAF, is the first U.S. Food and Drug Administration approval for the treatment of Erdheim-Chester disease (ECD). ECD is an extremely rare hematopoietic neoplasm that represents clonal proliferation of myeloid progenitor cells. ECD may involve bone and one or more organ systems, primarily affecting adults in their 5th and 7th decades of life, with a slight male predominance. This approval provides an effective and reasonably safe therapy for patients with a serious and life-threatening condition for which no approved therapy exists.

Dataset Information

Vemurafenib in patients with BRAFV600 mutation-positive metastatic melanoma: final overall survival results of the randomized BRIM-3 study.

Publications

Vemurafenib in patients with BRAFV600 mutation-positive metastatic melanoma: final overall survival results of the randomized BRIM-3 study.

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