Vemurafenib has previously demonstrated robust clinical activity in BRAFV600+ advanced/metastatic melanoma. We evaluated adjuvant vemurafenib in pts with BRAFV600+ melanoma with high recurrence risk.
This 2-cohort (C) study randomized 498 adult pts with fully resected stage IIC, IIIA, or IIIB (C1) melanoma or Stage IIIC melanoma (C2) 1:1 to vemurafenib 960 mg twice daily or placebo for 52 weeks. Stratification was by geographic region and additionally by disease stage in C1. The primary endpoint was disease-free survival (DFS). Hierarchical analysis of C2 before C1 was prespecified. Secondary objectives included safety, distant metastasis–free survival (DMFS), and overall survival (OS).
Median study followup was 34 months in C2 and 31 months in C1. In C2, median DFS was greater, though not statistically significant, with adjuvant vemurafenib vs placebo (Table). Adjuvant vemurafenib substantially improved DFS vs placebo in C1. Subgroup analyses by common disease and demographic covariates were consistent with the overall analysis. Results for DMFS were similar to that of DFS; OS data are immature. Median exposure to study drug was similar in both cohorts (median duration = 364.0 days; median dose intensity of ≈80% in both). Vemurafenib-treated pts in C1 and C2 had similar incidences of serious adverse events (AEs) (16.2% and 16.1% respectively); the rate of treatment discontinuation because of AEs was slightly higher in C1 (22.7%) than C2 (15.1%). Overall, the safety profile of adjuvant vemurafenib was consistent with previous data and no new safety signals were observed.
Although the study did not meet the primary DFS endpoint in pts with stage IIIC disease (C2), adjuvant vemurafenib appears to be effective and well tolerated in pts with resected stage IIC–IIIB BRAFV600+ melanoma (C1). Further followup is needed to assess OS benefit.Table:
LBA7_PR Summary of efficacy
|Cohort 1 (n = 314)||Cohort 2 (n = 184)||Overall (N = 498)|
|VEM (n = 157)||Placebo (n = 157)||VEM (n = 93)||Placebo (n = 91)||VEM (n = 250)||Placebo (n = 248)|
|Events, n (%)||45 (28.7)||72 (45.9)||52 (55.9)||53 (58.2)||97 (38.8)||125 (50.4)|
|Median time to event, months (95% CI)||NE||36.9 (21.4–NE)||23.1 (18.6–26.5)||15.4 (11.1–35.9)||NE (29.8–NE)||25.8 (20.5–NE)|
|HR (95% CI), Stratifieda log-rank P||0.54 (0.37–0.78) 0.0010||0.80 (0.54–1.18) 0.2598||0.65 (0.50–0.85) 0.0013|
|Events, n (%)||34 (21.7)||52 (33.1)||38 (40.9)||37 (40.7)||72 (28.8)||89 (35.9)|
|Median time to event, months (95% CI)||NE||NE (36.9–NE)||37.2 (22.1–NE)||30.7 (24.5–NE)||NE (37.2–NE)||47.8 (30.7–NE)|
|HR (95% CI), Stratifieda log-rank P||0.58 (0.37–0.90) 0.0133||0.91 (0.57–1.44) 0.6815||0.70 (0.52–0.96) 0.0265|
DFS, disease-free survival; DMFS, distant metastasis–free survival; HR, hazard ratio; NE, not evaluable; VEM, vemurafenib.a
Stratification was by region and disease stage for Cohort 1 and by region for Cohort 2.
Clinical trial identification
Trial protocol number: GO27826 v9 (14 March 2017). Data available from 12 July 2017.
Legal entity responsible for the study
F. Hoffmann-La Roche Ltd.
F. Hoffmann-La Roche Ltd.
K. Lewis: Grants from Roche/Genentech, Amgen, Incyte, and EMD Serono, and personal fees from Roche/Genentech, Incyte, and SunPharma, grants from Amgen, grants from EMD Serono. L. Demidov: Honoraria with MSD, Novartis (GSK), Roche, BMS; participated in a consulting or advisory role with BMS, MSD; received research funding with MSD, GSK, Roche, BMS, Novartis; and provided expert testimony for Amgen. M. Mandala: Grants and personal fees from Roche, and personal fees from Novartis, BMS, and MSD. P.A. Ascierto: Grants and personal fees from Roche-Genentech, BMS, and Array, and personal fees from MSD, Novartis, Amgen, Merck Serono, Pierre Fabre, and Incyte. P. Rutkowski: Grants and personal fees from Novartis, and personal fees from Roche, MSD, BMS, Amgen, Pfizer, and Blueprint. A. Guminski: Personal fees and other from BMS, personal fees from MSD, Merck, and Eisai, and travel support from Astellas. G. Goodman, B. Simmons, Y. Yan: Employee of and owns stock in Roche/Genentech. C. Ye: Employee of and owns stock and stock options in Roche/Genentech. D. Schadendorf: Patients\' fees from Novartis, Roche, Merck/MSD, GSK, and BMS, and personal fees from Amgen, Boehringer Ingelheim, Leo Pharma, Roche, Merck/MSD, and BMS. All other authors have declared no conflicts of interest.