Phase 3 Trial Shows Promise for Adjuvant BRAF/MEK Inhibitor Combination in High-Risk Melanoma
核心洞察
The phase 3 EORTC-2139-MG/Columbus-AD trial demonstrated that adjuvant encorafenib plus binimetinib improved 12-month recurrence-free survival to 86% versus 70% with placebo in patients with stage IIB/C BRAF (搜索) V600-mutant melanoma (搜索).
The combination therapy was generally well tolerated with a manageable safety profile, though 33% of patients discontinued treatment due to adverse events.
This represents the first randomized adjuvant trial of BRAF (搜索)-directed therapy in stage IIB/IIC melanoma (搜索), potentially offering patients an alternative to immunotherapy in the adjuvant setting.
The combination of encorafenib (Braftovi) plus binimetinib (Mektovi) demonstrated promising efficacy and tolerability as adjuvant therapy for patients with high-risk, stage IIB/C BRAF (搜索) V600-mutant melanoma (搜索), according to primary analysis results from the phase 3 EORTC-2139-MG/Columbus-AD trial presented at the 2025 American Society of Clinical Oncology Annual Meeting.
In the intention-to-treat population of 110 patients, the 12-month recurrence-free survival rates were 86% (95% CI, 65%-95%) in the encorafenib/binimetinib arm (n = 55) compared with 70% (95% CI, 46%-85%) in the placebo arm (n = 55). Recurrence-free survival events included distant metastasis (3 patients in combination arm vs 5 in placebo arm), locoregional recurrence (1 vs 3 patients), and new melanoma (搜索) (0 vs 1 patient).
Trial Design and Patient Population
The EORTC-2139-MG/Columbus-AD study enrolled patients with histologically confirmed stage IIB/IIC cutaneous melanoma (搜索) with fully resected, tumor-free margins. Eligible patients had sentinel node-negative disease, no microsatellite, satellite, or in-transit metastases, and centrally confirmed BRAF (搜索) V600E/V600K mutations with ECOG performance status of 0 or 1.
A total of 815 patients were stratified by stage according to the American Joint Committee on Cancer 8th edition before randomization to receive either encorafenib 450 mg once daily plus binimetinib 45 mg twice daily or double-matched placebos. The study was unblinded in November 2023, at which point placebo patients discontinued immediately while combination therapy patients completed their treatment course.
Patient demographics showed median ages of 58 years (range 27-81) in the combination arm versus 61 years (range 27-79) in the placebo arm. BRAF (搜索) V600E mutations were present in 80% of combination patients and 78% of placebo patients, while V600K mutations occurred in 20% and 22%, respectively. Ulceration was observed in 84% of combination patients versus 75% of placebo patients.
Safety Profile and Treatment Exposure
In the safety population of 54 patients receiving combination therapy, any-grade adverse events occurred in 98% of patients, with grade 3 events in 28%. Treatment-related adverse events of any grade and grade 3 occurred in 89% and 24% of patients, respectively. Serious adverse events of any grade and grade 3 occurred in 11% and 7% of patients, with treatment-related serious adverse events in 2% of patients.
Treatment discontinuation due to adverse events occurred in 33% of patients for any-grade events and 11% for grade 3 events, all suspected to be drug-related. The median treatment duration was 11.2 months, with 56% of patients completing normal treatment duration.
The most frequently reported adverse events in at least 10% of patients included nausea (37% any-grade, 0% grade 3), 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%). Only one grade 4 adverse event was reported: elevated alanine/aspartate aminotransferase levels.
Additional Efficacy Outcomes
The 12-month distant metastasis-free survival rates were 92% (95% CI, 77%-97%) in the combination arm compared with 82% (95% CI, 55%-93%) in the placebo arm. Quality of life measurements using the EORTC Core QOL Questionnaire showed mean global health status scores trending higher in the placebo arm versus the combination arm.
Median relative dose intensities were maintained at 98% for encorafenib and 96% for binimetinib, indicating good treatment adherence among patients who continued therapy.
Clinical Implications
"The key conclusions of our study are that stage IIB/IIC melanoma (搜索) has a high risk of recurrence. Encorafenib and binimetinib treatment is safe and feasible in stage IIB/IIC BRAF (搜索) V600-mutant melanoma, and adjuvant treatment with encorafenib/binimetinib may prevent cancer recurrence," stated lead study author Alexander C.J. van Akkooi, MD, PhD, FRACS, associate professor in the Department of Melanoma Surgical Oncology and chair of Melanoma Surgery at Melanoma Institute Australia in Sydney.
van Akkooi emphasized the potential clinical impact, noting 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 (搜索)."
The FDA previously approved encorafenib plus binimetinib in June 2018 for treating patients with unresectable or metastatic melanoma (搜索) harboring BRAF (搜索) V600E/V600K mutations, based on data from the phase 3 COLUMBUS trial.
van Akkooi concluded that "EORTC-2139-MG/Columbus-AD is the first and only randomized adjuvant trial of BRAF (搜索)-directed therapy with encorafenib and binimetinib in stage IIB/IIC BRAF V600-mutant melanoma (搜索). Encorafenib/binimetinib was a generally well tolerated combination with a manageable safety profile and highlights the potential utility of a BRAF/MEK (搜索) inhibition combination in the adjuvant setting to reduce recurrences for patients with stage IIB/IIC BRAF V600-mutant melanoma."