Kidney cancer research has reached another benchmark with the publication of the final five-year findings from the pivotal KEYNOTE-426 trial. This trial has established a new first-line treatment for advanced clear cell renal cell carcinoma (RCC) with the combination of pembrolizumab, a programmed cell death protein 1 (PD-1) inhibitor, and axitinib, which is a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor. KEYNOTE-426 is the first trial to examine this combination and offers the longest follow-up of any PD-1 or programmed death-ligand 1 (PD-L1) inhibitor and VEGFR-TKI combination. Even if patients receive pembrolizumab for only two years, increased analysis will be required to give important directions about the long-term durability of the drug. As well as clinical outcomes, researchers include exploratory biomarker analysis, which asks questions about molecular factors that include PD-L1 expression, interferon-gamma signatures, polybromo-1 (PBRM1) mutation, and potential predictors of treatment response. The findings may help improve patient selection, facilitating a more individualized approach to treatment for patients with RCC and correct allocation between pembrolizumab plus axitinib and sunitinib.
KEYNOTE-426 (NCT02853331) was a phase 3, global, randomized, open-label trial conducted across 129 medical centers. It was constructed by Good Clinical Practice (GCP) guidelines and was approved by institutional ethics committees and regulatory authorities. It was a written, fully informed consent obtained by all participants prior to enrollment. Adults were eligible if their stage IV disease or recurring clear-cell RCC was newly identified and had not previously received systemic therapy against their advanced stage. Additional requirements were a Karnofsky Performance Scale score (KPS) of 70% or greater, the presence of at least one measurable lesion defined according to response evaluation criteria in solid tumors version 1.1(RECIST v1.1), and the availability of a tumor specimen with which to perform biomarker analysis. The use of randomization was stratified by the International Metastatic RCC Database Consortium (IMDC) risk group and region. Treatment continued until disease progression, intolerable toxicity, or withdrawal by patient/physician.
A total of 861 patients with advanced clear-cell RCC were randomized (October 2016 to January 2018) to either pembrolizumab plus axitinib (n=432) or sunitinib (n=429) and followed a median of 67.2 months. The overall median survival was 47.2 months on pembrolizumab-axitinib and 40.8 months on sunitinib (hazard ratio (HR) 0.84; 95% confidence interval (CI) 0.71-0.99). The objective response rate (ORR) was 60.6% and 11.6% were complete, whereas 49.1% were partial; 39.6% were complete and 35.7% were partial with pembrolizumab, axitinib, and sunitinib, respectively. The median response time was 23.6 months versus 15.3 months, and 26.0% versus 14.4% responded five years later. Biomarker profiling showed that increased T-cell–inflamed gene expression profile (TcellinfGEP) scores correlated with improved efficacy with pembrolizumab axitinib, whereas sunitinib was preferred with angiogenesis signatures. A PBRM1 mutation was associated with a positive response rate in the arm of pembrolizumab and axitinib.
The five-year outcomes of the KEYNOTE-426 confirm that pembrolizumab and axitinib provide significantly longer survival and response compared to the use of sunitinib in advanced clear cell RCC. Exploratory biomarker analyses indicate that a high TcellinfGEP signature relates to better outcomes with the combination and may indicate an immuneTKI synergy, whereas angiogenesis signatures favored sunitinib. But trial-to-trial variability and small subgroup sizes preclude definitive biomarker-based selection of treatment. PD-L1 expression had no prognostic power. Although molecular insights are promising, the current evidence favors pembrolizumab-axitinib as a first-line therapy in all eligible individuals, and prospective clinical trials will be required to inform precision therapy in RCC.
References: Rini BI, Plimack ER, Stus V, 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. Nat Med. 2025; doi:10.1038/s41591-025-03867-5
