TY - JOUR
T1 - Pembrolizumab plus axitinib versus sunitinib for advanced clear cell renal cell carcinoma
T2 - 5-year survival and biomarker analyses of the phase 3 KEYNOTE-426 trial
AU - Rini, Brian I.
AU - Plimack, Elizabeth R.
AU - Stus, Viktor
AU - Gafanov, Rustem
AU - Waddell, Tom
AU - Nosov, Dmitry
AU - Pouliot, Frédéric
AU - Alekseev, Boris
AU - Soulières, Denis
AU - Melichar, Bohuslav
AU - Vynnychenko, Ihor
AU - de Azevedo, Sergio Jobim
AU - Borchiellini, Delphine
AU - McDermott, Raymond S.
AU - Bedke, Jens
AU - Tamada, Satoshi
AU - Wu, Sterling
AU - Markensohn, Julia
AU - Zhang, Yiwei
AU - Loboda, Andrey
AU - Vajdi, Amir
AU - Perini, Rodolfo F.
AU - Burgents, Joseph
AU - Powles, Thomas
N1 - © 2025. The Author(s).
PY - 2025/10
Y1 - 2025/10
N2 - 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.
AB - 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.
KW - Adult
KW - Aged
KW - Antibodies, Monoclonal, Humanized/administration & dosage
KW - Antineoplastic Combined Chemotherapy Protocols/therapeutic use
KW - Axitinib/administration & dosage
KW - B7-H1 Antigen/genetics
KW - Biomarkers, Tumor/genetics
KW - Carcinoma, Renal Cell/drug therapy
KW - Female
KW - Humans
KW - Kidney Neoplasms/drug therapy
KW - Male
KW - Middle Aged
KW - Progression-Free Survival
KW - Sunitinib/therapeutic use
UR - https://www.scopus.com/pages/publications/105012404675
U2 - 10.1038/s41591-025-03867-5
DO - 10.1038/s41591-025-03867-5
M3 - Article
C2 - 40750932
AN - SCOPUS:105012404675
SN - 1078-8956
VL - 31
SP - 3475
EP - 3484
JO - Nature Medicine
JF - Nature Medicine
IS - 10
ER -