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Clinical Trial
. 2025 Jun;26(6):781-794.
doi: 10.1016/S1470-2045(25)00133-0.

Combination of encorafenib and binimetinib followed by ipilimumab and nivolumab versus ipilimumab and nivolumab in patients with advanced melanoma with BRAFV600E or BRAFV600K mutations (EBIN): an international, open-label, randomised, controlled, phase 2 study

Caroline Robert  1 , Michal Kicinski  2 , Caroline Dutriaux  3 , Émilie Routier  4 , Anne-Sophie Govaerts  2 , Emanuel Bührer  2 , Eve-Marie Neidhardt  5 , Xavier Durando  6 , Barouyr Baroudjian  7 , Philippe Saiag  8 , Caroline Gaudy-Marqueste  9 , Paolo A Ascierto  10 , Ana Arance  11 , Michelangelo Russillo  12 , Jean-Luc Perrot  13 , Laurent Mortier  14 , Francois Aubin  15 , Stéphane Dalle  16 , Florent Grange  17 , Eva Muñoz-Couselo  18 , Sorilla Mary-Prey  19 , Mona Amini-Adle  5 , Sandrine Mansard  20 , Céleste Lebbe  7 , Elisa Funck-Brentano  8 , Sandrine Monestier  21 , Alexander M M Eggermont  22 , Felix Oppong  2 , Leen Wijnen  2 , Bastian Schilling  23 , Mario MandalÁ  24 , Paul Lorigan  25 , Alexander C J van Akkooi  26
Affiliations
Clinical Trial

Combination of encorafenib and binimetinib followed by ipilimumab and nivolumab versus ipilimumab and nivolumab in patients with advanced melanoma with BRAFV600E or BRAFV600K mutations (EBIN): an international, open-label, randomised, controlled, phase 2 study

Caroline Robert et al. Lancet Oncol. 2025 Jun.

Abstract

Background: Current first-line treatment for patients with metastatic melanoma with BRAFV600E or BRAFV600K mutations includes immunotherapy with immune checkpoint inhibitors and targeted therapy; however, the optimal sequencing of these treatments is unclear. We aimed to investigate the use of a targeted-therapy induction regimen before treatment with immune checkpoint inhibitors.

Methods: This open-label, randomised, controlled, phase 2 trial (EBIN) was conducted at 37 centres in eight European countries. Eligible patients were 18 years or older and had previously untreated, unresectable, stage III or IV melanoma with BRAFV600E or BRAFV600K mutations and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1) to one of two groups. Those in the induction group received targeted therapy (oral encorafenib 450 mg once a day plus oral binimetinib 45 mg twice a day for 12 weeks) followed by immune checkpoint inhibitors (intravenous nivolumab 3 mg/kg plus intravenous ipilimumab 1 mg/kg once every 3 weeks for four doses, followed by intravenous nivolumab 480 mg once every 4 weeks until unacceptable toxicity, disease progression, or 2 years of treatment). Patients in the control group received immune checkpoint inhibitors as above without any induction targeted therapy. Randomisation was conducted using a minimisation technique and was stratified by centre and a variable defined using stage and lactate dehydrogenase activity. The primary outcome was progression-free survival in the intention-to-treat population. Safety was assessed in all patients who initiated the protocol treatment. In this Article we report the primary analysis. The study is registered with ClinicalTrials.gov, NCT03235245, and is ongoing.

Findings: Between Nov 12, 2018, and July 11, 2022, 271 patients were randomly assigned: 136 to the induction group and 135 to the control group. 103 (38%) patients were female, 168 (62%) were male, and the median age was 55 years (IQR 43-66). The median follow-up time was 21 months (IQR 13-33). There was no evidence of a longer progression-free survival in the induction group than in the control group (hazard ratio 0·87, 90% CI 0·67-1·12; p=0·36). The median progression-free survival was 9 months (95% CI 7-13) in the induction group and 9 months (5-14) in the control group. Grade 3-5 treatment-related adverse events occurred in 57 (42%) of 136 patients who started treatment in the induction group and in 42 (32%) of 131 patients who started treatment in the control group. The most common grade 3-4 treatment-related adverse event was hepatitis (17 [13%] of 136 patients in the induction group and nine [7%] of 131 patients in the control group). Serious treatment-related adverse events occurred in 45 (33%) of 136 patients in the induction group and 33 (25%) of 131 patients in the control group. There were three treatment-related deaths: two from cardiac events (heart failure and arrhythmia) in the induction group and one from meningitis in the control group.

