Systematic review on inmunotherapy for POLE ultramutated and MSI-H advanced endometrial carcinoma

Abstract

BACKGROUND: Recent advances in molecular biology have enabled identification of microsatellite instability high (MSI-H), DNA polymerase epsilon mutation (POLE) as two of four endometrial carcinoma (EC) subtypes, plausibly amenable to treatment with immune checkpoint inhibitors (ICI). OBJECTIVE: To perform a systematic review of all available evidence with ICI in MSI-H and POLE advanced EC subtypes to assess efficacy and tolerability. MATERIAL AND METHODS: An electronic search of clinical trials with MSI-H and POLE advanced EC, published as a research article or in abstract form between 2010-2020, was performed. No language restrictions were applied. A predefined PROPERO-LIKE was designed in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Population was defined as POLE, mismatch repair deficiency (MMRd), MSI-H advanced EC; intervention as ICI, anti-PD1, Anti PDL1, PD1/PDL1 axis, immunotherapy, clinical trial. Response rate (RR), clinical benefit rate (CBR) progression free survival (PFS) and overall survival (OS), where available, as well as adverse events were assessed. RESULTS: The search identified 573 records. After screening phase and eligibility process, eleven phase I or II trials were included for final analysis, with 9 monotherapy trials (140 MSI-H patients in total, 1 POLE, 113 MSI-H/MMRd evaluable) and 2 in combination therapy trials (9 MSI-H/MMRd patients, 0 POLE). A pooled analysis in monotherapy MMRd/MSI-H patients yielded 48% RR (10% complete response; 38% partial response, some long lasting), with 57% CBR. Lack of results on PFS or OS in most trials preclude a pooled analysis on survival. Adverse events were as expected. CONCLUSION: ICI showed promising activity in MSI-H advanced EC, some of them long lasting. PFS and OS results are pending. Future investigation is needed to establish the role of these agents in monotherapy and/or in combination.