Elsevier

The Lancet Oncology

Volume 15, Issue 3, March 2014, Pages 323-332
The Lancet Oncology

Articles
Safety and efficacy of vemurafenib in BRAFV600E and BRAFV600K mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study

https://doi.org/10.1016/S1470-2045(14)70012-9Get rights and content

Summary

Background

In the BRIM-3 trial, vemurafenib was associated with risk reduction versus dacarbazine of both death and progression in patients with advanced BRAFV600 mutation-positive melanoma. We present an extended follow-up analysis of the total population and in the BRAFV600E and BRAFV600K mutation subgroups.

Methods

Patients older than 18 years, with treatment-naive metastatic melanoma and whose tumour tissue was positive for BRAFV600 mutations were eligible. Patients also had to have a life expectancy of at least 3 months, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate haematological, hepatic, and renal function. Patients were randomly assigned by interactive voice recognition system to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg/m2 of body surface area intravenously every 3 weeks). Coprimary endpoints were overall survival and progression-free survival, analysed in the intention-to-treat population (n=675), with data censored at crossover. A sensitivity analysis was done. This trial is registered with ClinicalTrials.gov, NCT01006980.

Findings

675 eligible patients were enrolled from 104 centres in 12 countries between Jan 4, 2010, and Dec 16, 2010. 337 patients were randomly assigned to receive vemurafenib and 338 to receive dacarbazine. Median follow-up was 12·5 months (IQR 7·7–16·0) on vemurafenib and 9·5 months (3·1–14·7) on dacarbazine. 83 (25%) of the 338 patients initially randomly assigned to dacarbazine crossed over from dacarbazine to vemurafenib. Median overall survival was significantly longer in the vemurafenib group than in the dacarbazine group (13·6 months [95% CI 12·0–15·2] vs 9·7 months [7·9–12·8]; hazard ratio [HR] 0·70 [95% CI 0·57–0·87]; p=0·0008), as was median progression-free survival (6·9 months [95% CI 6·1–7·0] vs 1·6 months [1·6–2·1]; HR 0·38 [95% CI 0·32–0·46]; p<0·0001). For the 598 (91%) patients with BRAFV600E disease, median overall survival in the vemurafenib group was 13·3 months (95% CI 11·9–14·9) compared with 10·0 months (8·0–14·0) in the dacarbazine group (HR 0·75 [95% CI 0·60–0·93]; p=0·0085); median progression-free survival was 6·9 months (95% CI 6·2–7·0) and 1·6 months (1·6–2·1), respectively (HR 0·39 [95% CI 0·33–0·47]; p<0·0001). For the 57 (9%) patients with BRAFV600K disease, median overall survival in the vemurafenib group was 14·5 months (95% CI 11·2–not estimable) compared with 7·6 months (6·1–16·6) in the dacarbazine group (HR 0·43 [95% CI 0·21–0·90]; p=0·024); median progression-free survival was 5·9 months (95% CI 4·4–9·0) and 1·7 months (1·4–2·9), respectively (HR 0·30 [95% CI 0·16–0·56]; p<0·0001). The most frequent grade 3–4 events were cutaneous squamous-cell carcinoma (65 [19%] of 337 patients) and keratoacanthomas (34 [10%]), rash (30 [9%]), and abnormal liver function tests (38 [11%]) in the vemurafenib group and neutropenia (26 [9%] of 287 patients) in the dacarbazine group. Eight (2%) patients in the vemurafenib group and seven (2%) in the dacarbazine group had grade 5 events.

Interpretation

Inhibition of BRAF with vemurafenib improves survival in patients with the most common BRAFV600E mutation and in patients with the less common BRAFV600K mutation.

Funding

F Hoffmann-La Roche-Genentech.

