Konstantinopoulos PA, Luo W, Liu JF, et al. - Given the tissue-agnostic approval of pembrolizumab in mismatch repair deficient (MMRD) solid tumors, researchers sought to address the important unanswered questions regarding the role of immune checkpoint blockade in mismatch repair–proficient (MMRP) and –deficient endometrial cancer (EC). In this phase 2 study, in two cohorts of patients with EC—(1) MMRD/POLE (polymerase ε) cohort, as defined by immunohistochemical (IHC) loss of expression of one or more mismatch repair (MMR) proteins and/or documented mutation in the exonuclease domain of POLE; and (2) MMRP cohort with normal IHC expression of all MMR proteins—the PD-L1 inhibitor avelumab was evaluated. The enrollment of 33 patients was done. In the MMRD cohort, no patient with POLE-mutated tumor was enrolled, and POLE-mutation was not evident in all MMRP tumors. Because of futility, closure of the MMRP cohort was done at the first stage: Only one of 16 patients exhibited both OR and PFS6 responses. Outcomes revealed the promising activity of avelumab in MMRD EC. This was observed regardless of PD-L1 status. They identified IHC for MMR assessment as a valuable tool for patient selection. They observed low activity of avelumab in MMRP/non-POLE–mutated ECs.