A phase 1 study of fianlimab (anti-LAG-3) in combination with cemiplimab (anti-PD-1) in patients with advanced ccRCC.
Authors: Kim Miso , McDermott Raymond S. , Williamson Stephen K. , Cho Byoung Chul , Dowlati Afshin , Lakhani Nehal J. , Malhotra Jyoti , Kaczmar John M. , Papadopoulos Kyriakos P. , Safran Howard , Aljumaily Raid , Mani Jayakumar , Fang Fang , Chen Shuquan , Salvati Mark , Lowy Israel , Fury Matthew G. , Lewis Karl 
Published: January 2024

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Background: Concurrent blockade of lymphocyte-activation gene 3 (LAG-3) may enhance efficacy of anti–programmed cell death protein 1 (PD-1) therapies. We present safety and clinical activity data from a Phase 1 study 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 2 previous regimens of anti-angiogenic therapy who were anti–PD-1/PD-L1-naïve (cohort 3) or anti–PD-1/L1-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 RECIST 1.1 every 6 weeks for 24 weeks, then every 9 weeks. Results: 15 patients (median age: 64 years) each in cohort 3 and 4 (total N=30) were enrolled and treated with fianlimab + cemiplimab as of 01 Nov 2022 data cutoff.For cohorts 3 and 4 respectively, 80% and 87% of patients were male, and 40% and 87% were White. All patients had prior cancer-related systemic therapy. 60% (9/15) and 93% (14/15) 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 TEAEs (TRAEs) were reported in 80% of patients in cohorts 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 cohorts 3. Treatment was discontinued due to any TEAE in 3 patients in cohort 3 and 1 patient in cohort 4. In cohort 3, there was one death. The patient was a 79-year-old woman with a history of antiphospholipid syndrome who died from complications of biopsy-proven ischemic colitis attributed to study treatment. RECIST 1.1-based investigator-assessed objective response rate (ORR) was 20% (3 partial responses [PRs]) in cohort 3 and 7% (1 PR) in cohort 4. The disease control rate (DCR) 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 patients. Duration of responses were 4, 7, and 26 months in 3 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 with anti–PD-1/PD-L1-naïve (cohort 3) and anti–PD-1/L1-experienced (cohort 4), with an acceptable safety profile. Clinical trial information: NCT03005782 .