Background: Folate receptor-alpha (FRα) is expressed on endometrial cancer (EC) cells and is associated with poor prognosis. Mirvetuximab soravtansine (ImmunoGen), an antibody drug conjugate (ADC) comprising a FRα-binding antibody, cleavable linker, and the tubulin-disrupting maytansinoid DM4, showed tolerability and single agent activity in a Phase 1 study with dose expansion in FRα+ advanced/recurrent EC (NCT01609556) and also when combined with chemotherapy, bevacizumab as well as pembrolizumab (NCT02606305). In addition to having direct target-mediated cytotoxicity, ADCs also stimulate the local tumor immune microenvironment. Mirvetuximab soravtansine has been shown to activate monocytes and promote phagocytosis of mirvetuximab-treated FRα-positive tumor cells through a mechanism of Fc-FcγR interaction. Further, the combination of ADCs with immune checkpoint inhibitors (ICI) can overcome primary resistance to immunotherapy in murine models. Given the low response of MSS endometrial cancers to PD-1 blockade, we hypothesized that addition of mirvetuximab may enhance response of these tumors to immunotherapy. Methods: This is a Phase 2, single cohort study of mirvetuximab soravtansine with pembrolizumab in recurrent or persistent EC. Patients must have advanced or recurrent MSS serous endometrial cancer with at least 1 and up to 3 prior lines of therapy. Confirmation of FRα expression (with PS2+ staining intensity in ≥ 50% of cells, performed centrally at Ventana Medical Systems, Inc) is required. Prior receipt of ICI is excluded. Patients will receive the combination of mirvetuximab soravtansine 6 mg/kg AIBW IV and pembrolizumab 200 mg IV administered every 21 days. The co-primary endpoint is progression-free survival at 6 months (PFS6) and objective response rate (ORR) by RECIST 1.1. Translational objectives include assessment of tumor infiltrating lymphocytes (TILs), expression of immune checkpoint markers, and whole exome sequencing (WES) for DNA repair pathway mutations, neoantigens, and polymorphisms in immunologically relevant genes. Statistical considerations are for a Simon two-stage optimal design with 16 patients in Stage 1 and 19 patients in Stage 2, to a total of 35. Prespecified activity for the first stage of accrual was met, and second stage accrual began November 2020. Clinical trial information: NCT03835819