Elsevier

The Lancet Oncology

Volume 17, Issue 9, September 2016, Pages 1248-1260
The Lancet Oncology

Articles
Cobimetinib combined with vemurafenib in advanced BRAFV600-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial

https://doi.org/10.1016/S1470-2045(16)30122-XGet rights and content

Summary

Background

The combination of cobimetinib with vemurafenib improves progression-free survival compared with placebo and vemurafenib in previously untreated patients with BRAFV600-mutant advanced melanoma, as previously reported in the coBRIM study. In this Article, we report updated efficacy results, including overall survival and safety after longer follow-up, and selected biomarker correlative studies.

Methods

In this double-blind, randomised, placebo-controlled, multicentre study, adult patients (aged ≥18 years) with histologically confirmed BRAFV600 mutation-positive unresectable stage IIIC or stage IV melanoma were randomly assigned (1:1) using an interactive response system to receive cobimetinib (60 mg once daily for 21 days followed by a 7-day rest period in each 28-day cycle) or placebo, in combination with oral vemurafenib (960 mg twice daily). Progression-free and overall survival were primary and secondary endpoints, respectively; all analyses were done on the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01689519, and is ongoing but no longer recruiting participants.

Findings

Between Jan 8, 2013, and Jan 31, 2014, 495 eligible adult patients were enrolled and randomly assigned to the cobimetinib plus vemurafenib group (n=247) or placebo plus vemurafenib group (n=248). At a median follow-up of 14·2 months (IQR 8·5–17·3), the updated investigator-assessed median progression-free survival was 12·3 months (95% CI 9·5–13·4) for cobimetinib and vemurafenib versus 7·2 months (5·6–7·5) for placebo and vemurafenib (HR 0·58 [95% CI 0·46–0·72], p<0·0001). The final analysis for overall survival occurred when 255 (52%) patients had died (Aug 28, 2015). Median overall survival was 22·3 months (95% CI 20·3–not estimable) for cobimetinib and vemurafenib versus 17·4 months (95% CI 15·0–19·8) for placebo and vemurafenib (HR 0·70, 95% CI 0·55–0·90; p=0·005). The safety profile for cobimetinib and vemurafenib was tolerable and manageable, and no new safety signals were observed with longer follow-up. The most common grade 3–4 adverse events occurring at a higher frequency in patients in the cobimetinib and vemurafenib group compared with the vemurafenib group were γ-glutamyl transferase increase (36 [15%] in the cobimetinib and vemurafenib group vs 25 [10%] in the placebo and vemurafenib group), blood creatine phosphokinase increase (30 [12%] vs one [<1%]), and alanine transaminase increase (28 [11%] vs 15 [6%]). Serious adverse events occurred in 92 patients (37%) in the cobimetinib and vemurafenib group and 69 patients (28%) in the vemurafenib group. Pyrexia (six patients [2%]) and dehydration (five patients [2%]) were the most common serious adverse events reported in the cobimetinib and vemurafenib group. A total of 259 patients have died: 117 (47%) in the cobimetinib and vemurafenib group and 142 (58%) in the vemurafenib group. The primary cause of death was disease progression in most patients: 109 (93%) of 117 in the cobimetinib and vemurafenib group and 133 (94%) of 142 in the vemurafenib group.

Interpretation

These data confirm the clinical benefit of cobimetinib combined with vemurafenib and support the use of the combination as a standard first-line approach to improve survival in patients with advanced BRAFV600-mutant melanoma.

Funding

F Hoffmann-La Roche–Genentech.

Introduction

Around 40% of cutaneous melanomas harbour mutations in the BRAF gene, resulting in constitutive activation of the mitogen-activated protein kinase (MAPK) pathway.1, 2 The treatment of advanced BRAF-mutant melanoma has been revolutionised by the introduction of new therapeutic agents such as the BRAF inhibitors vemurafenib or dabrafenib. These drugs have improved outcomes for patients with advanced BRAFV600-mutant melanoma, with high proportions of patients achieving a tumour response and improved progression-free and overall survival compared with cytotoxic chemotherapy.3, 4, 5, 6 Acquired resistance to BRAF inhibitor monotherapy is the most common cause of treatment failure, limiting median progression-free survival duration to around 6 months.3, 4 Although a diverse range of resistance mechanisms has been suggested, most mechanisms of resistance involve reactivation of the MAPK pathway mediated through MEK.7, 8, 9, 10, 11

Research in context

Evidence before this study

We searched PubMed up until Sept 30, 2015, with the terms “clinical trials”, “advanced melanoma”, “BRAF inhibitor”, and “MEK inhibitor”. We also searched conference abstracts from the American Society of Clinical Oncology and the European Society of Medical Oncology with the same terms. The results showed that, in addition to the combination of vemurafenib and cobimetinib, BRAF and MEK inhibitor combinations of dabrafenib and trametinib, LGX818 and MEK162 (encorafenib and binimetinib), have been or are being assessed in patients with advanced BRAFV600-mutant melanoma. Data from two phase 3 studies have shown a benefit for the trametinib and dabrafenib combination, whereas other combinations resulted in promising activity in early-phase trials.

