Study reports final clinical trial data for advanced kidney cancer treatment
A two-drug combination for treating advanced kidney cancer had sustained and durable clinical benefit in more than five years of follow-up, according to a study published in Nature Medicine.
The study reports final clinical data and biomarker analyses from the Phase 3 KEYNOTE-426 trial, which compared the drug combination pembrolizumab plus axitinib versus the single drug sunitinib for patients with previously untreated advanced clear cell renal cell carcinoma, the most common type of kidney cancer.
“KEYNOTE-426 was the first trial to combine a PD-1 inhibitor immunotherapy (pembrolizumab) with a VEGF receptor inhibitor antiangiogenic drug (axitinib) in the first-line setting for advanced renal cell carcinoma. It therefore has the longest follow-up duration among the various trials comparing these types of drug combinations,” said Brian Rini, MD, a medical oncologist at Vanderbilt-Ingram Cancer Center and the study’s lead and corresponding author.
Immunotherapy drugs like pembrolizumab stimulate the immune system to kill tumor cells. VEGF receptor inhibitors like axitinib and sunitinib block angiogenesis — the development of blood vessels that tumors need to grow and spread. Pembrolizumab plus axitinib and other immunotherapy-antiangiogenic drug combinations are now standard first-line treatments for advanced kidney cancer.
“Before the development of antiangiogenic drugs and immunotherapies, advanced renal cell carcinoma had a very poor prognosis. These drug combinations have dramatically improved treatment options and outcomes for patients,” said Rini, Ingram Professor of Cancer Research and Thomas F. Frist Sr. Professor of Medicine.
The first interim analysis of outcomes from KEYNOTE-426, published Feb. 16, 2019, in the New England Journal of Medicine, demonstrated that trial participants treated with pembrolizumab plus axitinib had longer overall and progression-free survival, and higher objective response rates compared to those taking sunitinib. The median follow-up was 12.8 months.
Now, with a median follow-up of 67.2 months, the current analysis confirms and extends the interim analysis and provides valuable information about biomarkers that could help guide treatment decisions.
The study in Nature Medicine reports that pembrolizumab plus axitinib had longer overall survival (47.2 months versus 40.8 months for sunitinib) and longer progression-free survival (15.7 months versus 11.1 months for sunitinib). The objective response rate was 60.6% for pembrolizumab plus axitinib and 39.6% for sunitinib.
The researchers reported a variety of associations between the expression of biomarkers and outcomes (overall survival, progression-free survival, objective response rate). The biomarkers they evaluated included an 18-gene T-cell-inflamed expression profile, angiogenesis signature, and PD-1 ligand expression.
“There is an unmet need for biomarkers that are predictive of patient outcomes following treatment with available first-line therapies for advanced renal cell carcinoma,” Rini said. “Although our analysis showed potential clinical utility of some RNA signatures in identifying patients who are likely to benefit the most from each treatment, further prospective clinical studies are needed.”
Pembrolizumab plus axitinib is a first-line treatment option for patients with advanced renal cell carcinoma regardless of biomarker subtypes, he noted.
Reference:
Rini, B.I., Plimack, E.R., 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). https://doi.org/10.1038/s41591-025-03867-5.
