1154P - Prospective multinational evaluation of alkylating-induced hypermutation in neuroendocrine neoplasms (NEN): Clinical and molecular profiles associated with response to immune checkpoint inhibitors (CPI)

Background

High tumor mutational burden (TMBh), a biomarker of benefit from CPI, may be induced by alkylating agents. The frequency of this phenomenon and the associated outcomes in patients (pts) with NEN are unknown.

Methods

Consecutive pts with metastatic NEN whose tumor progressed (PD) after CAPTEM (temozolomide-based regimen) had liquid and/or tumor tissue biopsy profiled by NGS. We evaluated the incidence of TMBh (≥ 10/mb), associated clinical and molecular features, and pts outcomes.

Results

From June 2020 to December 2023, 32 pts treated with alkylating agents had PD and had their tumors profiled: 23 (72%) had pancreatic NEN, and 10 (31%) developed TMB-h (median 51.5; 15 to 216), mostly detected by liquid NGS (90%). TMBh pts, compared with TMB low, received more CAPTEM cycles (mean number/pt: 10.6 vs 6) and showed a favorable trend in objective response rates (40% vs 20%; p 0.24), but were often pre-treated with PRRT and CAPTEM prior to NGS (60% vs 22.7%; p 0.03); TMBh tumors were microsatellite stable and presented more defects in DNA damage response and repair (DDR) genes (60% vs 18%; p 0.05) and in MMR genes (60% vs 0%; p 0.0004), although these were mostly subclonal. 8/10 TMBh pts had initial G1/G2 tumors, with 7 having biopsy upon PD: 5 became G3. Five TMBh pts received CPI: 2 had upfront PD (no DDR or MMR genes defects in NGS), one had disease control for 8 months (subclonal MSH6 mutated), 2 had major ongoing response (both MUTYH [VAF 5% and 62%] and MMR genes mutated). One pt experienced stable disease with sunitinib for 11 months and one pt died of PD 3 weeks after TMBh was identified.

Conclusions

TMBh NEN induced by alkylating agents occurs in about one third of cases, is more frequently associated with prior PRRT exposure, often develops from initial G2 that transform into G3 NEN, and most present subclonal defects in MMR and in DDR genes. TMBh alone does not seem to predict response to CPI in this context; yet, pts with somatic MUTYH and MMR genes pathogenic variants may derive benefit from CPI.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.