Mismatch repair deficiency, next-generation sequencing-based microsatellite instability, and tumor mutational burden as predictive biomarkers for immune checkpoint inhibitor effectiveness in frontline treatment of advanced stage endometrial cancer.

Molecular profiling is developing to inform treatment in endometrial cancer. Using real world evidence, we sought to evaluate frontline immune checkpoint inhibitor vs chemotherapy effectiveness in advanced endometrial cancer, stratified by Tumor Mutational Burden (TMB) ≥10 mut/MB and microsatellite instability (MSI). Patients with advanced endometrial cancer in the US-based de-identified Flatiron Health-Foundation Medicine Clinico-Genomic Database were included. Data originated from patients treated between January 2011- March 2022 at 280 US clinics. Next-generation sequencing assays were performed via FoundationOne or FoundationOneCDx. Longitudinal clinical data were derived from electronic health records. Immune checkpoint inhibitor treatment included pembrolizumab, dostarlimab, and nivolumab monotherapies. Time to next treatment, time to treatment discontinuation, and overall survival were assessed with the log-rank test and Cox proportional hazard models with adjusted hazard ratios (aHR) for known prognostic factors. We used the Likelihood ratio test to compare biomarker performance. A total of 343 patients received chemotherapy and 28 received immune checkpoint inhibitor monotherapy as frontline treatment. Patients who received monotherapy were more likely to be stage III at diagnosis (immune checkpoint inhibitor: 54.6% vs chemotherapy: 15.0%; p<0.001) and more likely to test MSI-high via next-generation sequencing (immune checkpoint inhibitor: 53.6% vs chemotherapy: 19.2%; p<0.001). In MSI-high cancers, single-agent immune checkpoint inhibitor had a more favorable time to next treatment (aHR: 0.18, p=0.001) and overall survival (aHR 0.29, p=0.045). Additional analyses on 70 unique tumor specimens revealed mismatch repair deficiency (dMMR) via immunohistochemistry and MSI-high via next-generation sequencing concordance (91%), with nominal improvement of MSI over dMMR to predict time to treatment discontinuation (p=0.030), time to next treatment (p=0.032), and overall survival (p=0.22). MSI status was concordant with tumor mutational burden ≥10 in 94.3% of cases. Immune checkpoint inhibitors may have improved efficacy over chemotherapy in frontline treatment for advanced endometrial cancer defined by MSI-high using next-generation sequencing as a nominally better predictor of outcomes than dMMR with immunohistochemistry. This provides the biologic rationale of active phase III trials.

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© IGCS and ESGO 2023. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.

Déclaration de conflit d'intérêts

Competing interests: Ryon P. Graf, PhD; Kunal Shah, BS; Natalie Danziger, BS; Douglas I. Lin, MD, PhD, Julia Quintanilha, PhD; Gerald Li, PhD; Julia Elvin, MD, PhD are employees of Foundation Medicine, a wholly owned subsidiary of Roche, and have equity interest in Roche. Roche produces atezolizumab, an ICI. Alessandro D. Santin receives grants from Puma, Immunomedics, Gilead, Synthon, Merck, Boehinger-Ingelheim, Genentech, Eisai, and Tesaro; and also personal fees from Merck, Tesaro, and Eisai. Brian Slomovitz has consultant roles with AstraZeneca, Clovis, GSK, Genentech, Lilly, Merck, Eisai, Genmab, Novartis, Addy, Immunogen. Ramez Eskander reports the following: consulting, advisory, and grant funding from AstraZeneca, Clovis Oncology, Genentech, Merck, Eisai, Genmab, Seagen, Immunogen, Mersana, Myriad. No other authors have conflicts of interest to report.