Background: Lenvatinib (LEN) is a multikinase inhibitor of VEGFR 1−3, FGFR 1−4, PDGFRα, RET, and KIT. Pembrolizumab (PEM), an anti-PD-1 antibody, is approved for first-line treatment of advanced melanoma (objective response rates [ORR], 21–34%). In preclinical studies, LEN decreased tumor-associated macrophage populations, increased CD8⁺ T cell infiltration, and augmented PD-1 inhibitor activity; thus, LEN is a rational combination partner for PEM. We report interim results of an ongoing phase 1b/2 trial of LEN + PEM in solid tumors, focusing on advanced melanoma. Methods: In this multicenter, open-label study, patients (pts) with measurable, confirmed, metastatic melanoma and ECOG PS ≤1 received oral LEN (20 mg/day) + PEM (200 mg Q3W, IV). Pts were not preselected for PD-L1 status. Tumor assessments were by investigator per immune-related RECIST (irRECIST). Phase 2 primary end point was ORR at 24 weeks (ORR_WK24). Secondary end points included ORR, progression-free survival (PFS) and duration of response (DOR). Results: At data cutoff (March 1, 2018), 21 pts were enrolled: 14 (67%) were PD-L1+, 4 (19%) were PD-L1-; 3 (14%) not tested. 38% had ≥1 prior anticancer therapy. ORR_WK24 was 47.6% (95% CI, 25.7–70.2). All pts had ≥1 treatment-related adverse event (TRAE). Grade 3 and 4 TRAEs occurred in 13 (62%) and 1 (5%; adrenal insufficiency) pts respectively. There were no fatal TRAEs. Most common any-grade TRAEs were fatigue (52%), decreased appetite (48%), diarrhea (48%), hypertension (48%), dysphonia (43%), and nausea (43%). Dose reduction and interruption due to TRAEs occurred in 13 (62%) and 10 (48%) pts, respectively. Conclusions: LEN + PEM was well-tolerated and had encouraging clinical activity. The combination may potentially improve on the antitumor activity of anti-PD-1 monotherapies, supporting further evaluation in advanced melanoma. Clinical trial information: NCT02501096