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

## TL;DR

This study compares real-world effectiveness of different first-line treatments for advanced kidney cancer using data from a German registry, finding that combining immunotherapy and a drug called TKI may offer better survival than other combinations.

## Contribution

The study provides real-world evidence comparing CPI+TKI, CPI+CPI, and TKI monotherapy for aRCC using a large registry and IPTW analysis.

## Key findings

- CPI+TKI showed better progression-free and overall survival compared to CPI+CPI and TKI monotherapy.
- TKI monotherapy remains a viable option for selected patients, especially those who cannot tolerate immunotherapy.
- Quality of life deterioration times were similar across all treatment strategies.

## Abstract

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.

What's new?

The current standard of care for locally advanced or metastatic renal cell carcinoma (aRCC) is either a combination of two immune checkpoint inhibitors (CPI) or a CPI plus a tyrosine kinase inhibitor (TKI). Here, the authors simulate a head‐to‐head trial comparing the real‐world effectiveness of these combination therapies with TKI monotherapy using a large dataset from the prospective, observational, multicenter German clinical registry CARAT. The analysis suggests better survival with CPI + TKI than with two CPIs, and TKI monotherapy remains a viable option, particularly for patients who cannot tolerate immunotherapy.