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.