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 .

Barts Health Biomedical Research Center Queen Mary's University of London ECMC London UK

Bell Land General Hospital Osaka Japan

Central Clinical Hospital With Outpatient Clinic Moscow Russia

Centre Antoine Lacassagne Université Côte d'Azur Nice France

Centre Hospitalier de l'Université de Montréal Montreal Quebec Canada

CHU of Québec and Laval University Quebec Quebec Canada

Department of Urology and Transplantation Surgery Eva Mayr Stihl Cancer Center Klinikum Stuttgart Stuttgart Germany

Dnipro State Medical University Dnipro Ukraine

Fox Chase Cancer Center Philadelphia PA USA

Hospital de Clínicas de Porto Alegre Porto Alegre Brazil

Merck and Co Inc Rahway NJ USA

P Herzen Moscow Oncology Research Institute Ministry of Health of the Russian Federation Moscow Russia

Palacký University Medical School and Teaching Hospital Olomouc Czech Republic

Russian Scientific Center of Roentgenoradiology Moscow Russia

St Vincent's University Hospital and University College Dublin Dublin Ireland

Sumy State University Sumy Regional Oncology Center Sumy Ukraine

The Christie NHS Foundation Trust Manchester UK

Vanderbilt Ingram Cancer Center Nashville TN USA

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ClinicalTrials.gov
NCT02853331