PURPOSE: In COLUMBUS part 1, patients with advanced BRAFV600-mutant melanoma were randomly assigned 1:1:1 to encorafenib 450 mg once daily plus binimetinib 45 mg twice a day (COMBO450), vemurafenib 960 mg twice a day, or encorafenib 300 mg once daily (ENCO300). As previously reported, COMBO450 improved progression-free survival (PFS) versus vemurafenib (part 1 primary end point) and ENCO300 (part 1 key secondary end point; not statistically significant). Part 2, requested by the US Food and Drug Administration, evaluated the contribution of binimetinib by maintaining the same encorafenib dosage in the combination (encorafenib 300 mg once daily plus binimetinib 45 mg twice daily [COMBO300]) and ENCO300 arms. METHODS: In part 2, patients were randomly assigned 3:1 to COMBO300 or ENCO300. ENCO300 (parts 1 and 2) data were combined, per protocol, for PFS analysis (key secondary end point) by a blinded independent review committee (BIRC). Other analyses included overall response rate (ORR), overall survival, and safety. RESULTS: Two hundred fifty-eight patients received COMBO300, and 86 received ENCO300. Per protocol, ENCO300 arms (parts 1 and 2 combined) were also evaluated (n = 280). The median follow-up for ENCO300 was 40.8 months (part 1) and 57.1 months (part 2). The median PFS (95% CI) was 12.9 months (10.9 to 14.9) for COMBO300 versus 9.2 months (7.4 to 11.1) for ENCO300 (parts 1 and 2) and 7.4 months (5.6 to 9.2) for ENCO300 (part 2). The hazard ratio (95% CI) for COMBO300 was 0.74 (0.60 to 0.92; two-sided P = .003) versus ENCO300 (parts 1 and 2). The ORR by BIRC (95% CI) was 68% (62 to 74) and 51% (45 to 57) for COMBO300 and ENCO300 (parts 1 and 2), respectively. COMBO300 had greater relative dose intensity and fewer grade 3/4 adverse events than ENCO300. CONCLUSION: COMBO300 improved PFS, ORR, and tolerability compared with ENCO300, confirming the contribution of binimetinib to efficacy and safety.

Cancer Center Massachusetts General Hospital Boston MA

Department of Dermatologic Oncology National Cancer Center Hospital Tokyo Japan

Department of Dermatology and Venereology 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Department of Dermatology Klinikum Bremen Ost Gesundheitnord gGmbH Bremen Germany

Department of Dermatology National Institute of Oncology Budapest Hungary

Department of Dermatology Skin Cancer Center Minden Mühlenkreiskliniken Ruhr University Bochum Minden Germany

Department of Dermatology University Hospital Essen Essen Germany

Department of Dermatology University Hospital Tübingen Tübingen Germany

Department of Dermatology University Hospital Zürich Skin Cancer Center Zürich Switzerland

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 Medicine Service of Dermatology Paris Saclay University Cedex France

Department of Oncologic Dermatology Bordeaux University Hospital Center Bordeaux Cédex France

German Cancer Consortium Partner Site Essen Essen Germany

Isala Oncology Center Isala Zwolle the Netherlands

Melanoma Cancer Unit Istituto Oncologico Veneto IRCCS Padua Italy

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

Santa Maria Misericordia Hospital University of Perugia Perugia Italy

doi: 10.1200/JCO.23.01380 PubMed

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Colombino M, Capone M, Lissia A, et al. : BRAF/NRAS mutation frequencies among primary tumors and metastases in patients with melanoma. J Clin Oncol 30:2522-2529, 2012 PubMed

Davies H, Bignell GR, Cox C, et al. : Mutations of the BRAF gene in human cancer. Nature 417:949-954, 2002 PubMed

Michielin O, van Akkooi ACJ, Ascierto PA, et al. : Cutaneous melanoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 30:1884-1901, 2019 PubMed

Ascierto PA, McArthur GA, Dréno B, et al. : Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): Updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol 17:1248-1260, 2016 PubMed

