Abstract
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.
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Data availability
The datasets that support the findings of this study are not publicly available because of regulations protecting participant privacy and consent under French and European laws. Access to the data requires prior approval from the ethics committee ‘Comité de Protection des Personnes Sud-Est II’. Requests for data can be directed to the corresponding author (A.I.). Proposals will be reviewed by the committee and access may be granted following approval of the proposal. The estimated timeframe for approval is approximately 4–6 weeks. Source data are provided with this paper.
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Acknowledgements
This study was sponsored by Institut Bergonié. Funding was provided by Bayer, the Association pour la Recherche contre le Cancer and the French NCI (INCA). Nonfinancial support was provided by Merck.
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Contributions
A.I., A.B. and C.B. conceptualized and designed the study. I.S. and L.V. performed the histologic analyses. S.C., L.J.P., S.P., J.P.M., E.A., I.K., P.A.C., A.H., M.K., H.S. and A.I. provided study material or treated participants. All authors collected and assembled the data. A.I., A.B., C.C. and J.P.G. developed the tables and figures. A.I., A.B. and J.P.G. conducted the literature search and wrote the manuscript. All authors were involved in critical review of the manuscript and approved the final version.
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A.B. and J.P.G. are employees of Explicyte. A.I. received research grants from Astra Zeneca, Bayer, BMS, Chugai, Merck, MSD, Pharmamar, Novartis and Roche and personal fees from Epizyme, Bayer, Lilly, Roche and Springworks. W.H.F. received a research grant from AstraZeneca and personal fees from Anaveon, AstraZeneca, Catalym, Elsalys, Novartis, OSE Immunotherapeutics and Parthenon. J.Y.B. received research grants from Bayer, GSK, Merck, Novartis, Pharmamar and Roche and personal fees from Bayer, GSK, Lilly, Novartis, Pharmamar and Roche. The other authors declare no competing interests.
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Extended data
Extended Data Fig. 1 Flow chart of the REGOMUNE study.
Forty-seven patients were enrolled in the study, of whom 46 were evaluated for safety and 42 for efficacy.
Extended Data Fig. 2 Growth modulation index.
Waterfall plot depicting the growth modulation index (GMI) in patients (n = 42) with advanced gastro-enteropancreatic neuroendocrine neoplasms receiving regorafenib and avelumab.
Extended Data Fig. 3 CD8+ and CD163+ cell infiltration are not associated with response to regorafenib and avelumab in GEP-NEN patients.
(A) Illustration of 7-plex immunohistofluorescence panel. (B-C) Boxplot representation (median ± interquartile range) of CD8+ (B) and CD163+ (C) cell density in patients with progressive disease (PD – n = 9 patients), stable disease (SD – n = 15 patients) and partial response (PR – n = 6 patients). P values were calculated using two-sided Wilcoxon tests.
Extended Data Fig. 4 IDO1 activity according to GEP-NEN histotypes.
Boxplot representations (median ± interquartile range) of the density of PanCK + /IDO+ (A) and the ratio of plasma Kyn/Trp levels (peripheral IDO1 activity) (B) in GEP-NEN patients according to histotypes (n = 30 patients for A and n = 37 for B). P values were calculated using two-sided Wilcoxon tests. (C) Heatmap representation of plasma levels of immune-related proteins dosed using Olink Target96 panels according to histotypes (n = 35 patients).
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Cousin, S., Guégan, JP., Palmieri, L.J. et al. Regorafenib plus avelumab in advanced gastroenteropancreatic neuroendocrine neoplasms: a phase 2 trial and correlative analysis. Nat Cancer 6, 584–594 (2025). https://doi.org/10.1038/s43018-025-00916-3
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DOI: https://doi.org/10.1038/s43018-025-00916-3
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