A Review of Immune Checkpoint Blockade Therapy in Endometrial Cancer

Abstract

Approximately 30% of primary endometrial cancers are microsatellite instability high/hypermutated (MSI-H), and 13% to 30% of recurrent endometrial cancers are MSI-H or mismatch repair deficient (dMMR). Given the presence of immune dysregulation in endometrial cancer as described, immune checkpoint blockade (ICB) has been explored as a therapeutic mechanism, both as monotherapy and in combination with cytotoxic chemotherapy, other immunotherapy, or targeted agents. In MSI-H or dMMR advanced endometrial cancers, PD-1 inhibitors dostarlimab and pembrolizumab have shown response rates of 49% and 57%, respectively, whereas PD-L1 inhibitors avelumab and durvalumab have shown response rates of 27% and 43%, respectively. In microsatellite stable (MSS) or PD-L1-positive advanced endometrial cancers, modest activity of PD-1 inhibitors nivolumab and dostarlimab and PD-L1 inhibitors atezolizumab, avelumab, and durvalumab has been seen, with response rates ranging from 3% to 23%. Based on substantial activity in a phase Ib/II study, the U.S. Food and Drug Administration (FDA) granted lenvatinib and pembrolizumab combination therapy accelerated approval in 2019 for the treatment of advanced endometrial cancer that is not MSI-H or dMMR and has progressed following prior therapy. Although these developments have been highly impactful, a more robust understanding of the molecular and immunologic drivers of response and resistance will be critical to optimally design next-generation studies in endometrial cancer.