Interpretation: The targeted-therapy induction regimen did not improve progression-free survival compared with first-line treatment with immune checkpoint inhibitors in unselected patients with advanced melanoma with BRAFV600E or BRAFV600K mutations.

Funding: Bristol Myers Squibb and Pierre Fabre.

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Conflict of interest statement

Declaration of interests CR reports consulting fees from BMS, Roche, Pierre Fabre, Novartis, Sanofi, Pfizer, MSD, Merck, Sun Pharma, Ultimovacs, Regeneron, Egle Therapeutics, Philogen, MaaT Pharma, and IO Biotech; honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Pierre Fabre, Sanofi, BMS, MSD, and Novartis; support for attending meetings and/or travel from Pierre Fabre; and participation on a data safety monitoring board or advisory board from BMS, Roche, Pierre Fabre, Novartis, Sanofi, Pfizer, MSD, Merck, Sun Pharma, Ultimovacs, Regeneron, Egle, Philogen, and Maar Pharma. MK reports study funding paid to their institution from BMS, MSD, Pierre Fabre, JnJ, and Immunocore. CD reports consulting fees; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events; support for attending meetings and/or travel; and participation on a data safety monitoring board or advisory board of BMS, Merck, Novartis, Sanofi, Regeneron, and Pierre Fabre. ÉR received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Pierre Fabre. EB's spouse and daughter hold shares in Sandoz, Galenica, Alcon, and Roche Novartis. BB received honoraria for lectures from BMS, Pierre Fabre, Sanofi, and MSD; support for travel from Pierre Fabre; and is a board member of Pierre Fabre, Sanofi, and MSD. PS reports personal fees from Novartis, MSD, NeraCare, BMS, and Pierre Fabre. CG-M reports consulting fees from Pierre Fabre, BMS, and MSD; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Pierre-Fabre, BMS, and MSD; support for attending meetings and/or travel from Pierre Fabre, BMS, MSD, and Janssen; and participation on a data safety monitoring board or advisory board for Sun Pharma and Pierre Fabre. PAA reports grants or contracts from BMS, Roche-Genentech, Pfizer, and Sanofi; consulting fees from BMS, Roche-Genentech, MSD, Novartis, Merck Serono, Pierre-Fabre, Sun Pharma, Sanofi, Sandoz, Italfarmaco, Pfizer, Lunaphore, Medicenna, Bio-Al Health, ValoTx, Replimmune, Bayer, Philogen, and BionTech; support for attending meetings and/or travel from Pfizer, Bio-Al Health, Replimmune, MSD, Pierre Fabre, and Philogen; and participation on a data safety monitoring board or advisory board for BMS, Roche-Genentech, MSD, Novartis, Boehringer-Ingelheim, Regeneron, Nouscom, Erasca, Anaveon, Genmab, and Menarini. AA reports speaker fees from BMS, MSD, Novartis, and Pierre Fabre; participation on an advisory board of BMS, MSD, Novartis, Pierre Fabre, and Biontech; and has received support for attending meetings and/or travel from BMS, MSD, Novartis, and Pierre Fabre. MR reports payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events; support for attending meetings and/or travel; and has participated on a data safety monitoring board or advisory board for BMS, MSD, Pierre Fabre, and Novartis. LM has received support for attending meetings and/or travel from BMS, Pierre Fabre, and Novartis and has participated on a data safety monitoring board or advisory board for Pierre Fabre and BMS. FA has received payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Novartis, Janssen, AbbVie, UCR, Amgen, Leo Pharma, Sanofi, and MSD and support for attending meetings and/or travel from Novartis, AbbVie, Janssen, UCB, Leo Pharma, Amgen, Sanofi, and