Elsevier

The Lancet Oncology

Volume 19, Issue 5, May 2018, Pages 603-615
The Lancet Oncology

Articles
Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial

https://doi.org/10.1016/S1470-2045(18)30142-6Get rights and content

Summary

Background

Combined BRAF-MEK inhibitor therapy is the standard of care for BRAFV600-mutant advanced melanoma. We investigated encorafenib, a BRAF inhibitor with unique target-binding properties, alone or in combination with the MEK inhibitor binimetinib, versus vemurafenib in patients with advanced BRAFV600-mutant melanoma.

Methods

COLUMBUS was conducted as a two-part, randomised, open-label phase 3 study at 162 hospitals in 28 countries. Eligible patients were aged 18 years or older and had histologically confirmed locally advanced (American Joint Committee on Cancer [AJCC] stage IIIB, IIIC, or IV), unresectable or metastatic cutaneous melanoma, or unknown primary melanoma; a BRAFV600E or BRAFV600K mutation; an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; and were treatment naive or had progressed on or after previous first-line immunotherapy. In part 1 of the study, patients were randomly assigned (1:1:1) via interactive response technology to receive either oral encorafenib 450 mg once daily plus oral binimetinib 45 mg twice daily (encorafenib plus binimetinib group), oral encorafenib 300 mg once daily (encorafenib group), or oral vemurafenib 960 mg twice daily (vemurafenib group). The primary endpoint was progression-free survival by blinded independent central review for encorafenib plus binimetinib versus vemurafenib. Efficacy analyses were by intention-to-treat. Safety was analysed in patients who received at least one dose of study drug and one postbaseline safety assessment. The results of part 2 will be published separately. This study is registered with ClinicalTrials.gov, number NCT01909453, and EudraCT, number 2013-001176-38.

Findings

Between Dec 30, 2013, and April 10, 2015, 577 of 1345 screened patients were randomly assigned to either the encorafenib plus binimetinib group (n=192), the encorafenib group (n=194), or the vemurafenib group (n=191). With a median follow-up of 16·6 months (95% CI 14·8–16·9), median progression-free survival was 14·9 months (95% CI 11·0–18·5) in the encorafenib plus binimetinib group and 7·3 months (5·6–8·2) in the vemurafenib group (hazard ratio [HR] 0·54, 95% CI 0·41–0·71; two-sided p<0·0001). The most common grade 3–4 adverse events seen in more than 5% of patients in the encorafenib plus binimetinib group were increased γ-glutamyltransferase (18 [9%] of 192 patients), increased creatine phosphokinase (13 [7%]), and hypertension (11 [6%]); in the encorafenib group they were palmoplantar erythrodysaesthesia syndrome (26 [14%] of 192 patients), myalgia (19 [10%]), and arthralgia (18 [9%]); and in the vemurafenib group it was arthralgia (11 [6%] of 186 patients). There were no treatment-related deaths except for one death in the combination group, which was considered possibly related to treatment by the investigator.

Interpretation

Encorafenib plus binimetinib and encorafenib monotherapy showed favourable efficacy compared with vemurafenib. Overall, encorafenib plus binimetinib appears to have an improved tolerability profile compared with encorafenib or vemurafenib. Encorafenib plus binimetinib could represent a new treatment option for patients with BRAF-mutant melanoma.

Funding

Array BioPharma, Novartis.

Introduction

Genetic alterations resulting in an activated MAPK pathway occur in almost all melanoma cases. The most frequent is the BRAFV600 mutation, which occurs in 35–50% of patients with a melanoma.1 Activating BRAF mutations drive constitutive MAPK pathway activation, with subsequent proliferation and enhanced cellular survival, making BRAF kinase a promising therapeutic target.1 In-vitro investigations have shown that growth of BRAF-mutated melanoma cells can be inhibited by BRAF or MEK inhibitors.2

Research in context

Evidence before this study

We searched for articles and abstracts during the development of this Article that were published in PubMed and Embase between Jan 1, 2014, and Dec 20, 2017. Search terms were comprehensive (“melanoma“ + “treatment” + “phase” [all fields]; “encorafenib”, “BRAF inhibition” + “melanoma” [all fields]). Selected abstracts were not limited to those in the English language and focused on phase 3 clinical trial data. Our search results indicated that a combination of available BRAF and MEK-pathway inhibitors provided additional benefit with reasonable tolerability in advanced melanoma compared with BRAF-inhibitor monotherapy. Preclinical and phase 1 and 2 clinical data suggested that the BRAF inhibitor encorafenib in combination with the MEK inhibitor binimetinib could further improve therapy for patients with BRAF-mutant melanoma.

