The Role of Immunotherapy in Advanced and Recurrent MMR Deficient and Proficient Endometrial Carcinoma

Abstract

ABSTRACT The incidence of endometrial cancer has increased approximately 40% in the last decade along with a 60% increase in the number of associated deaths. Although surgery along with possible adjuvant therapy provides good results in patients with early-stage disease, patients with advanced or recurrent disease have limited options and typically undergo chemotherapy with no standard second-line therapy. Immunotherapy with checkpoint inhibitors (ICIs) is a promising option in this setting. This review aims to improve knowledge on the role of ICIs in advanced/recurrent endometrial cancer in different contexts based on molecular and genomic profiling. The DNA mismatch repair (MMR) system is a highly conserved mechanism that acts to restore DNA integrity after mismatching mistakes during replication, recombination, or iatrogenic damage. Somatic or germline mutations or epigenetic silencing can all result in possible inactivation of MMR genes, resulting in an MMR-deficient (dMMR) genotype. Short tandem repeats, called microsatellites, are repetitive DNA sequences that facilitate slippage or replication errors that are generally repaired by MMR; however, in a dMMR context, these can result in repeat mutations called microsatellite instability (MSI). The presence of MSI characterizes a hypermutable state of cell, and MSI tumors have elevated expression of the checkpoint programmed death 1 ligand (PD-L1). Microsatellite instability/dMMR testing may have potential prognostic value as a predictor of response to immunotherapy. Endometrial cancer is the solid tumor characterized by the highest prevalence of MSI−/dMMR, which is present in 30% and 13% to 30% of primary and recurrent endometrial cancer, respectively. Recently, results from the KEYNOTE-158 trial reporting on the efficacy and safety of pembrolizumab (programmed death 1 [PD-1] ICI) in patients with MSI-H/dMMR endometrial cancer who progressed after a prior line of chemotherapy showed an objective response rate of 48%, median progression-free survival of 13.1 months, and a low rate of high-grade toxicity. Results from the GARNET study reporting on the use of dostarlimab (PD-1 ICI) in dMMR advanced endometrial tumors showed that 80% of patients experienced progression-free survival of 18 months and an objective response rate of 44.7%. Several trials have examined the use of ICIs for patients with advanced endometrial carcinoma in MMR-proficient tumors; however, they seem to show a lesser effect in this setting. Results are more promising in MMR-proficient patients when ICIs are combined with other agents such as tyrosine kinase inhibitors; however, the toxicity profile is significantly worse, and efficacy remains significantly higher in the dMMR group. The KEYNOTE-775 study, a phase III randomized controlled trial, found that in patients with advanced or recurrent endometrial cancer pembrolizumab plus lenvatinib (tyrosine kinase inhibitor) increased progression-free survival (6.6 vs 3.8 months) and overall survival (17.4 vs 12 months) compared with conventional chemotherapy; however, treatment discontinuation and dose reduction occurred in 33% and 70% of patients, respectively. This review describes and evaluates the use of new lines of treatment including immunotherapy agents for advanced and recurrent endometrial cancer. Many trials are still ongoing, with several testing ICIs alone or in combination with other agents to improve safety profiles and efficacy.