Real‐World Comparison of Dual Checkpoint Blockade and Immunotherapy Plus TKIs in Metastatic RCC

OBJECTIVES: To compare differences in clinical outcomes between dual immune checkpoint blockade and immunotherapy plus tyrosine kinase inhibitors (TKIs) as first-line treatment for metastatic renal cell carcinoma in routine clinical practice. PATIENTS AND METHODS: Retrospective multicenter cohort study including 311 patients with International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) intermediate or poor-risk metastatic RCC who received first-line immune checkpoint inhibitor (ICI)-based combination therapy between 2018 and 2023. Patients were treated with either ICI + ICI or ICI + TKI. Inverse probability of treatment weighting (IPTW) was applied to reduce baseline imbalances. Progression-free survival (PFS), second progression-free survival (PFS2), overall survival (OS), objective response rate (ORR), and duration of response (DOR) were analyzed using weighted survival models. RESULTS: After adjustment, ICI + TKI was associated with a trend toward longer PFS compared with ICI + ICI (median 28.7 vs. 16.6 months, HR 0.69, p = 0.050). No significant differences were observed in PFS2 (median 46.6 vs. 35.5 months, HR 0.84, p = 0.436) or OS (median 57.4 vs. 57.0 months, HR 1.01, p = 0.965). ORR (56.5% vs. 52.2%, p = 0.473) and DOR (median 54.6 vs. 44.9 months, HR 0.83, p = 0.502) were comparable. Subgroup analysis suggested more noticeable PFS benefit with ICI + TKI in intermediate-risk patients and those without central nervous system or bone metastases, whereas OS was similar across all subgroups. The incidence of grade ≥ 3 adverse events was comparable between groups. CONCLUSION: In this real-world cohort, TKI-containing combinations were associated with improved initial disease control, whereas no statistically significant difference in long-term survival was observed between treatment strategies. Given the retrospective design and potential for residual confounding despite IPTW adjustment, these findings should be interpreted with caution. Treatment selection should therefore be individualized according to therapeutic priorities, such as the need for initial tumor control versus the expectation of sustained immune-mediated benefit.