Encorafenib Combo May Limit Recurrence Risk in BRAF V600+ Melanoma

“EORTC-2139-MG/Columbus-AD is the first and only randomized adjuvant trial of BRAF-directed therapy with encorafenib and binimetinib in stage IIB/IIC BRAF V600–mutant melanoma," according to lead study author Alexander C.J. van Akkooi, MD, PhD, FRACS.

Primary analysis data from the phase 3 EORTC-2139-MG/Columbus-AD trial (NCT05270044) demonstrated the potential to reduce the risk of recurrence among patients with high-risk stage IIB/C BRAF V600–mutant melanoma who received encorafenib (Braftovi) plus binimetinib (Mektovi), according to findings presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.¹

In the intention-to-treat (ITT) population (n = 110), the 12-month recurrence-free survival (RFS) rates were 86% (95% CI, 65%-95%) vs 70% (95% CI, 46%-85%) in the encorafenib/binimetinib (n = 55) and placebo (n = 55) arms, respectively. Of note, the types of RFS events included distant metastasis (combination arm, n = 3; placebo arm, n = 5), locoregional recurrence (n = 1; n = 3), and new melanoma (n = 0; n = 1).

Regarding safety, in the safety population from the combination arm, any-grade and grade 3 adverse effects (AEs) occurred in 98% and 28% of patients; 89% and 24% patients had AEs of these respective grades that were suspected to be treatment related. Serious AEs of any grade and grade 3 occurred in 11% and 7% of patients, respectively, and any-grade serious AEs that were suspected to be treatment related occurred in 2% of patients. Any-grade and grade 3 treatment-emergent AEs leading to permanent treatment discontinuation occurred at rates of 33% and 11%, respectively, all of which were suspected to be drug related.

The most common AEs occurring in at least 10% of patients in the combination arm included nausea (any-grade, 37%; grade 3, 0%), diarrhea (28%; 2%), vomiting (26%; 0%), asthenia (24%; 0%), increased blood creatine phosphokinase levels (22%; 0%), abdominal pain (13%; 0%), upper abdominal pain (13%; 0%), constipation (13%; 0%), arthralgia (11%; 2%), pyrexia (11%; 0%), and visual impairment (11%; 0%). AEs that started or worsened from baseline between the start of treatment and up to 30 days after the last protocol treatment were considered. Notably, only 1 grade 4 AE—elevated alanine/aspartate aminotransferase levels—was reported.

“The key conclusions of our study are that stage IIB/IIC melanoma has a high risk of recurrence. Encorafenib and binimetinib treatment is safe and feasible in stage IIB/IIC BRAF V600–mutant melanoma, and adjuvant treatment with encorafenib/binimetinib may prevent cancer recurrence,” lead study author Alexander C.J. van Akkooi, MD, PhD, FRACS, said during a presentation of the data. “I’d like to take this opportunity to say that all of us would agree that both patients and physicians would love to have the choice between immuno-oncology and targeted therapy in the adjuvant setting for stage IIB/IIC melanoma.”

van Akkooi is an associate professor in the Department of Melanoma Surgical Oncology and chair of Melanoma Surgery at Melanoma Institute Australia in Sydney.

Background, EORTC-2139-MG/Columbus-AD Design, and Baseline Patient Characteristics

In June 2018, the FDA approved encorafenib plus binimetinib for the treatment of patients with unresectable or metastatic melanoma harboring BRAF V600E/V600K mutations determined via an FDA-approved test.² The regulatory decision was supported by data from the phase 3 COLUMBUS trial (NCT01909453).

The EORTC-2139-MG/Columbus-AD study evaluated encorafenib plus binimetinib in patients with histologically confirmed stage IIB/IIC cutaneous melanoma with fully resected, tumor-free margins.¹ Patients were required to have sentinel node–negative disease and no microsatellite, satellite, or in-transit metastases. Patients also needed to have a centrally confirmed BRAF V600E/V600K mutation and an ECOG performance status of 0 or 1. Patients (n = 815) were stratified by stage per the American Joint Committee on Cancer 8th edition (AJCC8; stage IIB vs IIC) before they were randomly assigned to receive encorafenib at 450 mg once daily plus binimetinib at 45 mg twice daily (arm A) or double-matched placebos (arm B). Of note, the study was unblinded in November 2023, at which point patients who had received placebo discontinued the trial immediately, and those treated with the combination discontinued after completing treatment. In the ITT analysis, there were 54 patients in each arm.

