Elsevier

The Lancet

Volume 386, Issue 9992, 1–7 August 2015, Pages 444-451
The Lancet

Articles
Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial

https://doi.org/10.1016/S0140-6736(15)60898-4Get rights and content

Summary

Background

Previously, a study of ours showed that the combination of dabrafenib and trametinib improves progression-free survival compared with dabrafenib and placebo in patients with BRAF Val600Lys/Glu mutation-positive metastatic melanoma. The study was continued to assess the secondary endpoint of overall survival, which we report in this Article.

Methods

We did this double-blind phase 3 study at 113 sites in 14 countries. We enrolled previously untreated patients with BRAF Val600Glu or Val600Lys mutation-positive unresectable stage IIIC or stage IV melanoma. Participants were computer-randomised (1:1) to receive a combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily), or dabrafenib and placebo. The primary endpoint was progression-free survival and overall survival was a secondary endpoint. This study is registered with ClinicalTrials.gov, number NCT01584648.

Findings

Between May 4, 2012, and Nov 30, 2012, we screened 947 patients for eligibility, of whom 423 were randomly assigned to receive dabrafenib and trametinib (n=211) or dabrafenib only (n=212). The final data cutoff was Jan 12, 2015, at which time 222 patients had died. Median overall survival was 25·1 months (95% CI 19·2–not reached) in the dabrafenib and trametinib group versus 18·7 months (15·2–23·7) in the dabrafenib only group (hazard ratio [HR] 0·71, 95% CI 0·55–0·92; p=0·0107). Overall survival was 74% at 1 year and 51% at 2 years in the dabrafenib and trametinib group versus 68% and 42%, respectively, in the dabrafenib only group. Based on 301 events, median progression-free survival was 11·0 months (95% CI 8·0–13·9) in the dabrafenib and trametinib group and 8·8 months (5·9–9·3) in the dabrafenib only group (HR 0·67, 95% CI 0·53–0·84; p=0·0004; unadjusted for multiple testing). Treatment-related adverse events occurred in 181 (87%) of 209 patients in the dabrafenib and trametinib group and 189 (90%) of 211 patients in the dabrafenib only group; the most common was pyrexia (108 patients, 52%) in the dabrafenib and trametinib group, and hyperkeratosis (70 patients, 33%) in the dabrafenib only group. Grade 3 or 4 adverse events occurred in 67 (32%) patients in the dabrafenib and trametinib group and 66 (31%) patients in the dabrafenib only group.

Interpretation

The improvement in overall survival establishes the combination of dabrafenib and trametinib as the standard targeted treatment for BRAF Val600 mutation-positive melanoma. Studies assessing dabrafenib and trametinib in combination with immunotherapies are ongoing.

Funding

GlaxoSmithKline.

Introduction

Dabrafenib, an oral BRAF inhibitor, combined with trametinib, an oral MEK inhibitor, improved progression-free survival compared with dabrafenib monotherapy in patients with BRAF Val600Lys/Glu mutation-positive stage IIIC unresectable melanoma or stage IV melanoma in a randomised phase 2 study1 and in the primary analysis of this phase 3 study (COMBI-d).2 In the primary analysis of COMBI-d, with a median follow-up of 9 months (range 0–16), median progression-free survival was 9·3 months for the combination and 8·8 months for dabrafenib monotherapy, with a hazard ratio (HR) of 0·75 (95% CI 0·57–0·99; p=0·0348). The combination also improved progression-free survival and overall survival compared with single agent vemurafenib, another oral BRAF inhibitor, in a second phase 3 study (COMBI-v).3 In that study, median overall survival was not reached for the combination and was 17·2 months for vemurafenib, with an HR of 0·69 (95% CI 0·53–0·89; p=0·0049). In all three studies, adverse events related to paradoxical activation of the MAPK pathway were reduced with the combination compared with BRAF inhibitor monotherapy, however, pyrexia was more common and more severe.

We report the final overall survival analysis for the randomised, double-blind phase 3 study of dabrafenib combined with trametinib compared with dabrafenib combined with placebo in previously untreated patients with BRAF Val600Glu/Lys mutation-positive metastatic melanoma, and provide the latest findings for progression-free survival, response rate, duration of response, and safety.

