Abstract Background Concurrent blockade of lymphocyte-activation gene 3 (LAG-3) may enhance efficacy of anti–programmed cell death-1 (PD-1) therapies. We present safety and clinical activity data from a Phase 1 study (NCT03005782) in patients with clear cell renal cell carcinoma (ccRCC) treated with anti–LAG-3 (fianlimab) + anti–PD-1 (cemiplimab). Methods Patients with advanced or metastatic ccRCC who had received no more than two previous regimens of anti-angiogenic therapy who were anti–PD-(ligand[L])1-naïve (cohort 3) or anti–PD-(L)1-experienced with most recent dose within 3 months prior to screening (cohort 4) were eligible. All patients were to receive fianlimab 1600 mg + cemiplimab 350 mg intravenously every 3 weeks for up to 24 months. Tumor measurements were performed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 every 6 weeks for 24 weeks, then every 9 weeks. The study objectives were to assess safety and antitumor activity of fianlimab + cemiplimab combination therapy in patients with ccRCC. Results Overall, 15 patients (median age: 64 years) each in cohorts 3 and 4 (total N=30) were enrolled and treated with fianlimab + cemiplimab as of November 1, 2022 data cutoff. For cohorts 3 and 4, 80% and 87% of patients were male, and 40% and 87% were White, respectively. All patients had prior cancer-related systemic therapy. In total, 60% and 93% of patients in cohorts 3 and 4 had ≥2 lines of prior therapies, respectively. For cohorts 3 and 4, median treatment duration was 27 weeks and 18 weeks, and median follow-up was 13 months and 24 months, respectively. Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 53% and 33% of patients in cohorts 3 and 4, respectively. Serious TEAEs occurred in 33% and 13% of patients in cohorts 3 and 4, respectively. Treatment-related AEs (TRAEs) were reported in 80% of patients in cohort 3 and 60% of patients in cohort 4. The most common TRAEs (any Grade) were rash (27%) and infusion related reaction (Grade 1 and 2; 27%) in cohort 3, and fatigue (20%) in cohort 4. Grade ≥3 TRAEs occurred in 27% of patients in cohort 3; there were no Grade ≥3 TRAEs in cohort 4. Treatment was discontinued due to any TEAE in three patients in cohort 3 and one patient in cohort 4. There was one death in cohort 3; a 79-year-old woman with a history of antiphospholipid syndrome died from complications of biopsy-proven ischemic colitis, which was attributed to study treatment. RECIST 1.1-based investigator-assessed objective response rate was 20% (3 partial responses [PRs]) in cohort 3 and 7% (1 PR) in cohort 4. The disease control rate was 60% and 73% in cohorts 3 and 4, respectively. Kaplan–Meier estimation of median progression-free survival was 4 months (95% confidence interval [CI] 1–10) in cohort 3 and 4 months (95% CI 1–7) in cohort 4. Durations of response were 4, 7, and 26 months in three responders in cohort 3, and 6 months in one responder in cohort 4. Conclusions Fianlimab + cemiplimab demonstrated promising signs of clinical activity with durable responses among patients who were anti–PD-(L)1-naïve (cohort 3) and anti–PD-(L)1-experienced (cohort 4), with an acceptable safety profile.