BACKGROUND: Combined BRAF-MEK inhibitor therapy is the standard of care for BRAFV600-mutant advanced melanoma. We investigated encorafenib, a BRAF inhibitor with unique target-binding properties, alone or in combination with the MEK inhibitor binimetinib, versus vemurafenib in patients with advanced BRAFV600-mutant melanoma. METHODS: COLUMBUS was conducted as a two-part, randomised, open-label phase 3 study at 162 hospitals in 28 countries. Eligible patients were aged 18 years or older and had histologically confirmed locally advanced (American Joint Committee on Cancer [AJCC] stage IIIB, IIIC, or IV), unresectable or metastatic cutaneous melanoma, or unknown primary melanoma; a BRAFV600E or BRAFV600K mutation; an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; and were treatment naive or had progressed on or after previous first-line immunotherapy. In part 1 of the study, patients were randomly assigned (1:1:1) via interactive response technology to receive either oral encorafenib 450 mg once daily plus oral binimetinib 45 mg twice daily (encorafenib plus binimetinib group), oral encorafenib 300 mg once daily (encorafenib group), or oral vemurafenib 960 mg twice daily (vemurafenib group). The primary endpoint was progression-free survival by blinded independent central review for encorafenib plus binimetinib versus vemurafenib. Efficacy analyses were by intention-to-treat. Safety was analysed in patients who received at least one dose of study drug and one postbaseline safety assessment. The results of part 2 will be published separately. This study is registered with ClinicalTrials.gov, number NCT01909453, and EudraCT, number 2013-001176-38. FINDINGS: Between Dec 30, 2013, and April 10, 2015, 577 of 1345 screened patients were randomly assigned to either the encorafenib plus binimetinib group (n=192), the encorafenib group (n=194), or the vemurafenib group (n=191). With a median follow-up of 16·6 months (95% CI 14·8-16·9), median progression-free survival was 14·9 months (95% CI 11·0-18·5) in the encorafenib plus binimetinib group and 7·3 months (5·6-8·2) in the vemurafenib group (hazard ratio [HR] 0·54, 95% CI 0·41-0·71; two-sided p<0·0001). The most common grade 3-4 adverse events seen in more than 5% of patients in the encorafenib plus binimetinib group were increased γ-glutamyltransferase (18 [9%] of 192 patients), increased creatine phosphokinase (13 [7%]), and hypertension (11 [6%]); in the encorafenib group they were palmoplantar erythrodysaesthesia syndrome (26 [14%] of 192 patients), myalgia (19 [10%]), and arthralgia (18 [9%]); and in the vemurafenib group it was arthralgia (11 [6%] of 186 patients). There were no treatment-related deaths except for one death in the combination group, which was considered possibly related to treatment by the investigator. INTERPRETATION: Encorafenib plus binimetinib and encorafenib monotherapy showed favourable efficacy compared with vemurafenib. Overall, encorafenib plus binimetinib appears to have an improved tolerability profile compared with encorafenib or vemurafenib. Encorafenib plus binimetinib could represent a new treatment option for patients with BRAF-mutant melanoma. FUNDING: Array BioPharma, Novartis.

Array BioPharma Boulder CO USA

Cancer Center Massachusetts General Hospital Boston MA USA

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

Department of Dermatologic Oncology National Cancer Center Hospital Tokyo Japan

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 Tüebingen Tüebingen Germany

Department of Dermatology University Hospital Zürich Skin Cancer Center 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 Oncologic Dermatology Centre Hospitalier Universitaire de Bordeaux Hôpital Saint André Bordeaux France

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

Melanoma Cancer Unit Oncology Institute of Veneto IRCCS Padua Italy

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

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

Translational Clinical Oncology Novartis Pharma AG Basel Switzerland

Lancet Oncol. 2018 May;19(5):580-581. doi: 10.1016/S1470-2045(18)30161-X. PubMed

Nat Rev Clin Oncol. 2018 Jun;15(6):344-345. doi: 10.1038/s41571-018-0019-x. PubMed

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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

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

Targeting Oncogenic Pathways in the Era of Personalized Oncology: A Systemic Analysis Reveals Highly Mutated Signaling Pathways in Cancer Patients and Potential Therapeutic Targets

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ClinicalTrials.gov
NCT01909453