Journal Article Epublish
PubMed: 41182464 DOI: 10.1007/s12022-025-09887-8
Immunotherapy for Metastatic Pancreatic Neuroendocrine Tumors with High Mutational Burden and Mismatch Repair Alterations Following Treatment with Alkylating Chemotherapy.
Endocr Pathol 36(1):42
Authors: Louis de Mestier, Thorvardur R Halfdanarson, Leonidas Apostolidis, Anna Koumarianou, Jorge Hernando, Rachel Riechelmann, Emily K Bergsland, Sara Cingarlini, Shagufta Shaheen, Joakim Crona, Simon Kreutzfeldt, Osama Mosalem, Taymeyah Al-Toubah, Jérôme Cros, Jonathan R Strosberg
Affiliations
- Department of Pancreatology and Digestive Oncology, Université Paris-Cité, Beaujon Hospital (APHP), Clichy, France.
- Mayo Clinic Comprehensive Cancer Center, Rochester, MN, USA.
- Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany.
- Hematology Oncology Unit, Fourth Department of Internal Medicine, "Attikon" University Hospital, National and Kapodistrian University of Athens, Athens, Greece.
- Medical Oncology Department, NET- VHIO Research Unit, Vall Hebron University Hospital, Vall Hebron Institute of Oncology (VHIO), Barcelona, Spain.
- AC Camargo Cancer Center, São Paulo, Brazil.
- University of California, San Francisco, San Francisco, CA, USA.
- University Trust of Verona, Verona, Italy.
- Division of Oncology, Stanford University, Stanford, CA, USA.
- Uppsala Universitet, Uppsala, Sweden.
- Division of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg, German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Mayo Clinic Florida, Jacksonville, FL, USA.
- H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
- Department of Pathology, Université Paris-Cité, Beaujon Hospital (APHP), Clichy, France.
Abstract
Alkylating agent-based chemotherapy is one of the main treatment options for patients with metastatic pancreatic neuroendocrine tumors (PanNETs).However, it favors the acquisition of a hypermutator phenotype, suggesting a potential benefit of immunotherapy.We aimed to describe the efficacy of immunotherapy in an international retrospective cohort of patients with metastatic well-differentiated PanNETs pretreated with alkylating therapy. The primary endpoint was progression-free survival (PFS) and the main secondary endpoint was the radiological objective response rate (ORR). We explored the impact of tumor mutation burden (TMB) and mismatch repair deficiency (MMRd), and evaluated variables associated with PFS.We included 64 patients with heavily pretreated PanNETs (median Ki-67 28%). Among 51 PanNETs with mutational profiling, 37 (73%) were TMB high (median 35 mut/Mb). Among 46 PanNETs with available MMR status, 18 (39%) were MMRd, representing 49% of all TMB high PanNETs. Immunotherapy consisted of a single (31%) or a dual (69%) immune checkpoint inhibitor. Median PFS was 3.2 months (95% CI, 1.3-5.0.3.0) and the ORR was 17%. Patients with TMB high PanNETs had longer PFS (median 3.8 vs. 2.3 months, p = 0.015) and higher ORR (30% vs. 0%, p = 0.002) compared with TMB low/unk cases. Patients with MMRd PanNETs had longer PFS (median 8.9 vs. 2.7 months, p = 0.003) and higher ORR (44% vs. 7%, p < 0.001) compared with MMRp/unk. On multivariable analyses, MMRd predicted longer PFS (HR 0.42, 95% CI [0.20-0.82], p = 0.015).Overall, immunotherapy may be effective against alkylating-pretreated metastatic PanNETs exhibiting TMB high and MMRd. MMR immunohistochemistry and TMB assessment could be implemented in the routine assessment of alkylating-pretreated metastatic PanNETs.
MeSH
Dna Mismatch Repair, Neoplasms, Drug Therapy, Immunotherapy, Neuroendocrine Tumors, Therapeutics, Mutation, Chemotherapy