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.
Abstract
Background
Previous results from the single-arm, phase II KEYNOTE-427 study showed antitumor activity with first-line pembrolizumab monotherapy in advanced clear cell renal cell carcinoma (ccRCC) and non-clear cell RCC (nccRCC). We report results of the final efficacy and safety analyses and exploratory, predictive biomarker analysis of KEYNOTE-427. PATIENTS AND
Methods
Eligible participants had histologically confirmed locally advanced, recurrent, or metastatic ccRCC (cohort A) or nccRCC (cohort B) with or without sarcomatoid features, measurable disease per RECIST v1.1, and no prior systemic therapy for advanced RCC. The primary end point was objective response rate (ORR) per RECIST v1.1 by blinded independent central review. Prespecified biomarker objectives were to evaluate the association of clinical outcomes with a T-cell-inflamed gene expression profile (TcellinfGEP), programmed cell death ligand 1 combined positive score (PD-L1 CPS), RCC driver gene mutations, and circulating tumor DNA (ctDNA; cohort A).
Results
After a median (range) follow-up of 61.1 months (54.7-65.5) in cohort A and 56.7 months (47.9-64.0) in cohort B, ORRs were 36.4% and 26.7%, respectively. Continuous TcellinfGEP was positively associated with ORR in cohort A (P=0.0208) and cohort B (P=0.0021). Continuous PD-L1 CPS was positively associated with ORR (P=0.0195) and progression-free survival (PFS; P=0.0307) in cohort A and ORR (P <0.0001), PFS (P=0.0002), and overall survival (OS; P=0.0014) in cohort B. RCC driver gene mutations showed no consistent patterns with ORR in either cohort. In cohort A, participants with detectable ctDNA at baseline had a shorter OS than participants with a ctDNA-negative status (median: 30.5 months [95% CI 18.1-56.4] vs 53.7 months [28.7-not reached]).
Conclusions
These results show that pembrolizumab is a highly active agent in ccRCC and nccRCC. Insights from the comprehensive analysis of RCC tumor molecular components and ctDNA may facilitate progress toward effective, biomarker-driven precision treatment in advanced RCC.