Pembrolizumab monotherapy delivers durable antitumor activity in advanced renal cell carcinoma, with median overall survival reaching 40.7 months in clear cell disease and 29.9 months in non-clear cell disease after long-term follow-up, oncodaily.com reported. The phase 2 KEYNOTE-427 trial findings, published September 28, 2026, in Annals of Oncology, establish long-term outcomes for first-line PD-1 blockade and identify specific biomarkers linked to patient response.
Five-Year Efficacy Across Histologies in KEYNOTE-427
The multicenter, single-arm trial evaluated pembrolizumab monotherapy in two distinct cohorts of patients with advanced renal cell carcinoma who received no prior systemic therapy. Cohort A enrolled participants with clear cell renal cell carcinoma, while Cohort B enrolled those with non-clear cell renal cell carcinoma. At a median follow-up of 61.1 months for the clear cell cohort and 56.7 months for the non-clear cell cohort, investigators observed confirmed objective response rates of 36.4% and 26.7%, respectively.
Duration of response varied between the two groups. The median duration reached 18.9 months in clear cell renal cell carcinoma and 29.0 months in non-clear cell renal cell carcinoma. Median progression-free survival stood at 7.1 months for clear cell disease and 4.2 months for non-clear cell disease. These final figures confirm that first-line pembrolizumab monotherapy provides sustained clinical benefit in a subset of patients across both primary histologies.
Biomarker Associations With Clinical Outcomes
Prespecified exploratory analyses revealed clear relationships between specific biomarkers and patient response rates. The T-cell-inflamed gene expression profile showed a positive association with objective response when analyzed as a continuous variable in both clear cell disease (P = 0.0208) and non-clear cell disease (P = 0.0021). Responders exhibited higher scores than nonresponders in both cohorts, although this profile did not reach statistical significance for progression-free survival or overall survival, and some patients with lower scores still achieved responses.
PD-L1 combined positive score demonstrated additional prognostic value. In the clear cell cohort, continuous PD-L1 combined positive score associated positively with both objective response rate (P = 0.0195) and progression-free survival (P = 0.0307). In the non-clear cell cohort, the score associated with objective response rate. Conversely, assessments of renal cell carcinoma driver gene mutations showed no consistent pattern of association with objective response in either group, despite responses occurring across multiple gene alterations.
Circulating Tumor DNA Dynamics in Clear Cell Disease
Investigators tracked circulating tumor DNA in Cohort A to evaluate its impact on long-term survival. Participants with detectable circulating tumor DNA at baseline experienced shorter overall survival compared to those with undetectable baseline levels. Median overall survival reached 30.5 months for patients with detectable baseline circulating tumor DNA, versus 53.7 months for those with negative baseline status.
Shifting from a detectable circulating tumor DNA status at baseline to an undetectable status by cycle 2 day 1 correlated with improved clinical outcomes.
Frequently Asked Questions About KEYNOTE-427 Results
What patient populations were included in the KEYNOTE-427 trial?
The trial enrolled participants with histologically confirmed locally advanced, recurrent, or metastatic renal cell carcinoma who had received no prior systemic therapy for advanced disease. Cohort A focused exclusively on clear cell histology, while Cohort B examined non-clear cell renal cell carcinoma.
How were T-cell-inflamed gene expression profiles measured?
Investigators used prespecified exploratory biomarker analyses to evaluate the T-cell-inflamed gene expression profile as a continuous variable, comparing scores between responders and nonresponders across both tumor histologies.
What specific survival differences were observed with circulating tumor DNA testing?
Patients in the clear cell cohort with detectable baseline circulating tumor DNA had a median overall survival of 30.5 months, compared to 53.7 months for patients who tested negative for circulating tumor DNA at baseline.
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