Larkin J, Ascierto PA, Dréno B, et al. : Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med 371:1867-1876, 2014 PubMed

Long GV, Stroyakovskiy D, Gogas H, et al. : Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: A multicentre, double-blind, phase 3 randomised controlled trial. Lancet 386:444-451, 2015 PubMed

Robert C, Karaszewska B, Schachter J, et al. : Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med 372:30-39, 2015 PubMed

Dummer R, Ascierto PA, Gogas HJ, et al. : Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): A multicentre, open-label, randomised phase 3 trial. Lancet Oncol 19:603-615, 2018 PubMed

Ascierto PA, Schadendorf D, Berking C, et al. : MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: A non-randomised, open-label phase 2 study. Lancet Oncol 14:249-256, 2013 PubMed

Stuart DD, Li N, Poon DJ, et al. : Preclinical profile of LGX818: A potent and selective RAF kinase inhibitor. Presented at 103rd Annual Meeting of the American Association for Cancer Research, Abstract 3790, Chicago, IL, April 15, 2012

Delord JP, Robert C, Nyakas M, et al. : Phase I dose-escalation and -expansion study of the BRAF inhibitor encorafenib (LGX818) in metastatic BRAF-mutant melanoma. Clin Cancer Res 23:5339-5348, 2017 PubMed

Koelblinger P, Thuerigen O, Dummer R: Development of encorafenib for BRAF-mutated advanced melanoma. Curr Opin Oncol 30:125-133, 2018 PubMed PMC

Sullivan RJ, Weber J, Patel S, et al. : A phase Ib/II study of the BRAF inhibitor encorafenib plus the MEK inhibitor binimetinib in patients with BRAFV600E/K-mutant solid tumors. Clin Cancer Res 26:5102-5112, 2020 PubMed

Dummer R, Ascierto PA, Gogas HJ, et al. : Overall survival in patients with BRAF-mutant melanoma receiving encorafenib plus binimetinib versus vemurafenib or encorafenib (COLUMBUS): A multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 19:1315-1327, 2018 PubMed

Dummer R, Flaherty KT, Robert C, et al. : 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. J Clin Oncol 40:4178-4188, 2022 PubMed PMC

Médicament PF: BRAFTOVI summary of product characteristics. https://www.ema.europa.eu/en/documents/product-information/braftovi-epar-product-information_en.pdf

Array BioPharma Inc : BRAFTOVI prescribing information. https://labeling.pfizer.com/ShowLabeling.aspx?id=12990

Eisenhauer EA, Therasse P, Bogaerts J, et al. : New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer 45:228-247, 2009 PubMed

Gogas H, Dummer R, Ascierto PA, et al. : Quality of life in patients with BRAF-mutant melanoma receiving the combination encorafenib plus binimetinib: Results from a multicentre, open-label, randomised, phase III study (COLUMBUS). Eur J Cancer 152:116-128, 2021 PubMed

McArthur GA, Dréno B, Larkin J, et al. : 5-year survival update of cobimetinib plus vemurafenib in BRAFV600 mutation-positive advanced melanoma: final analysis of the coBRIM study. Presented at 16th International Congress of the Society for Melanoma Research (SMR), Salt Lake City, UT, November 20-23, 2019

Long GV, Flaherty KT, Stroyakovskiy D, et al. : Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: Long-term survival and safety analysis of a phase 3 study. Ann Oncol 28:1631-1639, 2017 PubMed PMC

Robert C, Grob JJ, Stroyakovskiy D, et al. : Five-year outcomes with dabrafenib plus trametinib in metastatic melanoma. N Engl J Med 381:626-636, 2019 PubMed

Robert C, Karaszewska B, Schachter J, et al. : Three-year estimate of overall survival in COMBI-v, a randomized phase 3 study evaluating first-line dabrafenib (D)+ trametinib (T) in patients (pts) with unresectable or metastatic BRAF V600E/K–mutant cutaneous melanoma. Ann Oncol 27, 2016. (suppl 6; abstr VI575)

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