LBA9501 Background: Resected stage IIB/IIC melanoma has a high risk of recurrence. While, for decades, surgery was the only option for high-risk stage II disease in most countries, adjuvant therapies now exist. Anti-PD-1 significantly improve recurrence-free survival (RFS) vs. placebo in patients with fully resected stage IIB/IIC melanoma. Combined BRAF&MEK inhibitor therapy showed benefit in high-risk stage III & advanced disease, but its role in patients with fully resected BRAF -mutated stage IIB/IIC melanoma is unknown. Encorafenib and binimetinib could be considered a valuable alternative with a lower risk of chronic toxicities. Methods: Adult patients with fully resected stage IIB or IIC cutaneous melanoma who harbored a BRAF mutation V600E or K were randomized 1:1 to receive encorafenib (enco) 450 mg QD + binimetinib (bini) 45 mg BID orally for one year or placebo. The study planned to randomize 815 patients. It was designed to demonstrate superiority regarding the primary endpoint RFS defined as time from randomization to the earliest of recurrence, new melanoma that was either ulcerated, thick or requiring a treatment other than surgery, or death with a power of 97% to detect a hazard ratio (HR) of 0.55 and 91% to detect a HR of 0.6 with a level of statistical significance of 0.025 for a one-sided log-rank test. Following a premature termination of accrual, the study was amended to become a randomized trial with safety as the primary and RFS a secondary endpoint. Results: Between June 9, 2022, and October 9, 2023, 339 patients were screened for a BRAF mutation and 110 were equally randomized between enco+bini and placebo arms. Median age was 59 yrs and 54% were male. Data cutoff was on 19 Nov. 2024, after the last patient was discontinued from the study. Among randomized patients, 87 (79%) had BRAF V600E and 23 (21%) V600K mutation, 71 (65%) AJCC8 stage IIB and 39 (35%) IIC. Median follow-up was 12 and 7 months for enco+bini and placebo arms. Among 54 patients who initiated enco+bini, grade ≥3 treatment-related adverse events (AE) occurred in 13 (24%) patients, and 18 (33%) patients had an AE leading to permanent treatment discontinuation. A serious treatment-related adverse event occurred in 1 patient. No patients died. In the enco+bini and placebo arm, respectively, 4 and 9 patients had an RFS event and 3 and 5 developed distant metastases. Descriptive RFS at 12 months was 86% (95% CI: 65-95%) in the enco+bini and 70% (95% CI: 46-85%) in the placebo arm, Distant Metastasis-Free Survival (DMFS) at 12 months was 92% (95% CI: 77-97%) for enco+bini and 82% (95% CI: 55-93%) for placebo arms. Conclusion: EORTC 2139 - Columbus-AD demonstrated a consistent safety profile for enco+bini. Descriptive analyses of efficacy show encouraging results of the combination of enco+bini for adjuvant treatment of stage IIB/C BRAF V600E/K cutaneous melanoma. Clinical trial information: NCT05270044 .
