Outcomes of immune-checkpoint inhibitor rechallenge in metastatic clear-cell renal cell carcinoma: results from a global real-world evidence study

Background: Immune-checkpoint inhibitors (ICIs), with or without tyrosine kinase inhibitors (TKIs), represent the backbone first-line treatment of patients (pts) with metastatic clear-cell renal cell carcinoma (mccRCC). Although multiple ICI-based regimens are approved in the metastatic setting, limited data exist on the efficacy of ICI rechallenge, particularly in relation to the timing and efficacy of rechallenge initiation. Patients and methods: Using the TriNetX research database, we conducted a large-scale, retrospective analysis of pts with mccRCC treated with ≥2 lines of ICI-based therapy across major international centers (2016-2024). Kaplan–Meier analysis was used to estimate progression-free survival (PFS) and overall survival (OS) following ICI rechallenge. Propensity score matching (PSM) was applied to adjust for age, sex, disease stage, metastatic sites, prior ICI type, and treatment sequencing strategy. Results: Among 6737 pts with mccRCC, 288 (4.3%) received ≥2 lines of ICI. Median age was 63.8 years. The most common first-line regimens were nivolumab (N) + cabozantinib (44.1%), N + ipilimumab (26.5%), pembrolizumab (P) + axitinib (20%), and P + lenvatinib (8.4%). ICI rechallenge sequences were: N>N (47.6%), P>P (22.2%), N>P (17%), and P>N (13.2%). Median duration of prior ICI therapy was 19.5 months, and the median interval between ICI therapies was 8.91 months. After a median follow-up of 19.3 months, median OS following ICI rechallenge was 33.2 months, and median PFS was 8.5 months. Rechallenge ≥6 months after prior ICI was associated with improved PFS (8.8 versus 5.2 months) and OS (34.9 versus 19.4 months; P = 0.014). PSM confirmed that the OS benefit was independent of covariates (P = 0.03). Conclusions: Our results outline opportunities for optimal ICI rechallenge, regardless of the prior immunotherapy administered. Improved outcomes with longer intervals (≥6 months) between treatments suggest timing is a key driver of efficacy and should be investigated in prospective trials as a surrogate marker of likely treatment response.