PURPOSE: Combination treatment with BRAF and MEK inhibitors has demonstrated benefits on progression-free survival (PFS) and overall survival (OS) and is a standard of care for the treatment of advanced BRAF V600-mutant melanoma. Here, we report the 5-year update from the COLUMBUS trial (ClinicalTrials.gov identifier: NCT01909453). METHODS: Patients with locally advanced unresectable or metastatic BRAF V600-mutant melanoma, untreated or progressed after first-line immunotherapy, were randomly assigned 1:1:1 to encorafenib 450 mg once daily plus binimetinib 45 mg twice daily, vemurafenib 960 mg twice daily, or encorafenib 300 mg once daily. An updated analysis was conducted 65 months after the last patient was randomly assigned. RESULTS: Five hundred seventy-seven patients were randomly assigned: 192 to encorafenib plus binimetinib, 191 to vemurafenib, and 194 to encorafenib. The 5-year PFS and OS rates with encorafenib plus binimetinib were 23% and 35% overall and 31% and 45% in those with normal lactate dehydrogenase levels, respectively. In comparison, the 5-year PFS and OS rates with vemurafenib were 10% and 21% overall and 12% and 28% in those with normal lactate dehydrogenase levels, respectively. The median duration of response with encorafenib plus binimetinib was 18.6 months, with disease control achieved in 92.2% of patients. In comparison, the median duration of response with vemurafenib was 12.3 months, with disease control achieved in 81.2% of patients. Long-term follow-up showed no new safety concerns, and results were consistent with the known tolerability profile of encorafenib plus binimetinib. Interactive visualization of the data presented in this article is available at COLUMBUS dashboard. CONCLUSION: In this 5-year update of part 1 of the COLUMBUS trial, encorafenib plus binimetinib treatment demonstrated continued long-term benefits and a consistent safety profile in patients with BRAF V600-mutant melanoma.

Gustave Roussy and Paris Saclay University Villejuif France

Hannover Medical School Hannover and Ruhr University Bochum Minden Campus Germany

Hospital Clinic of Barcelona and IDIBAPS Barcelona Spain

Isala Oncology Center Zwolle the Netherlands

Istituto Nazionale Tumori IRCCS Fondazione Pascale Napoli Italy

Massachusetts General Hospital Boston MA

National and Kapodistrian University of Athens Athens Greece

National Cancer Center Hospital Tokyo Japan

National Institute of Oncology Budapest Hungary

Pfizer Milan Italy

Pfizer New York NY

PharPoint Research Durham NC

University Hospital Essen West German Cancer Center and German Cancer Consortium Partner Site Essen Essen Germany

University Hospital Prague Prague Czech Republic

University Hospital Tubingen Tubingen Germany

University Hospital Zurich Zurich Switzerland

University Medical Center of the Johannes Gutenberg University Mainz Mainz Germany

University of Perugia Perugia Italy

J Clin Oncol. 2022 Dec 20;40(36):4161-4165. doi: 10.1200/JCO.22.01066. PubMed

J Clin Oncol. 2023 Apr 20;41(12):2301. doi: 10.1200/JCO.23.00385. PubMed

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Krauthammer M, Kong Y, Bacchiocchi A, et al. : Exome sequencing identifies recurrent mutations in NF1 and RASopathy genes in sun-exposed melanomas. Nat Genet 47:996-1002, 2015 PubMed PMC

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

Seth R, Messersmith H, Kaur V, et al. : Systemic therapy for melanoma: ASCO guideline. J Clin Oncol 38:3947-3970, 2020 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

Keilholz U, Ascierto PA, Dummer R, et al. : ESMO consensus conference recommendations on the management of metastatic melanoma: Under the auspices of the ESMO Guidelines Committee. Ann Oncol 31:1435-1448, 2020 PubMed

Michielin O, van Akkooi A, Lorigan P, et al. : ESMO consensus conference recommendations on the management of locoregional melanoma: Under the auspices of the ESMO Guidelines Committee. Ann Oncol 31:1449-1461, 2020 PubMed

National Comprehensive Cancer Network : NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Cutaneous Melanoma (Version 3.2022). NCCN.org, 2022

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

Ascierto PA, Dreno B, Larkin J, et al. : 5-year outcomes with cobimetinib plus vemurafenib in BRAF (V600) mutation-positive advanced melanoma: Extended follow-up of the coBRIM study. Clin Cancer Res 27:5225-5235, 2021 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. : 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

