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.