Pembrolizumab plus axitinib shows sustained benefit vs sunitinib in ccRCC

Final long-term data from the phase 3 KEYNOTE-426 trial (NCT02853331) have been published in Nature Medicine, reinforcing pembrolizumab (Keytruda) plus axitinib (Inlyta) as a standard of care. At 5-year follow-up, the combination continued to show sustained superiority over sunitinib monotherapy (Sutent) in patients with previously untreated advanced clear cell renal cell carcinoma (ccRCC).¹

The final analysis also offered valuable insights into potential biomarkers that may be predictive of treatment response.

“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 lead author Brian I Rini, MD, a medical oncologist at Vanderbilt-Ingram Cancer Center in Nashville, Tennessee, in a news release on the findings.²

Clinical Outcomes

In total, the open-label KEYNOTE-426 trial enrolled 861 patients who were randomly assigned 1:1 to receive pembrolizumab plus axitinib (n = 432) or sunitinib monotherapy (n = 429). Patients enrolled in the study had not received prior systemic therapy for advanced RCC. The primary end points were overall survival (OS) and progression-free survival (PFS), and the secondary end point was objective response rate (ORR).

At a median follow-up of 67.2 months, the combination of pembrolizumab plus axitinib showed a sustained improvement in OS and PFS vs sunitinib monotherapy. Specifically, the median OS was 47.2 months in the pembrolizumab/axitinib arm vs 40.8 months in the sunitinib arm (HR, 0.84; 95% CI, 0.71–0.99). Further, the median PFS was 15.7 months with pembrolizumab plus axitinib compared with 11.1 months with sunitinib (HR, 0.69; 95% CI, 0.59–0.81).

The benefits in OS and PFS were consistent across patient subgroups.

The confirmed ORR was 60.6% in the pembrolizumab/axitinib arm vs 39.6% in the sunitinib arm. The authors also reported, “The estimated percentage of participants with an objective response who would have an ongoing response at 60 months was 26.0% in the pembrolizumab plus axitinib arm and 14.4% in the sunitinib arm.”

Further, the duration of response was 23.6 months among those who received the study combination vs 15.3 months among those who received sunitinib.

Biomarker Analyses

The investigators also conducted an exploratory biomarker analysis to identify genomic features that may predict response to immunotherapy-based treatment regimens.

Notably, data showed that higher 18-gene T-cell-inflamed gene expression profile (TcellinfGEP) was associated with improved clinical outcomes (OS, PFS, and ORR) in the pembrolizumab/axitinib arm. However, this association was not consistent in the sunitinib arm. According to the authors, the positive association between TcellinfGEP and clinical outcomes in the combination arm is consistent with previous data with pembrolizumab monotherapy, though the association appeared to be greater with the combination of pembrolizumab plus axitinib, “suggesting a potential positive interaction between the TKI and the PD-1 inhibitor.”

The investigators also found that an angiogenesis signature showed positive associations with OS (P = .004) in the pembrolizumab/axitinib cohort and with OS (P < .0001), PFS (P < .001) and ORR (P = .002) in the sunitinib cohort. Additionally, PBRM1 (polybromo-1) mutation was positively associated with ORR (P = .002) in the pembrolizumab plus axitinib arm.

Conversely, programmed cell death ligand 1 combined positive score showed a negative association with OS in the sunitinib arm (P = .025).

OS in the sunitinib arm was shown to be positively linked with von Hippel-Lindau tumor suppressor gene (P = .040) and PBRM1 (P = .010) mutations and was negatively associated with BRCA1-associated protein 1 mutation (P = .019).

“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 concluded in the news release.² “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.”

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. Study reports final clinical trial data for advanced kidney cancer treatment. News release. Vanderbilt University Medical Center. August 1, 2025. Accessed August 4, 2025. https://news.vumc.org/2025/08/01/study-reports-final-clinical-trial-data-for-advanced-kidney-cancer-treatment/