Research in context

Evidence before this study

We searched PubMed up to March 8, 2015, for phase 1–3 clinical trials with the terms “combination”, “BRAF”, “MEK”, and “melanoma”. We identified 154 articles; of which, five were phase 1, 2, or 3 clinical trials of combined BRAF and MEK inhibitors. We searched the American Society for Clinical Oncology conference abstracts and identified three additional abstracts of clinical trials of combined BRAF and MEK inhibition that had not been published in full. BRAF and MEK inhibition decreased the number of hyperkeratotic skin toxic effects caused by paradoxical activation of the MAPK pathway, and delayed the onset of resistance compared with single-drug BRAF inhibition in preclinical studies of Val600Glu BRAF mutant models. This finding led to a phase 1/2 study of combined dabrafenib and trametinib in patients with Val600 BRAF mutation-positive metastatic melanoma. The phase 1 part of the study showed more responses, longer progression-free survival, and fewer cases of cutaneous squamous-cell carcinoma compared with historic controls treated with a single BRAF inhibitor. In the randomised phase 2 part of the study, the combination resulted in more responses (76% vs 54%, p=0·0264) and longer progression-free survival (9·4 months vs 5·8 months, HR 0·39, p<0·0001) than did monotherapy, with decreased oncogenic toxic effects (cutaneous squamous cell carcinoma and hyperkeratosis). Similarly, results of early-phase studies of other BRAF inhibitor and MEK inhibitor combinations showed more responses, a longer progression-free survival, and reduced incidence of cutaneous squamous-cell carcinoma, strongly supporting the rationale for a phase 3 trial of combined dabrafenib and trametinib versus BRAF inhibitor monotherapy.

Added value of this study

We report the final overall survival analysis of a double-blind, placebo-controlled, phase 3, randomised trial of the combination of dabrafenib and trametinib versus dabrafenib monotherapy. This study is also the most mature survival analysis for any phase 3 trial assessing the superiority of combined BRAF and MEK inhibition versus BRAF inhibition alone; thus we report the first median overall survival for any of the BRAF and MEK combinations from a phase 3 study (25·1 months). It adds weight to the open-label phase 3 trial of the same combination versus vemurafenib (the first BRAF inhibitor shown to improve overall survival compared with chemotherapy), which also resulted in improved overall survival (HR 0·69, p=0·0049) in favour of the combination.

Implications of all the available evidence

Our findings confirm the superiority of dabrafenib and trametinib in terms of the number of responses, duration of response, progression-free survival, and overall survival compared with the internationally approved BRAF inhibitors dabrafenib and vemurafenib. The combination reduced oncogenic adverse events caused by MAPK pathway reactivation. These data support the use of combined dabrafenib and trametinib as the standard targeted treatment for patients with Val600 BRAF mutation-positive metastatic melanoma.

Section snippets

Study design and patients

We did this double-blind, randomised, phase 3 study at 113 sites in 14 countries. Eligible patients were at least 18 years old and had histologically confirmed, unresectable stage IIIC or stage IV metastatic melanoma with BRAF Val600Glu or Val600Lys mutations, as determined by PCR (ThxID BRAF Assay, bioMérieux) done at a central reference laboratory. Patients were ineligible if they had previous systemic treatment for advanced or metastatic cancer. Patients with brain metastases that had been

Results

From May 4, 2012, to Nov 30, 2012, we screened 947 patients. The most common reason for screening failure was absence of a BRAF mutation. 423 were randomly assigned to receive a combination of dabrafenib and trametinib (211 patients), or dabrafenib and placebo (212 patients; figure 1). The treatment groups were well balanced for age, sex, ECOG performance status, lactate dehydrogenase, and M stage (table 1). As of the Jan 12, 2015 final data cutoff, 64 (30%) of 211 patients in the dabrafenib

Discussion

In this study, we showed that first-line treatment with a combination of dabrafenib and trametinib significantly improved overall survival and reduced the risk of death by 29% in patients with BRAF Val600Glu/Lys positive metastatic melanoma compared with dabrafenib alone. This survival benefit occurred despite more patients in the dabrafenib only group having subsequent cancer treatments after progression and cessation of study treatment, including treatments that prolong survival in patients

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