Sequential immunotherapy and targeted therapy for metastatic BRAF V600 mutated melanoma: 4-year survival and biomarkers evaluation from the phase II SECOMBIT trial

Paolo A. Ascierto (), Milena Casula, Jenny Bulgarelli, Marina Pisano, Claudia Piccinini, Luisa Piccin, Antonio Cossu, Mario Mandalà, Pier Francesco Ferrucci, Massimo Guidoboni, Piotr Rutkowski, Virginia Ferraresi, Ana Arance, Michele Guida, Evaristo Maiello, Helen Gogas, Erika Richtig, Maria Teresa Fierro, Celeste Lebbe, Hildur Helgadottir, Paola Queirolo, Francesco Spagnolo, Marco Tucci, Michele Vecchio, Maria Gonzales Cao, Alessandro Marco Minisini, Sabino Placido, Miguel F. Sanmamed, Domenico Mallardo, Miriam Paone, Maria Grazia Vitale, Ignacio Melero, Antonio M. Grimaldi, Diana Giannarelli, Reinhard Dummer, Vanna Chiarion Sileni and Giuseppe Palmieri
Additional contact information
Paolo A. Ascierto: Cancer Immunotherapy and Development Therapeutics. I.N.T. IRCCS Fondazione “G. Pascale”
Milena Casula: University of Sassari - Unit of Cancer Genetics, IRGB-CNR
Jenny Bulgarelli: IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”
Marina Pisano: University of Sassari - Unit of Cancer Genetics, IRGB-CNR
Claudia Piccinini: IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”
Luisa Piccin: Veneto Institute of Oncology IOV-IRCCS
Antonio Cossu: Surgery and Pharmacy, University of Sassari
Mario Mandalà: University of Perugia
Pier Francesco Ferrucci: European Institute of Oncology, IRCCS
Massimo Guidoboni: IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”
Piotr Rutkowski: Maria Sklodowska Curie National Research Institute of Oncology, 02-781 –
Virginia Ferraresi: IRCCS Regina Elena National Cancer Institute
Ana Arance: Hospital Clínic Barcelona
Michele Guida: IRCCS Istituto dei Tumori “Giovanni Paolo II”
Evaristo Maiello: Foundation IRCCS Casa Sollievo della Sofferenza
Helen Gogas: National and Kapodistrian University of Athens
Erika Richtig: Medical University of Graz
Maria Teresa Fierro: Dermatologic Clinic, University of Turin
Celeste Lebbe: Dermato-Oncology and CIC AP-HP Hôpital Saint Louis,Cancer Institute APHP. Nord-Université Paris Cite F-75010
Hildur Helgadottir: Karolinska Institutet and Karolinska University Hospital Solna
Paola Queirolo: IRCCS Ospedale Policlinico San Martino
Francesco Spagnolo: IRCCS Ospedale Policlinico San Martino
Marco Tucci: Oncology Unit, University of Bari “Aldo Moro”
Michele Vecchio: Fondazione IRCCS Istituto Nazionale dei Tumori
Maria Gonzales Cao: University Hospital Dexeus
Alessandro Marco Minisini: Academic Hospital “Santa Maria della Misericordia”
Sabino Placido: University of Naples “Federico II”
Miguel F. Sanmamed: Oncology Unit, University of Bari “Aldo Moro”
Domenico Mallardo: Cancer Immunotherapy and Development Therapeutics. I.N.T. IRCCS Fondazione “G. Pascale”
Miriam Paone: Cancer Immunotherapy and Development Therapeutics. I.N.T. IRCCS Fondazione “G. Pascale”
Maria Grazia Vitale: Cancer Immunotherapy and Development Therapeutics. I.N.T. IRCCS Fondazione “G. Pascale”
Ignacio Melero: Clínica Universidad de Navarra
Antonio M. Grimaldi: Cancer Immunotherapy and Development Therapeutics. I.N.T. IRCCS Fondazione “G. Pascale”
Diana Giannarelli: Fondazione Policlinico Universitario A. Gemelli, IRCCS – Facility of Epidemiology and Biostatistics
Reinhard Dummer: University and University Hospital Zurich
Vanna Chiarion Sileni: Veneto Institute of Oncology IOV-IRCCS
Giuseppe Palmieri: University of Sassari - Unit of Cancer Genetics, IRGB-CNR

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: Abstract No prospective data were available prior to 2021 to inform selection between combination BRAF and MEK inhibition versus dual blockade of programmed cell death protein-1 (PD-1) and cytotoxic T lymphocyte antigen-4 (CTLA-4) as first-line treatment options for BRAFV600-mutant melanoma. SECOMBIT (NCT02631447) was a randomized, three-arm, noncomparative phase II trial in which patients were randomized to one of two sequences with immunotherapy or targeted therapy first, with a third arm in which an 8-week induction course of targeted therapy followed by a planned switch to immunotherapy was the first treatment. BRAF/MEK inhibitors were encorafenib plus binimetinib and checkpoint inhibitors ipilimumab plus nivolumab. Primary outcome of overall survival was previously reported, demonstrating improved survival with immunotherapy administered until progression and followed by BRAF/MEK inhibition. Here we report 4-year survival outcomes, confirming long-term benefit with first-line immunotherapy. We also describe preliminary results of predefined biomarkers analyses that identify a trend toward improved 4-year overall survival and total progression-free survival in patients with loss-of-function mutations affecting JAK or low baseline levels of serum interferon gamma (IFNy). These long-term survival outcomes confirm immunotherapy as the preferred first-line treatment approach for most patients with BRAFV600-mutant metastatic melanoma, and the biomarker analyses are hypothesis-generating for future investigations of predictors of durable benefit with dual checkpoint blockade and targeted therapy.

Date: 2024
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DOI: 10.1038/s41467-023-44475-6

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