Overall Survival With Encorafenib Plus Binimetinib vs Vemurafenib in Advanced BRAF-Mutant Melanoma
As reported in The Lancet Oncology by Dummer et al, the phase III COLUMBUS trial has shown a significant improvement in overall survival with the combination of the BRAF inhibitor encorafenib and the MEK inhibitor binimetinib vs vemurafenib in patients with advanced BRAF V600–mutant melanoma.
In a prior report from the trial, the combination significantly improved progression-free survival—the primary endpoint—vs vemurafenib alone, supporting the June 2018 U.S. Food and Drug Administration approval of the combination in this setting. Encorafenib alone also improved progression-free survival vs vemurafenib in the trial.
Study Details
The open-label trial included 577 patients with locally advanced (stage IIIB, IIIC, or IV), unresectable, or metastatic cutaneous melanoma or unknown primary melanoma with a BRAF V600E or BRAF V600K mutation from 162 sites in 28 countries. Patients were randomized 1:1:1 between December 2013 and April 2015 to receive oral encorafenib at 450 mg once daily, plus either oral binimetinib at 45 mg twice daily (n = 192), encorafenib at 300 mg once daily (n = 194), or oral vemurafenib at 960 mg twice daily (n = 191). Patients were treatment-naive or had disease progression on or after prior first-line immunotherapy and had to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Randomization was stratified by the American Joint Committee on Cancer stage, ECOG performance status, and BRAF mutation status.
Overall, patients had a median age of between 54 and 57 years; 56% to 60% were male; 71% to 73% had a performance status of 0; most had tumor stage of IVM1c (62%–65%); 24% to 29% had lactate dehydrogenase levels ≥ upper limit of normal; 88% to 89% had BRAF V600E mutation; 44% to 46% had ≥ 3 organs involved; and 30% in each group had received prior immunotherapy, consisting mainly of interferon or interleukin (26%–27%).
Progression-Free and Overall Survival
In the current report, median follow-up for progression-free survival was 32.1 months. Median progression-free survival was 14.9 months in the encorafenib plus binimetinib group (hazard ratio [HR] = 0.51, P < .001, vs vemurafenib; HR = 0.77, P = .050, vs encorafenib alone), 9.6 months in the encorafenib group (HR = 0.68, P = .0038, vs vemurafenib), and 7.3 months in the vemurafenib group. Confirmed overall response rates on independent central review were 64% in the encorafenib plus binimetinib group, 52% in the encorafenib group, and 41% in the vemurafenib group. Median durations of response were 18.6 months, 15.2 months, and 12.3 months, respectively.
After study drug discontinuation, systemic treatments were received by 42%, 56%, and 62% of patients, with the most common regimens (20%–25% of patients) involving anti–programmed cell death protein 1 (PD-1) or anti–programmed cell death-ligand 1 (PD-L1) agents as monotherapy.
Median follow-up for overall survival was 36.8 months. Median overall survival was 33.6 months in the encorafenib plus binimetinib group (HR = 0.61, P < .0001, vs vemurafenib; HR = 0.81, P = .12, vs encorafenib), 23.5 months in the encorafenib group (HR = 0.76, P = .033, vs vemurafenib), and 16.9 months in the vemurafenib group. Overall survival was 75.5%, 74.6%, and 63.1% at 1 year and 57.6%, 49.1%, and 43.2% at 2 years. Hazard ratios favored the combination over vemurafenib in all subgroups examined, except for a subgroup of 12 patients with brain metastases (9 in the combination group and 3 in the vemurafenib group).
Adverse Events
The most common grade 3 or 4 adverse events did not change substantially from the first report. Grade 3 or 4 adverse events occurred in 58% of the encorafenib plus binimetinib group, 66% of the encorafenib group, and 63% of the vemurafenib group. The most common grade 3 or 4 adverse events observed in more than 5% of patients were increased γ-glutamyltransferase (9%), increased creatine phosphokinase (7%), and hypertension (6%) in the encorafenib plus binimetinib group; palmar-plantar erythrodysesthesia syndrome (14%), myalgia (10%), and arthralgia (9%) in the encorafenib group; and arthralgia (6%) in the vemurafenib group. The most common secondary nonmelanoma skin cancers were squamous cell cancers, observed in 3% of the encorafenib plus binimetinib group, 8% of the encorafenib group, and 17% of the vemurafenib group.
Serious adverse events occurred in 34%, 34%, and 37% of patients, with the most common being pyrexia (3%) in the encorafenib plus binimetinib group, vomiting and nausea (3%) in the encorafenib group, and deterioration of general physical health (3%) in the vemurafenib group. Suspected treatment-related adverse events led to discontinuation of study treatment in 6%, 10%, and 14% of patients, with the most common causes being increased alanine transaminase and aspartate transaminase (2%) in the combination group; palmar-plantar erythrodysesthesia syndrome (3%) in the encorafenib group; and increased γ-glutamyltransferase, arthralgia, and photosensitivity reaction (2% each) in the vemurafenib group. One death in the combination treatment group was considered by the investigator to be possibly related to treatment.
The investigators concluded, “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 BRAF V600–mutant melanoma.”
The study was funded by Array BioPharma and Novartis.
Reinhard Dummer, MD, of the Department of Dermatology, University Hospital Zurich Skin Cancer Center, is the corresponding author of The Lancet Oncology article.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
