BACKGROUND: BRAF/MEK inhibitor combinations are established treatments for BRAF V600-mutant melanoma based on demonstrated benefits on progression-free survival (PFS) and overall survival (OS). Here, we report an updated analysis of the COLUMBUS (COmbined LGX818 [encorafenib] Used with MEK162 [binimetinib] in BRAF mutant Unresectable Skin cancer) trial with long-term follow-up. METHODS: In part 1 of the COLUMBUS trial, 577 patients with advanced/metastatic BRAF V600-mutant melanoma, untreated or progressed after first-line immunotherapy, were randomised 1:1:1 to 450 mg of encorafenib QD + 45 mg of binimetinib BID (COMBO450) vs 960 mg of vemurafenib BID (VEM) or 300 mg of encorafenib ENCO QD (ENCO300). An updated analysis was conducted that included PFS, OS, objective response rate, safety and tolerability and analyses of results by prognostic subgroups. RESULTS: At data cutoff, there were 116, 113 and 138 deaths in the COMBO450, ENCO300 and VEM treatment arms, respectively. The median OS was 33.6 months (95% confidence interval [CI], 24.4-39.2) for COMBO450, 23.5 months (95% CI, 19.6-33.6) for ENCO300 and 16.9 months (95% CI, 14.0-24.5) for VEM. Compared with VEM, COMBO450 decreased the risk of death by 39% (hazard ratio [HR], 0.61; 95% CI, 0.48-0.79). The updated median PFS for COMBO450 was 14.9 months (95% CI, 11.0-20.2), ENCO300 was 9.6 months (95% CI, 7.4-14.8) and VEM was 7.3 months (95% CI, 5.6-7.9). PFS was longer for COMBO450 vs VEM (HR, 0.51; 95% CI, 0.39-0.67). Landmark OS and PFS results show consistent results for each year analysed. Subgroups all favoured COMBO450 vs VEM. CONCLUSIONS: Updated PFS and OS results for COMBO450 from the COLUMBUS trial demonstrate a long-term benefit in patients with advanced BRAF V600-mutated melanoma.

Cancer Center Massachusetts General Hospital Boston MA USA

Department of Dermato oncology University Hospital Prague and Charles University 1st Medical Faculty Prague Czech Republic

Department of Dermatology and Allergy Skin Cancer Center Hannover Hannover Medical School Hannover Germany

Department of Dermatology National Institute of Oncology Budapest Hungary

Department of Dermatology University Hospital Essen Essen Germany; German Cancer Consortium Heidelberg Germany

Department of Dermatology University Hospital Tuebingen Tuebingen Germany

Department of Dermatology University Hospital Zürich Skin Cancer Center and University Zürich Zürich Switzerland

Department of Dermatology University Medical Center Mainz Mainz Germany

Department of Internal Medicine National and Kapodistrian University of Athens Laikon Hospital Athens Greece

Department of Medical Oncology Hospital Clinic of Barcelona Barcelona Spain

Department of Medical Oncology Isala Zwolle Netherlands

Department of Oncology and Haematology Papa Giovanni XXIII Cancer Center Hospital Bergamo Italy

Melanoma Unit Cancer Immunotherapy and Innovative Therapies Istituto Nazionale Tumori IRCCS Fondazione Pascale Naples Italy

Pfizer Inc Boulder CO USA

Service of Dermatology Department of Medicine and Paris Sud University Gustave Roussy Villejuif France

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COLUMBUS 5-Year Update: A Randomized, Open-Label, Phase III Trial of Encorafenib Plus Binimetinib Versus Vemurafenib or Encorafenib in Patients With BRAF V600-Mutant Melanoma