Immunotherapy for Metastatic Pancreatic Neuroendocrine Tumors with High Mutational Burden and Mismatch Repair Alterations Following Treatment with Alkylating Chemotherapy

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 TMBhigh (median 35 mut/Mb). Among 46 PanNETs with available MMR status, 18 (39%) were MMRd, representing 49% of all TMBhigh 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 TMBhigh 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 TMBlow/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 TMBhigh and MMRd. MMR immunohistochemistry and TMB assessment could be implemented in the routine assessment of alkylating-pretreated metastatic PanNETs.