Elsevier

The Lancet Oncology

Volume 19, Issue 10, October 2018, Pages 1315-1327
The Lancet Oncology

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

https://doi.org/10.1016/S1470-2045(18)30497-2Get rights and content

Summary

Background

Encorafenib plus binimetinib and encorafenib alone improved progression-free survival compared with vemurafenib in patients with BRAFV600-mutant melanoma in the COLUMBUS trial. Here, we report the results of the secondary endpoint of overall survival.

Methods

COLUMBUS was a two-part, randomised, open-label, phase 3 study done at 162 hospitals in 28 countries. Eligible patients were aged at least 18 years with histologically confirmed, locally advanced, unresectable, or metastatic cutaneous melanoma, or unknown primary melanoma, 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 first-line immunotherapy. In part 1 of the study, patients were randomly assigned (1:1:1) by use of interactive response technology to receive 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). Randomisation was stratified by the American Joint Committee on Cancer stage, ECOG performance status, and BRAF mutation status. The primary outcome of the trial, progression-free survival with encorafenib plus binimetinib versus vemurafenib, was reported previously. Here we present the prespecified interim overall survival analysis. Efficacy analyses were by intent to treat. Safety was analysed in patients who received at least one dose of study drug. Part 2 of the study was initiated at the request of the US Food and Drug Administration to better understand the contribution of binimetinib to the combination therapy by comparing encorafenib 300 mg once daily plus binimetinib 45 mg twice daily with encorafenib 300 mg once daily alone. Results of part 2 will be published separately. This trial is ongoing and 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 receive encorafenib plus binimetinib (n=192), encorafenib (n=194), or vemurafenib (n=191). Median follow-up for overall survival was 36·8 months (95% CI 35·9–37·5). Median overall survival was 33·6 months (95% CI 24·4–39·2) with encorafenib plus binimetinib and 16·9 months (14·0–24·5) with vemurafenib (hazard ratio 0·61 [95% CI 0·47–0·79]; two-sided p<0·0001). The most common grade 3 or 4 adverse events did not change substantially from the first report; those seen in more than 5% of patients treated with encorafenib plus binimetinib were increased γ-glutamyltransferase (18 [9%] of 192 patients), increased blood creatine phosphokinase (14 [7%]), and hypertension (12 [6%]); those seen with encorafenib alone were palmar-plantar erythrodysaesthesia syndrome (26 [14%] of 192 patients), myalgia (19 [10%]), and arthralgia (18 [9%]); and with vemurafenib the most common grade 3 or 4 adverse event was arthralgia (11 [6%] of 186 patients). One death in the combination treatment group was considered by the investigator to be possibly related to treatment.

Interpretation

The combination of encorafenib plus binimetinib provided clinically meaningful efficacy with good tolerability as shown by improvements in both progression-free survival and overall survival compared with vemurafenib. These data suggest that the combination of encorafenib plus binimetinib is likely to become an important therapeutic option in patients with BRAFV600-mutant melanoma.

Funding

Array BioPharma, Novartis.

Introduction

Approximately 50% of patients with metastatic melanoma have point mutations in BRAF, predominantly in the Val600 codon (BRAFV600 mutations), which promote melanoma progression through constitutive activation of the MAPK pathway.1, 2, 3 Small-molecule BRAF inhibitors, initially introduced as monotherapy treatment for patients with BRAFV600-mutant melanoma, showed improved efficacy compared with standard therapy, including improved response rates and progression-free and overall survival.4 However, response durations were short and BRAF inhibitor treatment was associated with the development of squamous cell skin cancer and other skin toxicities related to paradoxical MAPK pathway activation.4, 5, 6, 7

Research in context

Evidence before this study

BRAF–MEK inhibitor combinations have a central role in the targeted treatment of BRAFV600-mutant melanoma. We searched for articles and abstracts published in PubMed and Embase between Jan 1, 2014, and Mar 30, 2018, including the search terms “melanoma” AND “treatment” AND “phase” AND “encorafenib,” “BRAF inhibition” AND “melanoma”. The most relevant articles selected were phase 3 clinical trials. We found that the established BRAF–MEK inhibitor combinations provided a median progression-free survival of approximately 12 months and median overall survival of approximately 24 months, and both of the established combinations were associated with unique treatment-limiting and dose-limiting toxicities. The phase 3 COLUMBUS study was designed to compare a third BRAF–MEK inhibitor combination, encorafenib plus binimetinib versus vemurafenib or encorafenib alone. The initial report of COLUMBUS, published in March, 2018, showed that median progression-free survival was improved with encorafenib plus binimetinib, compared with vemurafenib. Here, we provide an efficacy and safety update based on an additional 18 months of follow-up, including an analysis of overall survival.

Added value of this study

We present further data from the COLUMBUS study that characterise the safety and efficacy of the combination with an additional 18 months of follow-up and analysis of overall survival relative to vemurafenib alone. Data also include a head-to-head comparison of encorafenib monotherapy versus vemurafenib, providing clinical evidence that the unique pharmacological characteristics of encorafenib might be, in part, responsible for the efficacy results observed in the combination arm. The new combination of encorafenib plus binimetinib showed favourable results in terms of the low rates of pyrexia and photosensitivity observed in COLUMBUS. These data suggest that there are inherent differences in the pharmacological characteristics of the drugs used in BRAF–MEK inhibitor therapy and that some combinations might provide additional clinical benefits to patients.

