Prolonged or indefinite systemic therapy remains standard for advanced clear cell renal cell carcinoma (ccRCC), often resulting in cumulative toxicities and treatment burden. We conducted a single-arm phase 2 trial (ClinicalTrials. gov identifier: NCT02964078) of a fixed-duration regimen of anti-PD1 pembrolizumab plus high-dose interleukin-2 in treatment-naive advanced ccRCC. Primary objectives of safety and response were previously reported. The study met its primary endpoint with an overall response rate exceeding the pre-specified threshold of 45%. Here we report long-term follow-up (median follow-up of 76.4 months) including overall response, progression-free survival, treatment-free interval, and correlative analysis. Among 26 patients treated, the objective response rate was 73%, with complete responses in 42% of patients. Median overall survival was >84 months with a 5-year restricted mean survival time of 48.6 months. Median progression-free survival was 19.3 months, and median treatment-free interval was 23.8 months. 42% of patients remained treatment-free at the 5-year timepoint. No grade 5 adverse events occurred, and no patients with durable disease control experienced persistent grade ≥2 toxicities. Correlative analyses identified exploratory immune patterns associated with durable benefit, including enrichment of CD16⁺ natural killer cells, suppression of PD-1⁺ T-cell frequencies, and coordinated chemokine, complement, and PKC/TGF-β pathway activation.
Nature communications. 2026 May 25 [Epub ahead of print]
Jeffrey S Johnson, Justin W Miller, Firas Hatoum, Michael J Schell, Xiaoqing Yu, Gabriel Roman Souza, Sarah Mizelle, Keerthi Gullapalli, Adnan Fazili, Rohit Jain, Jonathan Chatzkel, Ling Cen, Jasreman Dhillon, Christopher Cubitt, Jiqiang Yao, Junmin Whiting, Jiannong Li, Jennifer Swank, Ghazal Jameel, Jingsong Zhang, Xuefeng Wang, Philippe E Spiess, Mayer Fishman, Jad Chahoud
Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA., USF Health Morsani College of Medicine, Tampa, FL, USA., Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, FL, USA., Department of Genitourinary Oncology, Weill Cornell Medicine, New York, NY, USA., Department of Anatomic Pathology, H. Lee Moffitt Cancer Center, Tampa, FL, USA., Immune Monitoring Core, H. Lee Moffitt Cancer Center, Tampa, FL, USA., Department of Pharmacy, H. Lee Moffitt Cancer Center, Tampa, FL, USA., Department of Genitourinary Oncology, Orlando Health Cancer Institute, Orlando, FL, USA. .