In the original study design, the primary end point was RFS, and the secondary end points included distant metastasis-free survival (DMFS), overall survival (OS), quality of life (QOL), safety, and pharmacokinetics. The revised study design included safety in the encorafenib/binimetinib arm as the primary objective, as well as descriptive efficacy analyses.

The median ages were 58 years (range, 27-81) vs 61 years (range, 27-79) among patients in the combination and placebo arms, respectively. In total, 46% vs 62% of patients, respectively, were male. BRAF mutations included V600E (combination arm, 80%; placebo arm, 78%) and V600K (20%; 22%). Additionally, ulceration occurred in 84% vs 75% of patients. The median Breslow thickness was 4.3 mm (IQR, 3.1-6.0) in the combination arm vs 4.7 mm (IQR, 3.1-6.0) in the placebo arm; Breslow thickness of 2 to 4 mm was seen in 47% vs 40% of patients, respectively; Breslow thickness of greater than 4 mm was reported in 53% vs 60% of patients, respectively. AJCC8 stages included IIB (64%; 65%) and IIC (36%; 35%).

Treatment Exposure and Additional Efficacy Findings

Among patients in the safety population of the experimental arm (n = 54), the median treatment duration was 11.2 months, the mean treatment duration was 7.5 months, and the treatment durations during quartiles 1 to 3 were 1.6 to 11.7 months. Of note, the median relative dose intensities were 98% and 96% for encorafenib and binimetinib, respectively. Reasons for treatment discontinuation included disease relapse (2%), AEs leading to treatment discontinuation by the investigator (22%), patient refusal with a concomitant AE (11%), and patient refusal due to reasons other than concomitant AE (9%). In total, 56% of patients had normal treatment completion.

The 12-month DMFS rates in the ITT population were 92% (95% CI, 77%-97%) in the combination arm compared with 82% (95% CI, 55%-93%) in the placebo arm.

QOL was measured using the descriptive global EORTC Core QOL Questionnaire. The mean global health status/QOL scores trended higher in the placebo arm vs the combination arm.

“EORTC-2139-MG/Columbus-AD is the first and only randomized adjuvant trial of BRAF-directed therapy with encorafenib and binimetinib in stage IIB/IIC BRAF V600–mutant melanoma. Encorafenib/binimetinib was a generally well tolerated combination with a manageable safety profile and highlights the potential utility of a BRAF/MEK inhibition combination in the adjuvant setting to reduce recurrences for patients with stage IIB/IIC BRAF V600–mutant melanoma,” van Akkooi concluded in the presentation.

Disclosures: van Akkooi reported serving in institutional consulting or advisory roles with 4SC, Bristol-Myers Squibb, Merck/Pfizer, MSD Oncology, Novartis, Pierre Fabre, Sanofi, and Sirius Medical; serving in noninstitutional consulting or advisory roles with Genmab, Menarini Silicon Biosystems, NeraCare GmbH, Provectus Biopharmaceuticals, and Skyline Diagnostics; receiving institutional research funding from Amgen, Bristol-Myers Squibb, and Merck/Pfizer; and receiving travel expenses from Novartis.

References

1. van Akkooi A, Mandala M, Kicinski M, et al. Primary analysis of the EORTC-2139-MG/Columbus-AD trial: a randomized trial of adjuvant encorafenib and binimetinib versus placebo in high-risk stage II melanoma with a BRAF-V600E/K mutation. J Clin Oncol. 2025;43(suppl_17):LBA9501. doi:10.1200/JCO.2025.43.17_suppl.LBA9501
2. FDA approves encorafenib and binimetinib in combination for unresectable or metastatic melanoma with BRAF mutations. FDA. June 27, 2018. Accessed June 3, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-encorafenib-and-binimetinib-combination-unresectable-or-metastatic-melanoma-braf