Adjuvant vemurafenib in resected, BRAF^V600 mutation-positive melanoma (BRIM8): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial

Summary

Background

Systemic adjuvant treatment might mitigate the high risk of disease recurrence in patients with resected stage IIC–III melanoma. The BRIM8 study evaluated adjuvant vemurafenib monotherapy in patients with resected, BRAF^V600 mutation-positive melanoma.

Methods

BRIM8 was a phase 3, international, double-blind, randomised, placebo-controlled study that enrolled 498 adults (aged ≥18 years) with histologically confirmed stage IIC–IIIA–IIIB (cohort 1) or stage IIIC (cohort 2) BRAF^V600 mutation-positive melanoma that was fully resected. Patients were randomly assigned (1:1) by an interactive voice or web response system to receive twice-daily adjuvant oral vemurafenib 960 mg tablets or matching placebo for 52 weeks (13 × 28-day cycles). Randomisation was done by permuted blocks (block size 6) and was stratified by pathological stage and region in cohort 1 and by region in cohort 2. The investigators, patients, and sponsor were masked to treatment assignment. The primary endpoint was disease-free survival in the intention-to-treat population, evaluated separately in each cohort. Hierarchical analysis of cohort 2 before cohort 1 was prespecified. This trial is registered with ClinicalTrials.gov, number NCT01667419.

Findings

The study enrolled 184 patients in cohort 2 (93 were assigned to vemurafenib and 91 to placebo) and 314 patients in cohort 1 (157 were assigned to vemurafenib and 157 to placebo). At the time of data cutoff (April 17, 2017), median study follow-up was 33·5 months (IQR 25·9–41·6) in cohort 2 and 30·8 months (25·5–40·7) in cohort 1. In cohort 2 (patients with stage IIIC disease), median disease-free survival was 23·1 months (95% CI 18·6–26·5) in the vemurafenib group versus 15·4 months (11·1–35·9) in the placebo group (hazard ratio [HR] 0·80, 95% CI 0·54–1·18; log-rank p=0·026). In cohort 1 (patients with stage IIC–IIIA–IIIB disease) median disease-free survival was not reached (95% CI not estimable) in the vemurafenib group versus 36·9 months (21·4–not estimable) in the placebo group (HR 0·54 [95% CI 0·37–0·78]; log-rank p=0·0010); however, the result was not significant because of the prespecified hierarchical prerequisite for the primary disease-free survival analysis of cohort 2 to show a significant disease-free survival benefit. Grade 3–4 adverse events occurred in 141 (57%) of 247 patients in the vemurafenib group and 37 (15%) of 247 patients in the placebo group. The most common grade 3–4 adverse events in the vemurafenib group were keratoacanthoma (24 [10%] of 247 patients), arthralgia (17 [7%]), squamous cell carcinoma (17 [7%]), rash (14 [6%]), and elevated alanine aminotransferase (14 [6%]), although all keratoacanthoma events and most squamous cell carcinoma events were by default graded as grade 3. In the placebo group, grade 3–4 adverse events did not exceed 2% for any of the reported terms. Serious adverse events were reported in 40 (16%) of 247 patients in the vemurafenib group and 25 (10%) of 247 patients in the placebo group. The most common serious adverse event was basal cell carcinoma, which was reported in eight (3%) patients in each group. One patient in the vemurafenib group of cohort 2 died 2 months after admission to hospital for grade 3 hypertension; however, this death was not considered to be related to the study drug.

Interpretation

The primary endpoint of disease-free survival was not met in cohort 2, and therefore the analysis of cohort 1 showing a numerical benefit in disease-free survival with vemurafenib versus placebo in patients with resected stage IIC–IIIA–IIIB BRAF^V600 mutation-positive melanoma must be considered exploratory only. 1 year of adjuvant vemurafenib was well tolerated, but might not be an optimal treatment regimen in this patient population.

Funding

F Hoffman–La Roche Ltd.

