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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
Rini, B. I. Plimack, E. R. Stus, V. Gafanov, R. Waddell, T. Nosov, D. Pouliot, F. Alekseev, B. Soulières, D. Melichar, B.
Rini, B. I.
Plimack, E. R.
Stus, V.
Gafanov, R.
Waddell, T.
Nosov, D.
Pouliot, F.
Alekseev, B.
Soulières, D.
Melichar, B.
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 .
Authors
Rini, B. I.
Plimack, E. R.
Stus, V.
Gafanov, R.
Waddell, T.
Nosov, D.
Pouliot, F.
Alekseev, B.
Soulières, D.
Melichar, B.
Vynnychenko, I.
de Azevedo, S. J.
Borchiellini, D.
McDermott, R. S.
Bedke, J.
Tamada, S.
Wu, S.
Markensohn, J.
Zhang, Y.
Loboda, A.
Vajdi, A.
Perini, R. F.
Burgents, J.
Powles, T.
Plimack, E. R.
Stus, V.
Gafanov, R.
Waddell, T.
Nosov, D.
Pouliot, F.
Alekseev, B.
Soulières, D.
Melichar, B.
Vynnychenko, I.
de Azevedo, S. J.
Borchiellini, D.
McDermott, R. S.
Bedke, J.
Tamada, S.
Wu, S.
Markensohn, J.
Zhang, Y.
Loboda, A.
Vajdi, A.
Perini, R. F.
Burgents, J.
Powles, T.
Description
Date
2025
Publisher
Collections
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Article
Citation
Rini BI, Plimack ER, Stus V, Gafanov R, Waddell T, Nosov D, et al. 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. Nature medicine. 2025 Oct;31(10):3475-84.