Encorafenib Plus Binimetinib vs Vemurafenib and Encorafenib Alone in Advanced BRAF-Mutant Melanoma

Key Points

  • Encorafenib plus binimetinib was associated with significantly prolonged progression-free survival vs vemurafenib.
  • Encorafenib monotherapy prolonged progression-free survival vs vemurafenib. 

In the phase III COLUMBUS trial reported in The Lancet Oncology, Dummer et al 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. 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. They 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 on 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, and 71% to 73% had a performance status of 0. Most patients 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 the second part 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 consistently 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 response rates were 63% in the encorafenib plus binimetinib group, 51% in the encorafenib 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 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 in the three groups, respectively, with the most common in each group 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 discontinuation of study treatment in 6%, 10%, and 14% of patients, with the most common causes being increased alanine transaminase and aspartate transaminase levels (2%) in the combination group, palmar-plantar erythrodysesthesia syndrome (3%) in the encorafenib group, and increased γ-glutamyltransferase levels, arthralgia, and photosensitivity reactions (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.”

The study was funded by Array BioPharma and Novartis.

Reinhard Dummer, MD, of the Department of Dermatology, Skin Cancer Center, University Hospital Zurich, is the corresponding author for 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®.


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