Adjuvant vemurafenib provided substantial benefit to patients with completely resected stage IIC-IIIB BRAFV600 positive melanoma at high recurrence risk, where fewer disease-free survival (DFS) events and distant metastasis-free survival (DMFS) events were observed with vemurafenib compared to placebo, researchers reported during the ESMO 2017, the Annual Congress of the European Society for Medical Oncology in Madrid, Spain.
However, this benefit was not significant in patients with resected stage IIIC melanoma, where a trend towards improved DFS was seen.
Karl Lewis, an associate professor of medicine, Division of Medical Oncology, at the University of Colorado Denver School of Medicine, in Aurora, USA presented results of the BRIM8 trial, which compared adjuvant vemurafenib to placebo in patients with completely resected V600E BRAF-mutated melanoma who had a high risk of recurrence.
BRIM8 was a randomised, double-blind, placebo-controlled, 2-cohort study that placed 498 adult patients with fully resected stage IIC, IIIA, or IIIB melanoma into cohort 1 and patients with stage IIIC melanoma to cohort 2. Both cohorts were randomly assigned to vemurafenib at 960 mg twice daily or placebo for 52 weeks. In cohort 1, patients were also stratified by geographic region and disease stage.
The primary endpoint of BRIM8 was DFS. Secondary objectives included safety, DMFS, and overall survival (OS). A hierarchical analysis of cohort 2 data prior to cohort 1 was prespecified.
Greater DFS seen with vemurafenib at nearly three years of follow-up
As of the clinical cut-off date for the primary analysis, cohorts 2 and 1 had a median follow-up of 34 and 31 months, respectively.
Cohort 2 contained 184 patients with resected stage IIIC melanoma, including 93 patients on adjuvant vemurafenib and 91 patients on placebo. Analysis of the data revealed a trend towards improved DFS with adjuvant vemurafenib compared to placebo; DFS events occurred in 52 (55.9%) versus 53 (58.2%) of patients, respectively, hazard ratio [HR] 0.80; 95% confidence interval [CI] 0.54, 1.18 (p = 0.2598). The DMFS was similar between treatment arms in cohort 2, HR 0.91 (p = 0.6815).
However, in cohort 1, which included patients with resected stages IIC, IIIA, or IIIB melanoma, adjuvant vemurafenib substantially improved DFS versus placebo. Of the 157 patients in each treatment arm, 45 (28.7%) versus 72 (45.9%) patients receiving vemurafenib versus placebo experienced a DFS event and the median time to event was ‘not estimated’ versus 36.9 months (95% CI 21, NE), respectively, HR 0.54; 95% CI 0.37, 0.78 (p = 0.0010).
Cohort 1 data for DMFS reflected that of DFS: DMFS events occurred in 21.7% of vemurafenib patients versus 33.1% of placebo treated patients and the median time to DMFS event was not estimated for both groups, HR 0.58 (p = 0.0133).
Subgroup analyses were conducted in cohort 1 by common disease and demographic covariates that showed results that were consistent with the overall analysis.
The OS data are immature for both cohorts.
Both cohorts had a similar exposure to study drug with a median duration of 364.0 days and the median dose intensity was approximately 80% overall.
Patients receiving vemurafenib in cohorts 1 and 2 had a similar incidence of serious adverse events (AEs) of 16.2% and 16.1%, respectively. Cohort 1 showed a slightly higher rate of treatment discontinuation due to a treatment related AEs of 22.7% compared to 15.1% in cohort 2.
Vemurafenib is currently indicated in first line BRAFV600 positive advanced melanoma
Current indications for vemurafenib include approval by the European Medicines Agency as a monotherapy or in combination with cobimetinib for the treatment of adult patients with BRAF V600E mutation-positive unresectable or metastatic melanoma and US Food and Drug Administration (FDA) approval for the treatment of patients with unresectable or metastatic melanoma with the BRAF V600E mutation as detected by an FDA-approved test.
Conclusions
Although the study did not meet the primary DFS endpoint in patients with stage IIIC disease, adjuvant vemurafenib appeared to be well tolerated and effective in patients with resected stage IIC–IIIB BRAFV600 positive melanoma.
Overall, the safety profile of adjuvant vemurafenib was consistent with previous data and no new safety signals were observed.
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