Combining VEGFR tyrosine kinase inhibitors and PD-1/PD-L1 inhibitors versus VEGFR tyrosine kinase inhibitors monotherapy in renal cell carcinoma: a target trial emulation

Importance: Combinations of VEGFR tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs), such as antibodies to programmed cell death-1 (PD-1), or to its ligand PD-L1, are now first-line standard of care for renal cell carcinoma (RCC), but the pivotal clinical trials excluded patients with common comorbidities, leaving their real-world effectiveness uncertain. Objective: To determine whether adding PD-1/PD-L1 inhibitors to VEGFR-TKIs therapy is associated with improved overall survival in a real-world RCC cohort. Design, Setting, and Participants: This retrospective cohort study used a target trial emulation framework and real-world electronic health records data from the University of Florida Health Integrated Data Repository (IDR). Data was analyzed from September 2009 through June 2023. Adult patients ([≥]18 years) with confirmed RCC and at least one VEGFR-TKIs prescription were eligible. The date of the first VEGFR-TKIs prescription was defined as the index date, and patients were followed for up to 24 months. Variable-ratio propensity score matching (up to 2:1) across 13 baseline covariates was used to emulate randomized treatment assignments. Of 107,783 patients screened, 387 met eligibility criteria, and 319 remained in the matched cohort. Exposures: VEGFR-TKIs monotherapy (control group) versus VEGFR-TKIs combined with PD-1/PD-L1 inhibitors (experimental group). Main Outcomes and Measures: Overall survival (OS), analyzed by weighted Kaplan-Meier estimation, cluster-robust Cox regression, and restricted mean survival time (RMST) at {tau} = 24 months, prespecified given anticipated non-proportional hazards. Results: Among 319 matched patients (mean [SD] age, 62 [12] years; 76% male), 107 deaths occurred (33.5%). Twelve-month OS was higher in the combination arm (81.8%; 95% CI, 74.7--89.6%) than VEGFR-TKIs monotherapy (68.1%; 95% CI, 61.1--76.0%), converging by 24 months (61.1% vs 56.7%). The Cox hazard ratio was 0.718 (95% CI, 0.484-- 1.064; P = 0.0986). RMST was 2.79 months greater with combination therapy (95% CI, 0.93-- 4.65; P = 0.0033). Conclusions: Adding PD-1/PD-L1 inhibitors to VEGFR-TKIs therapy was associated with a statistically significant and clinically meaningful gain in restricted mean survival, supporting the real-world generalizability of combination therapy and the importance of appropriate treatment effect measures under non-proportional hazards.