MSD. SD reports research funding paid to their institution from BMS, MSD, and Pierre Fabre; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events paid to their institution from BMS and MSD; support for attending meetings and/or travel from BMS and MSD; the Trim 24 pending patent; participation on a data safety monitoring board or advisory board of BMS and MSD; and his spouse is a Sanofi employee and has stock options. EM-C reports consulting fees from BMS, MSD, Novartis, Pierre-Fabre, Immunocore, Menarini, and Regeneron; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from BMS, MSD, Regeneron, Pierre Fabre, and Novartis; support for attending meetings and/or travel from MSD and Pierre Fabre; and participation on a data safety monitoring board or advisory board for BMD, Regeneron, Pierre Fabre, and MSD. MA-A reports grants or contracts from BMS; payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Pierre Fabre, BMS, Alexion, and MSD; and support for attending meetings and/or travel from Pierre Fabre, BMS, Alexion, and MSD. SMa reports payments for participation in educational events from BMS; participation on an advisory board for MSD; and support for attending meetings and/or travel from Pierre Fabre. EF-B reports consulting fees from BMS, MSD, Novartis, Pierre Fabre, and Sun Pharma; payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from BMS, MSD, Pierre Fabre, and Novartis; and support for attending meetings and/or travel from MSD and Pierre Fabre. SMo reports consulting fees from BMS; payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from BMS, Pierre Fabre, and MSD; and support for attending meetings and/or travel from BMS, Pierre Fabre, Novartis, and MSD. AMME reports consulting fees from Agenus, Boehringer Ingelheim, BioInvent, BioNTech, Brenus, CatalYm, Eurobio, GenOzyme, GSK, Imcheck, Immatics, Ipsen, IO Biotech, IQVIA, ISA Pharmaceuticals, Merck&Co, MSD, Oncolytics, Pfizer, Pierre Fabre, QBiotics, Regeneron, Replimune, ScanCell, Scorpion Therapeutics, Secarna, Sellas, Thermosome, TigaTX, and Trained Immunity Discovery; speaker honoraria from BMS and Merck&Co/MSD; participation on a data safety monitoring board or advisory board of Agenus, Boehringer Ingelheim, BioInvent, BioNTech, Brenus, CatalYm, Eurobio, GenOzyme, GSK, Imcheck, Immatics, Ipsen, IO Biotech, IQVIA, ISA Pharmaceuticals, Merck&Co, MSD, Oncolytics, Pfizer, Pierre Fabre, QBiotics, Regeneron, Replimune, ScanCell, Scorpion Therapeutics, Secarna, Sellas, Thermosome, TigaTX, and Trained Immunity Discovery; and stock or stock options for IO Biotech, Sairopa BV, and SkylineDX BV. BS reports personal fees or honoraria from IO Biotech, Sairopa BV, SkylineDX BV, Immunocore, and Sun Pharma. MM reports consulting fees from BMS, MSD, Novartis, Pierre Fabre, Immunocore, Regeneron, and Sun Pharma; and payment for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Novartis, Regeneron, BMS, MSD, and Sun Pharma. PL reports grants or contracts from Pierre Fabre and BMS; consulting fees from Iovance and MLA Diagnostics; payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from BMS and MSD; and support for attending meetings and/or travel from MSD. ACJvA reports grants or contracts from Amgen, Merck, Sorono-Pfizer, and SkylineDx; participation on advisory board; and receiving consultancy honoraria from 4SC AG, Amgen, Bristol-Myers Squibb, Genmab, Menarini Silicon Biosystems, Serono-Pfizer, MSD-Merck, Neracare, Novartis, Pierre Fabre, Sanofi, Sirius Medical, and SkylineDX. All other authors declare no competing interests.

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