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<p>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<sub>inf</sub>GEP) was positively associated with OS (<i>P</i> = 0.002), PFS (<i>P</i> &lt; 0.0001) and ORR (<i>P</i> &lt; 0.0001) within the pembrolizumab plus axitinib arm. An angiogenesis signature was positively associated with OS (<i>P</i> = 0.004) within the pembrolizumab plus axitinib arm and with OS (<i>P</i> &lt; 0.0001), PFS (<i>P</i> &lt; 0.001) and ORR (<i>P</i> = 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 (<i>P</i> = 0.025). Additionally, <i>PBRM1</i> (polybromo-1) mutation had a positive association with ORR (<i>P</i> = 0.002) within the pembrolizumab plus axitinib arm. Within the sunitinib arm, OS was positively associated with <i>VHL</i> (von Hippel–Lindau tumor suppressor gene) (<i>P</i> = 0.040) and <i>PBRM1</i> (<i>P</i> = 0.010) mutations and was negatively associated with <i>BAP1</i> (<i>BRCA1-</i>associated protein 1) mutation (<i>P</i> = 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: <a href="https://clinicaltrials.gov/study/NCT02853331">NCT02853331</a>.</p>

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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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月1日

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  • 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

摘要

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.