COUSIN, Sophie; GUEGAN, Jean-Philippe; PALMIERI, Lola Jade; METGES, Jean Philippe; PERNOT, Simon; BELLERA, Carine A; ASSENAT, Eric; KORAKIS, Iphigenie; CASSIER, Philippe Alexandre; HOLLEBECQUE, Antoine; CANTAREL, Coralie; KIND, Michele; SOUBEYRAN, Isabelle; SOKOL, Harry; VANHERSECKE, Lucile; BESSEDE, Alban; ITALIANO, Antoine

doi:10.1038/s43018-025-00916-3

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Nature Cancer. 2025-04-01, vol. 6, n° 4, p. 584-594

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Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are heterogeneous tumors with limited treatment options. This phase 2 Bayesian study evaluated the combination of regorafenib, a multikinase inhibitor, and avelumab, a programmed death 1 (PD1) ligand 1 inhibitor, in advanced grade 2-grade 3 well-differentiated GEP neuroendocrine tumors or grade 3 GEP neuroendocrine carcinomas after progression on prior therapies. A total of 47 participants were enrolled and 42 were evaluable for efficacy. Participants received regorafenib (160 mg per day) and avelumab (10 mg kg-1 biweekly) in 28-day cycles. The primary endpoint, 6-month objective response rate per the response evaluation criteria in solid tumors version 1.1, was 18% (95% confidence interval (CI): 8-31%), with a median progression-free survival of 5.5 months (95% CI: 3.6-8). Durable responses were noted (16.6 months; 95% CI: 3.7-no response). Treatment-related adverse events were manageable, with fatigue, diarrhea and palmar-plantar erythrodysesthesia being most common. Exploratory biomarker analysis identified PD1 and indoleamine 2,3-dioxygenase 1 expression and activity as potential resistance markers. These findings highlight the clinical potential of regorafenib and avelumab in GEP-NENs, emphasizing the need for predictive biomarkers and validation in future randomized trials. Clinical Trial registration:NCT03475953.< Réduire

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Regorafenib plus avelumab in advanced gastroenteropancreatic neuroendocrine neoplasms: a phase 2 trial and correlative analysis

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