First-line durvalumab and tremelimumab with chemotherapy in RAS-mutated metastatic colorectal cancer: a phase 1b/2 trial
Marion Thibaudin, Jean-David Fumet, Benoist Chibaudel, Jaafar Bennouna, Christophe Borg, J. Martin-Babau, Romain Cohen, Marianne Fonck, Julien Taı̈eb, Emeric Limagne, Julie Blanc, Elise Ballot, Léa Hampe, Marjorie Bon, Susy Daumoine, Morgane Peroz, Hugo Mananet, Valentin Dérangère, Romain Boidot, Henri-Alexandre Michaud, Caroline Laheurte, Olivier Adotévi, Aurélie Bertaut, Caroline Truntzer, François Ghiringhelli
Abstract
Although patients with microsatellite instable metastatic colorectal cancer (CRC) benefit from immune checkpoint blockade, chemotherapy with targeted therapies remains the only therapeutic option for microsatellite stable (MSS) tumors. The single-arm, phase 1b/2 MEDITREME trial evaluated the safety and efficacy of durvalumab plus tremelimumab combined with mFOLFOX6 chemotherapy in first line, in 57 patients with RAS-mutant unresectable metastatic CRC. Safety was the primary objective of phase Ib; no safety issue was observed. The phase 2 primary objective of efficacy in terms of 3-month progression-free survival (PFS) in patients with MSS tumors was met, with 3-month PFS of 90.7% (95% confidence interval (CI): 79.2-96%). For secondary objectives, response rate was 64.5%; median PFS was 8.2 months (95% CI: 5.9-8.6); and overall survival was not reached in patients with MSS tumors. We observed higher tumor mutational burden and lower genomic instability in responders. Integrated transcriptomic analysis underlined that high immune signature and low epithelial-mesenchymal transition were associated with better outcome. Immunomonitoring showed induction of neoantigen and NY-ESO1 and TERT blood tumor-specific T cell response associated with better PFS. The combination of durvalumab-tremelimumab with mFOLFOX6 was tolerable with promising clinical activity in MSS mCRC. Clinicaltrials.gov identifier: NCT03202758 .