464TiP - Phase III study of adjuvant encorafenib plus binimetinib vs placebo in fully resected stage IIB/C BRAFV600-mutated melanoma: COLUMBUS-AD study design

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 surveillance 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 melanoma. 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 recurrence, unacceptable toxicity, death or withdrawal of consent. Patients will be followed up routinely with periodic imaging assessments up to a maximum of 10 years. Inclusion criteria include adult patients (≥18 years of age), fully resected stage IIB/C 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 hematologic, 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 randomized in June 2022. Anticipated accrual completion mid 2025.

Clinical trial identification

NCT05270044.

Legal entity responsible for the study

Pierre Fabre in conjunction with the EORTC.

Funding

Pierre Fabre.

Disclosure

A.C.J. van Akkooi: Financial Interests, Institutional, Advisory Board: Amgen, Bristol Myers Squibb, Novartis, MSD-Merck, Merck-Pfizer, Pierre Fabre, Sanofi, Sirius Medical, 4SC; Financial Interests, Personal, Advisory Board: Provectus. A. Hauschild: Financial Interests, Personal, Advisory Board: BMS, MSD, Philogen, PierreFabre, Regereron, Roche, Sanofi, Novartis, Eisai, Immunocore, Replimune, Seagen; Financial Interests, Personal, Invited Speaker: MerckPfizer; Financial Interests, Institutional, Invited Speaker: BMS, MSD, PierreFabre, Amgen, Regeneron, Roche, Novartis. G.V. Long: Financial Interests, Personal, Other, Consultant Advisor: Agenus Inc, Amgen Inc, Array Biopharma Inc, Boehringer Ingelheim International GmbH, Bristol Myers Squibb, Evaxion Biotech A/S, Hexal AG (Sandoz Company), Merck Sharpe & Dohme (Australia) Pty Limited, Novartis Pharma AG, OncoSec Medical Australia, Pierre Fabre, Provectus Australia, Qbiotics Group Limited, Regeneron Pharmaceuticals Inc; Financial Interests, Personal, Advisory Board, Consultant Advisor: Highlight Therapeutics S.L. M. Mandala: Financial Interests, Personal, Advisory Board: MSD, Novartis, Sanofi, BMS, Pierre Fabre; Financial Interests, Personal, Invited Speaker: Sun Pharma. I. Klauck, M. Ouali: Financial Interests, Personal, Other: Pierre Fabre. P. Lorigan: Financial Interests, Personal, Advisory Board: BMS, Merck, Novartis, GSK, Amgen, Chugai, Pierre Fabre, NeraCare, Roche; Financial Interests, Personal, Invited Speaker: Oncology Education Canada. A.M.M. Eggermont: Financial Interests, Personal, Advisory Board: Biocad, BioInvent, BioNTech, Bristol Myers Squibb, CatalYm, Ellipses, GSK, IO Biotech, ISA Pharmaceuticals, MSD Merck, Nektar, Novartis, Pfizer, Sellas, TigaTx, TTxDiscovery; Financial Interests, Personal, Stocks/Shares: SkylineDx, SAiRoPA. All other authors have declared no conflicts of interest.