Long-term follow-up from the phase 2 KEYNOTE-427 study showed durable antitumor activity with first-line pembrolizumab monotherapy in both clear cell and non–clear cell renal cell carcinoma (RCC). Exploratory biomarker analyses also identified associations between clinical outcomes and PD-L1 combined positive score (CPS), a T-cell–inflamed gene expression profile, and, in the ccRCC cohort, circulating tumor DNA (ctDNA).
The final results were published in Annals of Oncology on September 28, 2026, in the original article, “Final results and predictive biomarkers of response and long-term outcomes with first-line pembrolizumab monotherapy in advanced renal cell carcinoma in the phase II KEYNOTE-427 study.”
Authors: D.F. McDermott, S. Signoretti, J.-L. Lee, F. Donskov, S.S. Tykodi, P. Tomczak, G.A. Bjarnason, J.M.G. Larkin, M.D. Kochenderfer, R.A. Gafanov, R. Cristescu, J. Markensohn, M. Nebozhyn, Y. Zhang, X. Peng, K. Rodriguez-Lopez, J. Burgents, R.F. Perini, and M.B. Atkins.
KEYNOTE-427 at Final Follow-Up
KEYNOTE-427 was a multicenter, single-arm phase 2 study evaluating first-line pembrolizumab monotherapy in advanced RCC. Cohort A included patients with clear cell RCC (ccRCC), while cohort B included patients with non–clear cell RCC (nccRCC). Eligible participants had histologically confirmed locally advanced, recurrent, or metastatic disease, with or without sarcomatoid features, measurable disease by RECIST v1.1, and no prior systemic therapy for advanced RCC.
The primary endpoint was objective response rate (ORR) by blinded independent central review. Prespecified exploratory biomarker analyses evaluated PD-L1 CPS, TcellinfGEP, and RCC driver gene mutations in both cohorts, as well as ctDNA in the ccRCC cohort. The final analysis reports efficacy and safety after more than 5 years of follow-up together with exploratory biomarker findings.
Durable Responses Across RCC Histologies
At the final analysis, median follow-up was 61.1 months in the ccRCC cohort and 56.7 months in the nccRCC cohort. ORR was 36.4% in ccRCC and 26.7% in nccRCC. Median duration of response was 18.9 months and 29.0 months, respectively.
Median PFS was 7.1 months in ccRCC and 4.2 months in nccRCC, while median OS was 40.7 months and 29.9 months, respectively. These long-term data confirmed durable antitumor activity with pembrolizumab monotherapy across both RCC histologies.
TcellinfGEP Linked With Response
TcellinfGEP was positively associated with objective response in both cohorts. When analyzed as a continuous variable, TcellinfGEP was associated with ORR in ccRCC (P = 0.0208) and nccRCC (P = 0.0021). Scores were also higher among responders than nonresponders in both cohorts. However, TcellinfGEP was not significantly associated with PFS or OS in either cohort, and responses were still observed among patients with lower TcellinfGEP scores.
PD-L1 CPS and Clinical Outcomes
PD-L1 CPS was also associated with several clinical outcomes. In ccRCC, continuous PD-L1 CPS was positively associated with ORR (P = 0.0195) and PFS (P = 0.0307). In nccRCC, PD-L1 CPS was positively associated with ORR (P < 0.0001), PFS (P = 0.0002), and OS (P = 0.0014). PD-L1 CPS was higher among responders in both cohorts, although the authors noted that its clinical utility as a standalone biomarker remains limited.
RCC Driver Mutations Show No Consistent Pattern
The investigators also assessed the relationship between RCC driver gene mutations and response to pembrolizumab. Objective responses were observed among participants across gene alterations associated with clear cell and non–clear cell RCC. However, RCC driver gene mutations showed no consistent pattern of association with ORR in either cohort. In contrast, positive associations with ORR were observed for TcellinfGEP and PD-L1 CPS.
ctDNA and Long-Term Outcomes
ctDNA was evaluated in cohort A. Participants with detectable ctDNA at baseline had shorter overall survival than those who were ctDNA-negative at baseline. Median OS was 30.5 months (95% CI, 18.1–56.4) among participants with detectable baseline ctDNA compared with 53.7 months (95% CI, 28.7–not reached) among those with ctDNA-negative status.
A change from ctDNA-positive status at baseline to ctDNA-negative status at cycle 2 day 1 was associated with better clinical outcomes. Because ctDNA was evaluated in cohort A, these findings relate specifically to the clear cell RCC cohort.
Takeaway
After more than 5 years of follow-up, KEYNOTE-427 showed durable antitumor activity with first-line pembrolizumab monotherapy in both ccRCC and nccRCC. Exploratory analyses linked higher PD-L1 CPS and TcellinfGEP with response, while RCC driver gene mutations showed no consistent association with ORR. In ccRCC, baseline ctDNA positivity was associated with shorter OS, and conversion to ctDNA-negative status during treatment was associated with better outcomes. These findings may support further investigation of tumor- and blood-based biomarkers to refine the use of PD-1 blockade in RCC.
The full article is available in ESMO Annals of Oncology.
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