At the first interim analysis of the phase 3 KEYNOTE-426 trial, first-line pembrolizumab plus axitinib showed superior overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) over sunitinib for advanced renal cell carcinoma (RCC). To assess long-term durability of clinical outcomes and elucidate predictive biomarkers for RCC, we performed efficacy and prespecified exploratory biomarker analyses from KEYNOTE-426 with ≥5 years of follow-up. Pembrolizumab plus axitinib showed sustained benefits in OS (hazard ratio: 0.84; 95% confidence interval: 0.71-0.99), PFS (hazard ratio: 0.69; 95% confidence interval: 0.59-0.81) and ORR (60.6% versus 39.6%) compared to sunitinib. An 18-gene T-cell-inflamed gene expression profile (TcellinfGEP) was positively associated with OS (P = 0.002), PFS (P < 0.0001) and ORR (P < 0.0001) within the pembrolizumab plus axitinib arm. An angiogenesis signature was positively associated with OS (P = 0.004) within the pembrolizumab plus axitinib arm and with OS (P < 0.0001), PFS (P < 0.001) and ORR (P = 0.002) within the sunitinib arm. Across arms, programmed cell death ligand 1 combined positive score was only associated (negatively) with OS within the sunitinib arm (P = 0.025). Additionally, PBRM1 (polybromo-1) mutation had a positive association with ORR (P = 0.002) within the pembrolizumab plus axitinib arm. Within the sunitinib arm, OS was positively associated with VHL (von Hippel-Lindau tumor suppressor gene) (P = 0.040) and PBRM1 (P = 0.010) mutations and was negatively associated with BAP1 (BRCA1-associated protein 1) mutation (P = 0.019). Results showed a sustained clinical benefit with pembrolizumab plus axitinib over sunitinib and provide valuable information on biomarkers for immunotherapy-based treatment combinations in advanced RCC. Prospective clinical investigations are needed for biomarker-directed treatment for advanced RCC. ClinicalTrials.gov identifier: NCT02853331 .
Nature medicine. 2025 Aug 01 [Epub ahead of print]
Brian I Rini, Elizabeth R Plimack, Viktor Stus, Rustem Gafanov, Tom Waddell, Dmitry Nosov, Frédéric Pouliot, Boris Alekseev, Denis Soulières, Bohuslav Melichar, Ihor Vynnychenko, Sergio Jobim de Azevedo, Delphine Borchiellini, Raymond S McDermott, Jens Bedke, Satoshi Tamada, Sterling Wu, Julia Markensohn, Yiwei Zhang, Andrey Loboda, Amir Vajdi, Rodolfo F Perini, Joseph Burgents, Thomas Powles
Vanderbilt-Ingram Cancer Center, Nashville, TN, USA. ., Fox Chase Cancer Center, Philadelphia, PA, USA., Dnipro State Medical University, Dnipro, Ukraine., Russian Scientific Center of Roentgenoradiology, Moscow, Russia., The Christie NHS Foundation Trust, Manchester, UK., Central Clinical Hospital With Outpatient Clinic, Moscow, Russia., CHU of Québec and Laval University, Quebec, Quebec, Canada., P. Herzen Moscow Oncology Research Institute, Ministry of Health of the Russian Federation, Moscow, Russia., Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada., Palacký University Medical School and Teaching Hospital, Olomouc, Czech Republic., Sumy State University, Sumy Regional Oncology Center, Sumy, Ukraine., Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil., Centre Antoine Lacassagne, Université Côte d'Azur, Nice, France., St. Vincent's University Hospital and University College Dublin, Dublin, Ireland., Department of Urology and Transplantation Surgery, Eva Mayr-Stihl Cancer Center, Klinikum Stuttgart, Stuttgart, Germany., Bell-Land General Hospital, Osaka, Japan., Merck & Co., Inc., Rahway, NJ, USA., Barts Health Biomedical Research Center, Queen Mary's University of London ECMC, London, UK.