Sustained Benefit in Advanced RCC with Pembrolizumab and Axitinib

Final analysis of the KEYNOTE-426 trial (NCT02853331) provides clinicians with a clearer picture of the long-term effectiveness of pembrolizumab (Keytruda) plus axitinib (Inlyta) for advanced renal cell carcinoma (RCC).^1,2 The 5-year follow-up data confirms the combination's sustained superiority over sunitinib (Sutent) monotherapy, reinforcing its role as a standard of care. This final analysis also offers valuable new insights into potential biomarkers that may help predict treatment response in the future.

Long-Term Efficacy Confirmed

The KEYNOTE-426 trial, a randomized, open-label, phase 3 study, compared pembrolizumab plus axitinib with sunitinib monotherapy in 861 patients with newly diagnosed or recurrent advanced clear cell RCC. The final analysis, with a median follow-up of 67.2 months, demonstrated a clear, long-lasting clinical benefit for the combination therapy.

The median overall survival (OS) was 47.2 months in the pembrolizumab plus axitinib arm compared with 40.8 months in the sunitinib arm (HR, 0.84; 95% CI, 0.71–0.99). The median progression-free survival (PFS) was 15.7 months for the combination, significantly longer than the 11.1 months for sunitinib (HR 0.69; 95% CI 0.59–0.81). Additionally, the combination therapy achieved an overall response rate (ORR) of 60.6%, including 11.6% complete responses, nearly double the 39.6% ORR seen with sunitinib, with only 4% complete responses.

Additionally, the study showed the remarkable durability of response in the combination arm. The estimated percentage of patients with an ongoing objective response at 60 months was 26.0% for pembrolizumab plus axitinib compared with 14.4% for sunitinib. For the subset of patients who completed the full 2-year course of pembrolizumab, the outcomes were even more impressive, with a median OS not yet reached and a 60-month OS rate of 70.7%.

Biomarker Analysis Offers Predictive Clues

A key component of this final analysis was the prespecified exploratory biomarker analysis, which sought to identify genomic features that could predict patient outcomes. While this research is exploratory and requires further validation, it provides a foundation for future, more personalized treatment strategies.

One notable finding was the positive association between a higher T-cell-inflamed gene expression profile (TcellinfGEP) and improved outcomes (OS, PFS, and ORR) in the pembrolizumab plus axitinib arm. This was not the case in the sunitinib arm. This finding suggests that a more "inflamed" tumor microenvironment may be a key factor in predicting a positive response to this specific immunotherapy combination. This is consistent with previous findings for pembrolizumab monotherapy in other tumor types. The lack of association with sunitinib further supports the hypothesis that the TcellinfGEP is a predictor of response to the PD-1 inhibitor component, not the TKI.

In contrast, a positive angiogenesis signature was strongly associated with improved outcomes in the sunitinib arm (PFS and ORR), and also with OS in the pembrolizumab plus axitinib arm. This finding aligns with the known mechanism of action of sunitinib, a TKI that targets VEGFRs to inhibit the growth of new blood vessels.

Surprisingly, PD-L1 expression, a biomarker often used in other settings, did not show a significant association with clinical outcomes in the pembrolizumab plus axitinib arm. This suggests that PD-L1 expression alone may not be a reliable predictive marker for this specific combination in advanced RCC.

The analysis also explored the role of specific gene mutations. The PBRM1 mutation was positively associated with a higher ORR in the combination arm. In the sunitinib arm, VHL and PBRM1 mutations were positively associated with longer OS, while the BAP1 mutation was negatively associated with OS. These mutational data add to a growing but sometimes conflicting body of research and highlight the need for further investigation to clarify their predictive and prognostic value.

Looking Ahead

This 5-year analysis of KEYNOTE-426 confirms the long-term, durable clinical benefits of pembrolizumab plus axitinib, solidifying its place as a cornerstone of first-line therapy for advanced RCC. The biomarker analysis, while exploratory, provides crucial insights into the underlying disease biology and the potential for a more targeted treatment approach. However, study authors note, “[a]lthough the analysis showed potential clinical utility of some RNA signatures in identifying patients who are likely to benefit the most from each treatment, additional correlative data and further prospective clinical investigations are needed to inform biomarker-directed treatment of patients with advanced or metastatic RCC who are being considered for combination treatment with antiangiogenic and PD-1 inhibitor therapies.”

REFERENCES:

1. 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

2. MacMillan L. Study reports final clinical trial data for advanced kidney cancer treatment. VUMC News. August 1, 2025. Accessed August 1, 2025. https://tinyurl.com/3dfrzk3f