Phase III study of adjuvant encorafenib plus binimetinib vs placebo in fully resected stage IIB/C BRAFV600-mutated melanoma: COLUMBUS-AD study design

Abstract

Background: Melanoma treatment has radically changed during the past decade. This is due to the discovery that BRAFV600-mutant directed targeted therapy, next to immune checkpoint blockade. In the Columbus study, encorafenib in combination with binimetinib has shown safety and efficacy in BRAF V600E/K mutant advanced / metastatic stage IV melanoma. Standard of care for stage II melanoma was surveil lance follow-up after full resection. Considering that stage IIB/IIC melanoma has an equal or higher risk of recurrence and mortality compared to stage IIIA/B, there is an unmet medical need for stage IIB/C melanoma. Trial design: COLUMBUS-AD (NCT05270044) trial is a placebo-controlled, randomized, triple-blind Phase 3 study evaluating 1 year of adjuvant encorafenib + binimetinib against placebo in patients with fully resected stage IIB/C BRAF V600-mutant mela noma. 2200 will be screened to enroll 815 patients. Patients will receive encorafenib + binimetinib or placebo for up to a maximum of 12 months, or until disease recur rence, unacceptable toxicity, death or withdrawal of consent. Patients will be followed up routinely with periodic imaging assessments up to a maximum of 10 years. In clusion criteria include adult patients ( 18 years of age), fully resected stage IIB/cutaneous melanoma, mandatorily within 12 weeks of negative sentinel lymph node biopsy (SLNB) staging, no other signs of metastases (including no (micro-)satellites or in-transit metastases), fully recovered from surgery, ECOG 0/1 with adequate he matologic, hepatic, cardiac, coagulation and renal functions. The primary endpoint of this trial is recurrence-free survival (RFS), with the hypothesis that the combination of encorafenib + binimetinib will prolong RFS. Secondary endpoints include distant metastasis-free survival (DMFS), overall survival (OS) health-related quality of life (QoL), and safety and tolerability between the two arms and to provide additional pharmacokinetic data. The exploratory objectives include evaluation of the role of circulating tumor DNA (ctDNA) as a biomarker. The first patient was screened in May 2022 and first ran domized in June 2022. Anticipated accrual completion mid 2025