Implications of all the available evidence

BRAF–MEK inhibitor combinations have improved progression-free and overall survival in patients with BRAF-mutant melanoma but with treatment-limiting and dose-limiting toxicities. The combination of encorafenib plus binimetinib might be an important addition to the treatment options available to patients with BRAFV600-mutant melanoma. The favourable tolerability of encorafenib plus binimetinib could benefit patients in first-line treatment, as an option for those with poor tolerance to other BRAF–MEK inhibitor combinations, and for subsequent treatment after progression on immunotherapy. Trials are underway to assess the use of encorafenib plus binimetinib as adjuvant treatment or in combination with immunotherapy.

Dual MAPK pathway inhibition with the addition of a MEK inhibitor to a BRAF inhibitor showed promising initial results8, 9 that were substantiated in three phase 3 studies.10, 11, 12 BRAF–MEK inhibitor combination therapy for BRAF-mutant melanoma improved clinical outcomes, delayed development of resistance, and reduced toxicities associated with BRAF inhibitors resulting from paradoxical MAPK pathway activation.10, 12

Consequently, BRAF–MEK inhibitor combinations are recommended as first-line or second-line therapies for advanced BRAF-mutant melanoma.13 All BRAF–MEK inhibitor therapies are associated with characteristic adverse events, but both of the established combinations (dabrafenib plus trametinib and vemurafenib plus cobimetinib) have distinct safety profiles with unique toxicities that affect overall tolerability and might affect the ability to deliver optimal treatment.11, 12, 14, 15 Although the available combinations are effective, resulting in a median progression-free survival of approximately 12 months and overall survival of approximately 24 months, further improvements in treatment are needed.6, 10, 12, 14, 16, 17, 18, 19, 20

An additional combination, the BRAF inhibitor encorafenib plus the MEK inhibitor binimetinib, was introduced into late-stage clinical trials in 2013. Preliminary clinical data suggested activity and safety profiles distinct from those of available BRAF–MEK inhibitor combinations, including low rates of pyrexia and photosensitivity.21 Additionally, the improved tolerability with encorafenib plus binimetinib resulted in a higher tolerated dose of encorafenib in the combination (450 mg once daily) than the recommended phase 2 monotherapy dose (300 mg once daily), thereby allowing increased dose intensity of encorafenib when used in combination with binimetinib.21, 22

COLUMBUS was a three-arm, two-part, phase 3 study in patients with advanced BRAFV600-mutant melanoma. Part 1 assessed encorafenib 450 mg once daily plus binimetinib 45 mg twice daily compared with encorafenib 300 mg once daily or vemurafenib 960 mg twice daily. The primary endpoint of progression-free survival comparing the combination therapy with vemurafenib was met; median progression-free survival was 14·9 months (95% CI 11·0–18·5) with encorafenib plus binimetinib versus 7·3 months (5·6–8·2) with vemurafenib.23 Here, we report the results of overall survival, a secondary endpoint of the study, and update efficacy and safety results on the basis of additional follow-up data at 18 months.

Section snippets

Study design and participants

COLUMBUS was a two-part, multicentre, randomised, open-label, phase 3 study. Primary results of part 1 have been published.23 Part 2, which was added to the study protocol via amendment 3 (dated Nov 4, 2014), was a request by the US Food and Drug Administration (FDA) to understand the contribution of binimetinib to the combination. Part 2 enrolled further patients to investigate an encorafenib dose of 300 mg once daily in combination with binimetinib 45 mg twice daily compared with encorafenib

Results

Between Dec 30, 2013, and April 10, 2015, 1345 patients were screened; of these, 768 were excluded (364 did not have the BRAFV600E or BRAFV600K mutation, 350 did not meet other inclusion criteria or met other exclusion criteria, and 54 declined consent after pre-screening). 577 patients were enrolled and randomly assigned to receive encorafenib plus binimetinib (n=192), encorafenib (n=194), or vemurafenib (n=191). At the data cutoff date of Nov 7, 2017, 43 (22%) of 192 patients in the

Discussion

We present overall survival and updated efficacy data from the COLUMBUS study, extending the findings of the initial report on the primary efficacy endpoint.23 The observed median overall survival with encorafenib plus binimetinib was 33·6 months (95% CI 24·4–39·2). Together with a mature median progression-free survival of 14·9 months (95% CI 11·0–20·2), these data represent a new benchmark for BRAF–MEK inhibitor therapy for BRAF-mutant melanoma.

Encorafenib plus binimetinib is the third

References (30)

  • KT Flaherty et al.

    Inhibition of mutated, activated BRAF in metastatic melanoma

    N Engl J Med

    (2010)
  • G Bollag et al.

    Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma

    Nature

    (2010)
  • R Dummer et al.

    Ultraviolet A and photosensitivity during vemurafenib therapy

    N Engl J Med

    (2012)
  • JD Rinderknecht et al.

    RASopathic skin eruptions during vemurafenib therapy

    PLoS One

    (2013)
  • KT Flaherty et al.

    Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations

    N Engl J Med

    (2012)
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