Reinhard Dummer, MD

AS REPORTED in The Lancet Oncology by Reinhard Dummer, MD, of the University Hospital Zurich Skin Cancer Center, and colleagues, the phase III COLUMBUS trial has shown a significant improvement in overall survival with the combination of the BRAF inhibitor encorafenib (Braftovi) and the MEK inhibitor binimetinib (Mektovi) vs vemurafenib (Zelboraf) in patients with advanced BRAF V600–mutant melanoma.¹

In a prior report from the trial,² the combination therapy significantly improved progression-free survival, the primary endpoint, vs vemurafenib alone, supporting the June 2018 approval of the combination in this setting. Encorafenib alone also improved progression-free survival vs vemurafenib in the trial.

Study Details

IN THE OPEN-LABEL 2-part trial, 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 were randomly assigned 1:1:1 between December 2013 and April 2015 to one of 3 treatments: oral encorafenib at 450 mg once daily plus oral binimetinib at 45 mg twice daily (n = 192), encorafenib at 300 mg once daily alone (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.

The primary endpoint was progression-free survival on blinded independent central review for encorafenib plus binimetinib vs vemurafenib. The current analysis is a prespecified interim analysis of the secondary endpoint of overall survival. Efficacy analyses were performed in the intention-to-treat population.

Part 2 of the study was initiated at the request of the U.S. Food and Drug Administration to clarify the contribution of binimetinib to combination therapy by comparing encorafenib at 300 mg once daily plus binimetinib at 45 mg twice daily with encorafenib at 300 mg once daily alone; results will be published separately.

Progression-Free and Overall Survival

IN THE CURRENT REPORT, the median follow-up for progression-free survival was 32.1 months. The median progression-free survival was 14.9 months in the encorafenib plus binimetinib group (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. The confirmed overall response rate on independent central review was 64% in the encorafenib plus binimetinib group, 52% in the encorafenib group, and 41% in the vemurafenib group. The median duration of response was 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 or anti–programmed cell death ligand 1 agents as monotherapy.

“These data suggest that the combination of encorafenib plus binimetinib is likely to become an important therapeutic option in patients with <em>BRAF</em> V600–mutant melanoma."

— Reinhard Dummer, MD, and colleagues

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The median follow-up for overall survival was 36.8 months. The 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, respectively. 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 follow: 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.

Serious adverse events occurred in 34%, 34%, and 37% of patients, respectively, with the most common being pyrexia (3%) in the encorafenib plus binimetinib group, vomiting and nausea (each in 3%) in the encorafenib group, and deterioration of general physical health (3%) in the vemurafenib group. Suspected treatment-related adverse events led to treatment discontinuation in 6%, 10%, and 14% of patients.

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.” ■

DISCLOSURE: The study was funded by Array BioPharma and Novartis. Dr. Dummer is a consultant/advisor to and has received honoraria from Roche, Bristol-Myers Squibb, MSD, Novartis, Amgen, Takeda, Pierre Fabre, and Sun Pharma; he also has received institutional research funding from Bristol-Myers Squibb, Novartis, MSD, and Amgen. For full disclosures of the other study authors, visit www.thelancet.com.

REFERENCES

1. Dummer R, Ascierto PA, Gogas HJ, et al: 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. Lancet Oncol 19:1315-1327, 2018.

2. Dummer R, Ascierto PA, Gogas HJ, et al: Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): A multicentre, open-label, randomised phase 3 trial. Lancet Oncol 19:603-615, 2018.