Introduction

Surgical resection of the primary tumour or affected lymph nodes is the standard of care in patients with stage II–III melanoma.¹ Despite full resection, patients with stage IIC–III melanoma remain at high risk for disease recurrence and death.2, 3, 4 This situation warrants the use of adjuvant approaches to improve clinical outcomes. Clinical studies of systemic adjuvant options that were approved at the time when this study was being designed (2011) had shown either limited effectiveness or unfavourable toxicity profiles. Data for overall survival benefit in individual studies of adjuvant interferon-α are conflicting,2, 5, 6 and although ipilimumab monotherapy significantly improved outcomes versus placebo (recurrence-free survival hazard ratio [HR] 0·76 [95% CI 0·64–0·89]; p<0·001), it was associated with substantial toxicity (53% of patients discontinued treatment because of adverse events, 42% had grade 3–4 immune-related adverse events, and 1% had fatal immune-related adverse events).⁷ More recently, the COMBI-AD and CheckMate 238 studies showed improved survival in patients with resected stage III or stage IIIB–IV melanoma, respectively.8, 9

Research in context

Evidence before this study

At the time this study was conceived (2011), patients with an initial diagnosis of stage IIC–III melanoma (per AJCC version 7 criteria) that was fully resected continued to have a clinically significant risk of recurrence and death, and interferons were the only approved adjuvant option. We searched PubMed from inception until Dec 31, 2011, for reports from large controlled clinical studies in this patient population with the search terms “melanoma” and “adjuvant” (sorted by publication date and clinical trial; abstracts were manually curated to include only studies with more than 100 patients). We also searched across major international oncology congresses. Studies showed that various interferon regimens, including interferon-α2a, interferon-α2b, and pegylated interferon-α2b, had been explored. A synthesis of data from these studies suggested that no clear evidence showed that interferon improved overall survival, and that there was no consensus regarding the optimal dosing intensity and duration of adjuvant interferon treatment. Moreover, the tolerability of these interferon regimens was not favourable, as evidenced by discontinuation rates ranging from around 30% to 57% and a decline in patient-reported health-related quality of life in some of these studies.

Added value of this study

Most controlled studies of adjuvant treatment so far have been single-cohort studies in patients with resected stage III–IV disease. In BRIM8, a two-cohort design was used to separately evaluate efficacy in patients with fully resected, BRAF^V600 mutation-positive disease that was either stage IIC–IIIB or stage IIIC at diagnosis, because the risk of recurrence or death is quite different in these populations. This design allowed for differentiation of clinical benefit in these patient populations, with prespecified and distinct statistical considerations in each cohort. The study showed that although vemurafenib monotherapy was biologically active in patients with stage IIIC disease, a significant improvement in disease-free survival was not observed and the study did not achieve the primary endpoint. Vemurafenib monotherapy did provide a risk reduction of disease-free survival events in patients with resected stage IIC–IIIB disease, but the result could not be considered significant because of the protocol-defined prerequisite for the disease-free survival benefit in patients with stage IIIC disease to be significant.

Implications of all the available evidence

The study did not meet its primary endpoint. The data from the BRIM8 study suggest that the optimal dosing and intensity of adjuvant treatment might vary by the magnitude of recurrence risk.

In patients with melanoma, 5-year survival rates vary quite broadly by stage of disease at diagnosis. In patients with stage IIC–IIIB melanoma, 5-year survival ranges from approximately 55% to 78%, whereas 5-year-survival for patients with stage IIIC disease is around 40%.² Approximately 50% of patients with melanoma have tumours that harbour the BRAF^V600 mutation,¹⁰ and the orally administered BRAF inhibitor vemurafenib has been shown to be an effective and safe treatment for patients with BRAF^V600 mutation-positive advanced or metastatic melanoma.11, 12 Accordingly, we did a placebo-controlled study to evaluate the efficacy and safety of 1 year of adjuvant vemurafenib in two cohorts of patients with resected, BRAF^V600 mutation-positive melanoma: one cohort of patients with stage IIC–IIIB disease and the other with patients with stage IIIC disease only. The planned treatment duration of 1 year of adjuvant vemurafenib was based on previous studies of various adjuvant interferon regimens for melanoma.⁵