Background: Lenvatinib (LEN) is an inhibitor of VEGFR 1−3, FGFR 1−4, and other kinases. Pembrolizumab (PEM) is an anti-PD-1 antibody. We report updated interim results from a phase 1b/2 study evaluating LEN + PEM in patients (pts) with advanced endometrial cancer (EC) (NCT02501096). Methods: In this multicenter, open-label study, pts with histologically confirmed EC irrespective of microsatellite instability (MSI) or mismatch repair (MMR) status and measurable disease per immune-related RECIST (irRECIST) received LEN (20 mg PO QD) plus PEM (200 mg IV Q3W). Tumor assessments were performed by investigators using irRECIST. The primary phase 2 endpoint was objective response rate at 24 weeks (ORR_WK24), calculated only for evaluable pts who had 24 weeks of follow up or discontinued treatment or died prior to 24 weeks. Secondary endpoints included ORR (full analysis set), progression-free survival (PFS), and duration of response (DOR). Results: At data cutoff of Aug 1 2017, 54 pts were enrolled [endometrioid: Gr 1 (7), Gr 2 (12), Gr 3 (5); serous (18); others (8); unknown (4)]. Three (6%) pts were MSI-high (MSI-H); 43 (80%) were non-MSI-H/proficient MMR (MMRp); 8 (15%) were not done/unknown. Median follow-up for PFS was 4.0 months (95% confidence interval [CI], 2.7–7.6). ORR_WK24 was 50.0% (95% CI, 32.4–67.6), and all responses were confirmed. ORR was 36.7% (95% CI, 23.4–51.7), which reflects the short follow-up time for pts with later enrollment. Median DOR has not yet been reached (not estimable [NE], 95% CI, 4.1–NE) and median PFS was 10.1 months (95% CI, 5.3–NE). Of the 3 MSI-H pts, 1 achieved partial response, 1 had stable disease, and 1 had progressive disease. For non-MSI-H/MMRp pts, ORR_WK24 was 50.0% (95% CI, 29.9–70.1). Grade 3 treatment-related adverse events (TRAEs) occurred in 32 (59%) pts; there were no Grade 4 TRAEs. 3 (6%) pts discontinued treatment due to a TRAE. The most common TRAEs were hypertension (59%), fatigue (50%), diarrhea (44%), hypothyroidism (35%), and stomatitis (33%). Conclusions: Combination LEN + PEM demonstrated encouraging activity in advanced EC regardless of MSI/MMR status, with no new safety signals identified. A randomized, international, 2-arm, phase 3 study in recurrent EC is planned. Clinical trial information: NCT02501096