Head‐to‐head comparison of <scp>TKI</scp> and <scp>CPI</scp> first‐line treatment strategies in advanced renal cell carcinoma—Real‐world data from the German research platform <scp>CARAT</scp>

The combination of two immune checkpoint inhibitors (CPI) or a CPI with a tyrosine kinase inhibitor (TKI) has expanded the therapeutic options for advanced/metastatic renal cell carcinoma (aRCC) beyond TKI monotherapy. In the absence of head-to-head randomized trials comparing these strategies, we estimate their real-world effectiveness by emulating a hypothetical randomized trial. A total of 936 patients with aRCC from the prospective, observational, multicenter clinical registry CARAT (NCT03374267) starting first-line treatment after January 15, 2019, were included. Inverse probability of treatment weighting (IPTW) was used to compare first-line CPI + TKI (n = 447), CPI + CPI (n = 257), and TKI monotherapy (n = 166). Real-world progression-free survival (rwPFS), overall survival (OS), and time-to-deterioration (TTD) of health-related quality of life (HRQoL) were analyzed, also stratified by patients' prognostic risk according to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model. IPTW-adjusted median rwPFS and OS independent of IMDC risk were 12.3 [10.4-15.6] and 29.0 months [25.6-36.3] for TKI + CPI, 8.3 [6.5-10.9] and 21.9 months [16.3-34.5] for CPI + CPI, and 8.5 [6.4-10.0] and 31.7 months [21.0-40.0] for TKI monotherapy. Compared to CPI + TKI, survival tended to be worse for CPI + CPI (rwPFS: hazard ratio (HR) 1.25 [1.00-1.58]; OS: HR 1.25 [0.95, 1.63]). This finding was more pronounced for rwPFS in patients at intermediate risk. Median TTD of HRQoL did not substantially differ between the strategies. Despite the lack of statistically significant HR differences in rwPFS and OS, there was a trend toward superior survival with first-line CPI + TKI compared to CPI + CPI. TKI monotherapy may remain a viable first-line treatment option in selected patient populations. Further analyses, preferentially randomized clinical trials, are warranted.