Added value of this study

We report the protocol-specified overall survival analysis of a double-blind, multicentre, placebo-controlled phase 3 study assessing the efficacy and safety of cobimetinib and vemurafenib compared with placebo and vemurafenib in previously untreated patients with BRAFV600 mutation-positive unresectable stage IIIC or IV melanoma. Effectiveness of the combination of cobimetinib and vemurafenib was superior to that of vemurafenib plus placebo for all efficacy endpoints and across a wide range of patient baseline characteristics, including in patients with normal baseline lactate dehydrogenase concentrations. To our knowledge, this is the first phase 3 comparative trial to do biomarker analyses to study the effect of baseline values of Ki67, pERK, and pS6 on median overall survival in both treatment groups.

Implications of all the available evidence

These data confirm the clear and definitive clinical benefit of the addition of cobimetinib to vemurafenib in patients with advanced BRAFV600-mutant melanoma and support the use of the combination as a standard targeted therapy for first-line treatment in this population.

Combined BRAF and MEK inhibition enables greater inhibition of the MAPK pathway, and combination therapy with cobimetinib (a MEK inhibitor) and vemurafenib (a BRAF inhibitor) has resulted in clinical benefit.12, 13 The randomised, double-blind, phase 3 coBRIM study13 compared the combination of cobimetinib and vemurafenib versus placebo and vemurafenib in previously untreated patients with advanced melanoma harbouring BRAFV600 mutations. In the primary analysis, with a median follow-up of 7·3 months (range 0·5–16·5), cobimetinib and vemurafenib significantly improved progression-free survival compared with vemurafenib alone (median 9·9 months [95% CI 9·0–not estimable] vs 6·2 months [5·6–7·4], hazard ratio [HR] 0·51 [0·39–0·68]; p<0·0001). Improvement in progression-free survival was recorded in every clinical subgroup assessed, including patients with disease characteristics recognised as poor prognostic factors: notably, increased lactate dehydrogenase (LDH) concentrations14 and stage M1c disease.14, 15 The proportion of patients achieving an objective response was also significantly greater in the combination therapy group compared with the vemurafenib plus placebo group (68% with cobimetinib and vemurafenib vs 45% with vemurafenib plus placebo; p<0·0001).13 Another BRAF inhibitor and MEK inhibitor combination—dabrafenib and trametinib—has resulted in efficacy similar to that of the combination of cobimetinib and vemurafenib with respect to several efficacy measures, including proportion of patients achieving an overall response, progression-free survival, and overall survival, compared with either dabrafenib16, 17 or vemurafenib18 as monotherapy in phase 3 trials in advanced melanoma.

In this Article, we report the results of an updated progression-free survival analysis and the final overall survival analysis for the coBRIM trial. Additionally, we report the results of exploratory analyses correlating molecular markers of MAPK and PI3K pathway activation in pre-treatment tumour samples with overall survival.

Section snippets

Study design and participants

coBRIM is an ongoing double-blind, multicentre, placebo-controlled, phase 3 study assessing the efficacy and safety of the combination of cobimetinib and vemurafenib, compared with placebo and vemurafenib, in previously untreated patients with BRAFV600 mutation-positive unresectable stage IIIC or stage IV melanoma. The study is being done at 135 clinical sites in 19 countries: the USA, Australia, New Zealand, Israel, Canada, and 14 countries in Europe (including Russia). The complete methods of

Results

Between Jan 8, 2013, and Jan 31, 2014, 1045 patients were screened, and 495 eligible patients with BRAFV600-mutant metastatic melanoma were randomly assigned to receive cobimetinib and vemurafenib (n=247) or placebo and vemurafenib (n=248; figure 1). The most common cause of screening failure was a negative test result for the BRAFV600 mutation. Baseline patient characteristics were generally well balanced between the two study groups (table 1).13 Of those patients in the cobimetinib and

Discussion

This updated analysis of the coBRIM study, including more than a minimum of 1 year of follow-up, demonstrates a statistically significant and clinically meaningful improvement in median overall survival, progression-free survival, and the overall response in patients treated with the combination of cobimetinib and vemurafenib versus patients treated with vemurafenib plus placebo. Moreover, the estimated landmark 2-year overall survival shows sustained benefit of the combination of cobimetinib

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