FOLFIRI Plus Durvalumab With or Without Tremelimumab in Second-Line Treatment of Advanced Gastric or Gastroesophageal Junction Adenocarcinoma
David Tougeron, Laëtitia Dahan, Ludovic Evesque, Karine Le Malicot, Farid El Hajbi, T. Aparicio, Olivier Bouché, N. Bonichon Lamichhane, Benoist Chibaudel, Antoine Angelergues, Anaïs Bodère, Jean–Marc Phelip, May Mabro, Laure Kaluzinski, Caroline Pétorin, Gilles Breysacher, Yves Rinaldi, Aziz Zaanan, Denis Smith, Marie-Claude Gouttebel, Clément Perret, Nicolas Etchepare, Jean‐François Emile, Ivan Sanfourche, Frédéric Di Fiore, Côme Lepage, Pascal Artru, Christophe Louvet, PRODIGE 59-FFCD 1707-DURIGAST Investigators/Collaborators, Vincent HAUTEFEUILLE, Anne Thirot‐Bidault, Rania Boustany-Grenier, Marjorie Faure, C. Debelleix, David Tavan, Amr El Weshi, You-Heng Lam, Denis Pezet, Marion Bolliet, Ariane Darut‐Jouve, Jean-François Paitel, Aurélien Carnot, Diane Pannier, Valérie Le Brun Ly, Jérôme Desrame, Julie Gigout, Philippe Dominici, Muriel Duluc, Emmanuelle Norguet Monnereau, Christophe Locher, Morgan ANDRE, Éric François, Romain Cohen, Olivier Dubreuil, Mostefa Bennamoun, Christophe Louvet, Émilie Soularue, Éric Terrebonne, Rayan Elfadel, Aurélie Ferru, Damien Botsen, Romain Desgrippes, Thierry MURON, Asmahane BENMAZIANE-TEILLET, Thierry Lecomte
Abstract
Importance: Efficacy of second-line chemotherapy in advanced gastric or gastrooesphageal junction (GEJ) adenocarcinoma remains limited. Ojectives: To determine the efficacy of 1 or 2 immune checkpoint inhibitors combined with FOLFIRI (leucovorin [folinic acid], fluorouracil, and irinotecan) in the treatment of advanced gastric/GEJ adenocarcinoma. Design, Setting, and Participants: The PRODIGE 59-FFCD 1707-DURIGAST trial is a randomized, multicenter, noncomparative, phase 2 trial, conducted from August 27, 2020, and June 4, 2021, at 37 centers in France that included patients with advanced gastric/GEJ adenocarcinoma who had disease progression after platinum-based first-line chemotherapy. Intervention: Patients were randomized to receive FOLFIRI plus durvalumab (anti-programmed cell death 1 [PD-L1]) (FD arm) or FOLFIRI plus durvalumab and tremelimumab (anti-cytotoxic T-lymphocyte associated protein 4 [CTLA-4]) (FDT arm). The efficacy analyses used a clinical cutoff date of January 9, 2023. Main outcome and Measures: The primary end point was progression-free survival (PFS) at 4 months according to RECIST 1.1 criteria evaluated by investigators. Results: Overall, between August 27, 2020, and June 4, 2021, 96 patients were randomized (48 in each arm). The median age was 59.7 years, 28 patients (30.4%) were women and 49 (53.3%) had GEJ tumors. Four month PFS was 44.7% (90% CI, 32.3-57.7) and 55.6% (90% CI, 42.3-68.3) in the FD and FDT arms, respectively. The primary end point was not met. Median PFS was 3.8 and 5.4 months, objective response rates were 34.7% and 37.7%, and median overall survival was 13.2 and 9.5 months in the FD and FDT arms, respectively. Disease control beyond 1 year was 14.9% in the FD arm and 24.4% in the FDT arm. Grade 3 to 4 treatment-related adverse events were observed in 22 (47.8%) patients in each arm. A combined positive score (CPS) PD-L1 of 5 or higher was observed in 18 tumors (34.0%) and a tumor proportion score (TPS) PD-L1 of 1% or higher in 13 tumors (24.5%). Median PFS according to CPS PD-L1 was similar (3.6 months for PD-L1 CPS ≥5 vs 5.4 months for PD-L1 CPS <5) by contrast for TPS PD-L1 (6.0 months for PD-L1 TPS ≥1% vs 3.8 months for PD-L1 TPS <1%). Conclusions and Relevance: Combination of immune checkpoint inhibitors with FOLFIRI in second-line treatment for advanced gastric/GEJ adenocarcinoma showed an acceptable safety profile but antitumor activity only in a subgroup of patients. Trial Registration: ClinicalTrials.gov Identifier: NCT03959293.