Pembrolizumab plus axitinib versus sunitinib for advanced clear cell renal cell carcinoma: 5-year survival and biomarker analyses of the phase 3 KEYNOTE-426 trial

Abstract 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 (Tcell inf GEP) 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 .