Sequencing of Ipilimumab Plus Nivolumab and Encorafenib Plus Binimetinib for Untreated BRAF -Mutated Metastatic Melanoma (SECOMBIT): A Randomized, Three-Arm, Open-Label Phase II Trial

• Published in: Journal of clinical oncology Vol. 41; no. 2; pp. 212 - 221
• Main Authors: Ascierto, Paolo A, Mandalà, Mario, Ferrucci, Pier Francesso, Guidoboni, Massimo, Rutkowski, Piotr, Ferraresi, Virginia, Arance, Ana, Guida, Michele, Maiello, Evaristo, Gogas, Helen, Richtig, Erika, Fierro, Maria Teresa, Lebbè, Celeste, Helgadottir, Hildur, Queirolo, Paola, Spagnolo, Francesco, Tucci, Marco, Del Vecchio, Michele, Gonzales Cao, Maria, Minisini, Alessandro Marco, De Placido, Sabino, Sanmamed, Miguel F, Mallardo, Domenico, Curvietto, Marcello, Melero, Ignacio, Palmieri, Giuseppe, Grimaldi, Antonio M, Giannarelli, Diana, Dummer, Reinhard, Chiarion Sileni, Vanna
• Format: Journal Article
• Language: English
• Published: United States 10.01.2023
• Subjects: Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Humans; Immunotherapy - methods; Ipilimumab; Medicin och hälsovetenskap; Melanoma - genetics; Melanoma - therapy; Nivolumab - therapeutic use; Prospective Studies; Proto-Oncogene Proteins B-raf - genetics; Skin Neoplasms - genetics; Skin Neoplasms - therapy
• ISSN: 0732-183X; 1527-7755; 1527-7755
• DOI: 10.1200/JCO.21.02961

Limited prospective data are available on sequential immunotherapy and BRAF/MEK inhibition for -mutant metastatic melanoma. SECOMBIT is a randomized, three-arm, noncomparative phase II trial (ClinicalTrials.gov identifier: NCT02631447). Patients with untreated, metastatic -mutant melanoma from 37 sites in nine countries were randomly assigned to arm A (encorafenib [450 mg orally once daily] plus binimetinib [45 mg orally twice daily] until progressive disease [PD] -> ipilimumab plus nivolumab [ipilimumab 3 mg/kg once every 3 weeks and nivolumab 1 mg/kg once every 3 weeks × four cycles -> nivolumab 3 mg/kg every 2 weeks]), arm B [ipilimumab plus nivolumab until PD -> encorafenib plus binimetinib], or arm C (encorafenib plus binimetinib for 8 weeks -> ipilimumab plus nivolumab until PD -> encorafenib plus binimetinib). The primary end point was overall survival (OS) at 2 years. Secondary end points included total progression-free survival, 3-year OS, best overall response rate, duration of response, and biomarkers in the intent-to-treat population. Safety was analyzed throughout sequential treatment in all participants who received at least one dose of study medication. A total of 209 patients were randomly assigned (69 in arm A, 71 in arm B, and 69 in arm C). At a median follow-up of 32.2 (interquartile range, 27.9-41.6) months, median OS was not reached in any arm and more than 30 patients were alive in all arms. Assuming a null hypothesis of median OS of ≤ 15 months, the OS end point was met for all arms. The 2-year and 3-year OS rates were 65% (95% CI, 54 to 76) and 54% (95% CI, 41 to 67) in arm A, 73% (95% CI, 62 to 84) and 62% (95% CI, 48 to 76) in arm B, and 69% (95% CI, 59 to 80) and 60% (95% CI, 58 to 72) in arm C. No new safety signals emerged. Sequential immunotherapy and targeted therapy provide clinically meaningful survival benefits for patients with -mutant melanoma.