Dummer R, Ascierto PA, Gogas H, et al. : Results of COLUMBUS Part 2: A phase 3 trial of encorafenib (ENCO) plus binimetinib (BINI) versus ENCO in BRAF-mutant melanoma, Presented at 42nd Annual Congress of the European Society for Medical Oncology, Madrid, Spain, September 8-12, 2017 (abstr 1215O)

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

Holderfield M, Merritt H, Chan J, et al. : RAF inhibitors activate the MAPK pathway by relieving inhibitory autophosphorylation. Cancer Cell 23:594-602, 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, Chicago, IL, March 31-April 4, 2012 (abstr 3790)

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

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

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

Gogas HJ, Flaherty KT, Dummer R, et al. : Adverse events associated with encorafenib plus binimetinib in the COLUMBUS study: Incidence, course and management. Eur J Cancer 119:97-106, 2019 PubMed

Ascierto PA, Dummer R, Gogas HJ, et al. : Update on tolerability and overall survival in COLUMBUS: Landmark analysis of a randomised phase 3 trial of encorafenib plus binimetinib vs vemurafenib or encorafenib in patients with BRAF V600-mutant melanoma. Eur J Cancer 126:33-44, 2020 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

Long GV, Grob JJ, Nathan P, et al. : Factors predictive of response, disease progression, and overall survival after dabrafenib and trametinib combination treatment: A pooled analysis of individual patient data from randomised trials. Lancet Oncol 17:1743-1754, 2016 PubMed

Hauschild A, Larkin J, Ribas A, et al. : Modeled prognostic subgroups for survival and treatment outcomes in BRAF V600-mutated metastatic melanoma: Pooled analysis of 4 randomized clinical trials. JAMA Oncol 4:1382-1388, 2018 PubMed PMC

Clinical Trials Dashboard: COLUMBUS trial 5-year results. https://clinical-trials.dimensions.ai/columbus

Ascierto PA, Del Vecchio M, Mackiewicz A, et al. : Overall survival at 5 years of follow-up in a phase III trial comparing ipilimumab 10 mg/kg with 3 mg/kg in patients with advanced melanoma. J Immunother Cancer 8:e000391, 2020 PubMed PMC

Ribas A, Daud A, Pavlick AC, et al. : Extended 5-year follow-up results of a phase Ib study (BRIM7) of vemurafenib and cobimetinib in BRAF-mutant melanoma. Clin Cancer Res 26:46-53, 2020 PubMed PMC

Larkin J, Chiarion-Sileni V, Gonzalez R, et al. : Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med 381:1535-1546, 2019 PubMed

Ascierto PA, McArthur GA, Dreno 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

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, 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

Dréno B, Ribas A, Larkin J, et al. : Incidence, course, and management of toxicities associated with cobimetinib in combination with vemurafenib in the coBRIM study. Ann Oncol 28:1137-1144, 2017 PubMed

Booth AEC, Hopkins AM, Rowland A, et al. : Risk factors for MEK-associated retinopathy in patients with advanced melanoma treated with combination BRAF and MEK inhibitor therapy. Ther Adv Med Oncol 12:1758835920944359, 2020 PubMed PMC

Meirson T, Asher N, Bomze D, et al. : Safety of BRAF+MEK inhibitor combinations: Severe adverse event evaluation. Cancers (Basel) 12:1650, 2020 PubMed PMC

Holbrook K, Lutzky J, Davies MA, et al. : Intracranial antitumor activity with encorafenib plus binimetinib in patients with melanoma brain metastases: A case series. Cancer 126:523-530, 2020 PubMed PMC

Fukushima H, Iwata Y, Saito K, et al. : Successful rechallenge therapy for BRAF/MEK inhibitor-resistant multiple brain metastases of melanoma. J Dermatol 48:1291-1295, 2021 PubMed

Khullar K, Hanft S, Mehnert JM, et al. : Complete response of brainstem metastasis in BRAF-mutated melanoma without stereotactic radiosurgery after initiation of encorafenib and binimetinib. Melanoma Res 31:393-396, 2021 PubMed

McLoughlin EM, Fadul CE, Patel SH, et al. : Clinical and radiographic response of leptomeningeal and brain metastases to encorafenib and binimetinib in a patient with BRAF V600E-mutated lung adenocarcinoma. J Thorac Oncol 14:e269-e271, 2019 PubMed

Contribution of MEK Inhibition to BRAF/MEK Inhibitor Combination Treatment of BRAF-Mutant Melanoma: Part 2 of the Randomized, Open-Label, Phase III COLUMBUS Trial

Randomized, Double-Blind, Placebo-Controlled, Global Phase III Trial of Talimogene Laherparepvec Combined With Pembrolizumab for Advanced Melanoma

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ClinicalTrials.gov
NCT01909453