Introduction

In the USA, more than 76 000 cases of melanoma are expected to be diagnosed in 2013, with 9180 deaths.1, 2 Most are diagnosed at a localised stage with a 5-year overall survival of 91·2%.1 However, metastatic melanoma has a poor prognosis, and 5-year survival is 61·7% with regional stage disease and 15·2% with distant stage disease.1

Chemotherapy has limited success in metastatic melanoma, with responses noted in 6·3–12·1% of patients, and a median overall survival of 5·6–9·7 months in phase 3 trials of dacarbazine.3, 4, 5, 6 Combinations of cytostatic drugs and cytokines have not improved survival.7, 8 High-dose interleukin 2 can induce complete remission in some patients, which was the basis of its approval,9 but no predictive biomarkers for the patient's response exist. In 2011, with the approval of the CTLA-4 antibody ipilimumab for all patients with advanced disease and of the BRAF inhibitor vemurafenib for BRAF-mutated disease, treatment for advanced disease finally improved.9, 10, 11 Dabrafenib, a BRAF inhibitor, and trametinib, a MEK inhibitor, have also been approved recently. Benefit from BRAF inhibition is consistent with the role of an activated RAS-RAF-MEK-ERK MAPK pathway as a major driver for transformation into malignant melanoma.12

The prevalence of BRAF codon 600 mutations in patients with melanoma ranges between 40% and 60%. The most prevalent mutations in melanoma are BRAFV600E (about 80%) and BRAFV600K (5–30%); other mutations are rare.12, 13 In the phase 2 trial of vemurafenib,14 8% of patients had BRAFV600K melanoma; in a phase 2 trial15 of dabrafenib in patients with metastatic melanoma with brain metastases, 19% of patients had the BRAFV600K mutation. The ability to detect the BRAFV600K mutation also differs according to the methods used for mutation testing. The cobas 4800 BRAF V600 Mutation Test (cobas test; Roche Molecular Systems, Pleasanton, CA, USA), although specifically designed to detect the BRAFV600E mutation, detects 70% of BRAFV600K mutations, and is approved by the US Food and Drug Administration.16 By contrast with BRAFV600E, the frequency of BRAFV600K seems to increase with age.13 BRAFV600K mutation-positive melanoma is also associated with a higher degree of cumulative sun-induced damage, which might explain the variable frequency of BRAFV600K between studies in view of geographical variation in ultraviolet exposure.13 Data from a retrospective analysis of 80 patients with BRAF-mutated tumours, including 56 patients with melanoma, suggest that BRAFV600K mutations in metastatic melanoma might be associated with more frequent brain and lung metastases and a shorter time from diagnosis to metastasis and death than other BRAF mutations.17

BRIM-311 was a randomised phase 3 trial that compared vemurafenib with dacarbazine in patients with unresectable, previously untreated stage IIIc or IV melanoma that was positive for the BRAFV600 mutation. In the initial, prespecified analysis for the coprimary endpoints of overall survival and progression-free survival (Dec 30, 2010, cutoff), vemurafenib was associated with significant reductions in the risk for death and of either death or disease progression, compared with dacarbazine.11 Benefit with vemurafenib compared with dacarbazine was noted across patient subgroups, including those with stage IIIc and stage IV disease, and irrespective of lactate dehydrogenase concentrations.11

We present an update of safety and efficacy for the BRIM-3 study11 with extended follow-up for the entire population, and also analyse the efficacy and safety of vemurafenib versus dacarbazine in patients with BRAFV600E and BRAFV600K mutation-positive disease.

Section snippets

Study design and patients

Details of the BRIM-3 study have been reported elsewhere.11 Patients recruited from 104 centres in 12 countries worldwide with treatment-naive metastatic melanoma (unresectable stage IIIc or stage IV M1a, M1b, or M1c disease) were eligible if their tumour tissue was positive for the presence of BRAFV600 mutations by the cobas test. Additional key inclusion criteria included age of 18 years or older, a life expectancy of 3 months or longer, an Eastern Cooperative Oncology Group (ECOG)

Results

Of 2107 patients screened, we enrolled 675 eligible patients between Jan 4, 2010, and Dec 16, 2010. 337 patients were randomly assigned to receive vemurafenib and 338 to receive dacarbazine (figure 1). 399 (59%) patients had died by data cutoff (Feb 1, 2012). Five non-melanoma deaths occurred in the dacarbazine group and 11 in the vemurafenib group. The baseline characteristics of the intention-to-treat patient population have been described previously;11 the dacarbazine and vemurafenib groups

Discussion

This analysis, with a median follow-up of 12·5 months in the vemurafenib group and 9·5 months in the dacarbazine group, confirms the improved efficacy of vemurafenib versus dacarbazine for patients with BRAFV600 mutation-positive metastatic melanoma noted in the primary analysis of this study; the safety profile was also consistent with that in the primary analysis (panel).11

The HR for overall survival favouring vemurafenib in the present analysis is lower than that reported in the initial

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