Purpose:Immune checkpoint inhibitor and VEGFR inhibitor combinations are effective treatments for patients with metastatic renal cell carcinoma (mRCC). This phase I/II clinical trial evaluated the safety and efficacy of pembrolizumab and cabozantinib in patients with mRCC.Experimental Design:Eligible patients had mRCC with clear-cell or non-clear cell histology, adequate organ function, Eastern Cooperative Oncology Group 0–1 performance status, and no prior exposure to pembrolizumab or cabozantinib. The primary endpoint was objective response rate (ORR) at the recommended phase II dose (RP2D). Secondary endpoints included safety, disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), and overall survival (OS).Results:Forty-five patients were enrolled. A total of 40 patients were treated at the RP2D of pembrolizumab 200 mg i.v. every 3 weeks and cabozantinib 60 mg orally once daily, 38 of which were evaluable for response. The ORR was 65.8% [95% confidence interval (CI), 49.9–78.8] for all evaluable patients [78.6% as first-line therapy, 58.3% as second-line therapy]. The DCR was 97.4% (95% CI, 86.5–99.9). Median DoR was 8.3 months (interquartile range, 4.6–15.1). At a median follow-up of 23.54 months, the median PFS was 10.45 months (95% CI, 6.25–14.63) and median OS was 30.81 months (95% CI, 24.2–not reached). The most common grade 1 and/or 2 treatment-related adverse events (TRAE) were diarrhea, anorexia, dysgeusia, weight loss, and nausea. The most common grade 3 and/or 4 TRAEs were hypertension, hypophosphatemia, alanine transaminase elevation, diarrhea, and fatigue. There was one grade 5 TRAE of reversible posterior encephalopathy syndrome related to cabozantinib.Conclusions:Pembrolizumab and cabozantinib treatment in patients with mRCC demonstrated encouraging preliminary efficacy and a manageable toxicity profile comparable with other available checkpoint inhibitor-tyrosine kinase inhibitor combinations.Trial Registration:ClinicalTrials.gov Identifier: NCT03149822https://clinicaltrials.gov/ct2/show/NCT03149822Significance:This study evaluated the safety and effectiveness of the combination of pembrolizumab and cabozantinib in patients with mRCC. The safety profile was manageable. The combination showed promising activity with an objective response rate of 65.8%, median PFS of 10.45 months, and median OS of 30.81 months.