Added value of this study

In this randomised trial in patients with BRAF-mutant melanoma, treatment with the combination of the BRAF inhibitor encorafenib 450 mg and the MEK inhibitor binimetinib 45 mg improved progression-free survival and overall response compared with encorafenib 300 mg or vemurafenib, with better tolerability. Furthermore, in what to our knowledge is the first controlled head-to-head comparison of BRAF-inhibitor monotherapy, encorafenib showed a progression-free survival advantage compared with vemurafenib. Additionally, the combination of encorafenib with binimetinib ameliorated toxic effects associated with encorafenib monotherapy, enabling the use of a higher dose of encorafenib. Consistent with preclinical findings, our results show that encorafenib monotherapy provides improved clinical efficacy compared with vemurafenib monotherapy, and that high-intensity, extended BRAF inhibition, in combination with MEK inhibition, could result in improved tumour control.

Implications of all the available evidence

Encorafenib in combination with binimetinib is a well tolerated and efficacious treatment option for BRAF-mutant metastatic melanoma. Overall survival data and long-term safety data will provide additional insights into the efficacy and tolerability of this combination. Additionally, our findings indicate that the combination of encorafenib with binimetinib has a different toxicity profile from other combinations of BRAF-MEK inhibitors, with low frequencies of pyrexia and photosensitivity.

A crystallography-guided drug design approach produced several candidate ATP-competitive BRAF-kinase inhibitors that were investigated in clinical trials. Vemurafenib was the first to show efficacy in BRAF-mutant melanoma,3, 4 followed by dabrafenib.5 MAPK pathway reactivation is implicated in BRAF-inhibitor monotherapy resistance.6 Additionally, toxic effects associated with BRAF inhibition, notably secondary squamous-cell skin cancer and other skin toxicities, are caused by BRAF inhibitors paradoxically activating the wild-type BRAF kinase, promoting dimerisation that triggers RAS-independent transactivation, and activation of the MAPK pathway in normal tissues.7 Subsequent clinical trials8, 9, 10, 11 in patients with BRAFV600-mutant melanoma have shown that dual MAPK-pathway targeting with a BRAF inhibitor and a MEK inhibitor improves efficacy and ameliorates paradoxical MAPK activation-related toxic effects associated with BRAF-inhibitor monotherapy. Two BRAF-MEK inhibitor combinations (dabrafenib-trametinib and vemurafenib-cobimetinib) are regarded as treatment options for metastatic or unresectable BRAFV600-mutant melanoma in current guidelines.12, 13 These BRAF-MEK inhibitor combinations are highly effective. However, both are associated with disease progression at approximately 12 months, and each combination causes different toxic effects in patients, highlighting the need for more effective and better tolerated therapies.8, 9, 10, 14, 15, 16, 17

Encorafenib is an ATP-competitive BRAF inhibitor that suppresses the MAPK pathway in tumour cells that express several mutated forms of BRAF kinase (eg, V600E, V600D, and V600K mutations), with a more than 10-times longer dissociation half-life (>30 h) than either dabrafenib or vemurafenib, which enables sustained target inhibition.18 Preclinical studies suggest that this property could enhance antitumour activity while reducing paradoxical activation of MAPK pathways in normal tissues.18, 19 Binimetinib is an orally available, non-ATP-competitive, allosteric inhibitor of MEK1 and MEK2.20

Promising clinical activity and tolerability of the combination of encorafenib and binimetinib has been seen in patients with BRAFV600-mutated melanoma in a phase 1b/2 and a phase 2 study.21, 22 Furthermore, the maximum tolerated dose of encorafenib when combined with binimetinib was higher than the maximum tolerated dose of encorafenib monotherapy, thus allowing the use of a higher encorafenib dose when combined with binimetinib in subsequent trials.22 Here, we describe the results of part one of the COLUMBUS trial, a phase 3 study of encorafenib plus binimetinib versus vemurafenib or encorafenib monotherapy in patients with advanced BRAFV600-mutant unresectable melanoma.

Section snippets

Study design and participants

COLUMBUS is a two-part, multicentre, randomised, open-label phase 3 study of the efficacy and safety of encorafenib plus binimetinib combination therapy versus vemurafenib or encorafenib monotherapy in patients with locally advanced unresectable or metastatic BRAFV600-mutant melanoma. The study was originally designed to compare the efficacy of encorafenib 450 mg once daily plus binimetinib 45 mg twice daily with vemurafenib given at its clinically indicated dose, and with encorafenib given at

Results

Between Dec 30, 2013, and April 10, 2015, 1345 patients were assessed, of whom 577 were enrolled and randomly assigned to a treatment group (192 to the encorafenib plus binimetinib group, 194 to the encorafenib group, and 191 to the vemurafenib group; figure 1). As of the data cutoff on May 19, 2016, treatment was ongoing in 68 (35%) of 192 patients in the encorafenib plus binimetinib group, 46 (24%) of 194 patients in the encorafenib group, and 27 (14%) of 191 patients in the vemurafenib

Discussion

In this phase 3, randomised trial in patients with BRAF-mutant melanoma, encorafenib plus binimetinib showed a favourable efficacy and safety profile compared with vemurafenib monotherapy. Progression-free survival in patients treated with encorafenib plus binimetinib was significantly longer than in those treated with vemurafenib, and progression-free survival results were consistent with those seen in previous trials using vemurafenib in this setting.9, 10 The encorafenib plus binimetinib

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