Reinhard Dummer, MD

IN THE PHASE III COLUMBUS trial reported in The Lancet Oncology, Reinhard Dummer, MD, of University Hospital Zurich, and colleagues found that the combination of the BRAF inhibitor encorafenib and the MEK inhibitor binimetinib improved progression-free survival vs vemurafenib (Zelboraf) in patients with advanced BRAF V600–mutant melanoma.¹ Dual targeting of the MAPK pathway with a BRAF inhibitor plus a MEK inhibitor improves efficacy and ameliorates certain adverse events associated with BRAF inhibitor monotherapy, and such combinations are recommended treatment options for patients with BRAF V600–mutant melanoma. 

Encorafenib suppresses the MAPK pathway in tumor cells that express several mutated forms of BRAF kinase. It has been found to have a dissociation half-life that is more than 10 times longer than the BRAF inhibitors dabrafenib (Tafinlar) and vemurafenib, which may permit sustained target inhibition. Encorafenib alone also improved progression-free survival vs vemurafenib. 

Study Details 

THE OPEN-LABEL trial enrolled 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. The patients were randomized 1:1:1 between December 2013 and April 2015 to receive 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. Patients had to have an Eastern Cooperative Oncology Group performance status of 0 or 1. The primary endpoint was progression-free survival by blinded independent central review for encorafenib plus binimetinib vs vemurafenib. Efficacy analyses were performed in the intention-to-treat population. 

Overall, patients had a median age of 54 to 57 years; 56% to 60% were male; 71% to 73% had a performance status of 0; most had a tumor stage of IVM1c (62%–65%); 24% to 29% had lactate dehydrogenase levels greater than or equal to the upper limit of normal; 88% to 89% had a BRAF V600E mutation; 44% to 46% had at least 3 organs involved; and 30% in each group had received prior immunotherapy, consisting mainly of interferon or interleukin (26%–27%). 

In a second part of the trial, patients are being randomized to the combination of encorafenib at its monotherapy maximum tolerated dose plus binimetinib or encorafenib monotherapy at the same dose; results of part 2 are to be published separately. 

Progression-Free Survival 

MEDIAN FOLLOW-UP was 16.6 months. Median progression-free survival was 14.9 months in the combination group vs 7.3 months in the vemurafenib group (hazard ratio = 0.54, P < .0001). Subgroup analyses showed that hazard ratios favored the combination, except among the small number of patients (n = 12) with brain metastases at baseline. Median progression-free survival in the encorafenib group was 9.6 months, with hazard ratios of 0.75 (P = .051) for the combination vs encorafenib and 0.68 (P = .0070) for encorafenib vs vemurafenib. 

Overall confirmed response rates were 63% in the encorafenib-plus-binimetinib group, 51% in the encorafenib-alone group, and 40% in the vemurafenib group. Median time to response was 1.8 months, 1.9 months, and 1.9 months. Median duration of response was 16.6 months, 14.9 months, and 12.3 months. Overall survival data are to be reported in a separate publication. 

Adverse Events 

GRADE 3 OR 4 adverse events occurred in 58% of the encorafenib-plus-binimetinib group, 66% of the encorafenib-alone group, and 63% of the vemurafenib group. The most common grade 3 or 4 adverse events observed in > 5% of patients were increased γ-glutamyltransferase levels (9%), increased creatine phosphokinase levels (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 events in each group being pyrexia (3%) among encorafenib-plus-binimetinib recipients, vomiting and nausea (each in 3%) among encorafenib recipients, and deterioration of general physical health (3%) among vemurafenib recipients. 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. 

No deaths considered likely related to study treatment were observed. One death in the combination group, due to suicide 15 days after the patient stopped treatment on day 9, was considered possibly related to treatment. 

The investigators concluded: “Encorafenib plus binimetinib and encorafenib monotherapy showed favourable efficacy compared with vemurafenib. Overall, encorafenib plus binimetinib appears to have an improved tolerability profile compared with encorafenib or vemurafenib. Encorafenib plus binimetinib could represent a new treatment option for patients with BRAF-mutant melanoma.” ■

DISCLOSURE: The study was funded by Array BioPharma and Novartis. For full disclosures of the authors, visit www.thelancet.com. 

REFERENCE 

1. 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. March 22, 2018 (early release online).