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.

Immune Checkpoint Blockade in Gynecologic Cancers: State of Affairs

“…These tumors lack estrogen sensitivity, are not associated with obesity, tend to be high grade tumors, and are associated with diagnosis at a later stage and poorer prognosis. Tumors in the type 2 subgroup are associated with a higher rate of p53 mutations and overexpression of HER2/neu [28,29]. Recently, the Cancer Genome Atlas analysis stratified endometrial cancer (EC) into four distinct molecular subtypes as follows: polymerase ε (POLE)-mutant ultramutated, microsatellite instability high (MSI-H, hypermutated), copy number low, and copy number high [30].…”

“…Combination therapy has the potential to afford additive or synergistic benefits, as compared to single agent treatment, as well as to overcome resistance mechanisms that are observed with ICI monotherapy administration, due to the upregulation of alternative immune checkpoint molecules or to emerging resistance caused by the presence of cells such as myeloid-derived suppressor cells (MDSCs) [61][62][63][64][65]. Currently, several clinical trials are ongoing with ICI treatment in EC patients, which are used in combination with cytotoxic chemotherapy, other ICI, vaccines and other immunotherapies, or targeted therapies [25,26,29,32,66].…”

“…Based on these and other studies, ICI treatment is generally regarded as very promising as an alternative therapy option for advanced/recurrent EC. A more detailed list of ongoing EC clinical trials using monotherapy and combination therapy regimens are summarized elsewhere [25,26,29,32].…”

Biological Omics Analysis of Tumor Mutation Burden Combined with Immune Infiltrates in Uterine Corpus Endometrial Carcinoma

“…In the past few decades, the incidence and mortality of endometrial cancer have been on the rise. This makes it the third most common cause of death in cancers which only affect women, behind ovarian and cervical cancer (2,3). According to the pathogenesis and biological behavioral characteristics, UCEC can be divided into estrogen-dependent type (type I) and non-estrogen-dependent type (type II) (4).…”

“…The prognosis of UCEC is based largely on histologic grade and clinical stage (7,8). Although patients with early-stage disease have a 5-year overall survival rate of about 80%, those with advanced-stage have a 5-year overall survival rate of less than 20% (3). As overall survival remains poor in advanced and recurrent cases, the emergence of new targeted therapeutics and immunotherapies for these sub-patients offers hope for improved outcomes (9).…”