Real-world outcomes of third-line systemic therapy after immune checkpoint inhibitor combinations and subsequent VEGFR-TKIs in advanced renal cell carcinoma

BACKGROUND: Evidence regarding treatment outcomes of third-line systemic therapy after failure of immune checkpoint inhibitor (ICI) combinations and subsequent VEGFR-TKIs in advanced renal cell carcinoma (RCC) remains limited. METHODS: We retrospectively evaluated clinical data from 35 patients with advanced RCC who received third-line therapy following ICI-based first-line regimens and subsequent VEGFR-TKIs. Treatment effectiveness and safety during third-line therapy were assessed. RESULTS: The most frequently administered first-line, second-line, and third-line drugs were nivolumab plus ipilimumab (n = 25, 71%), axitinib (n = 21, 60%), and cabozantinib (n = 15, 43%), respectively. Clear-cell histology was observed in 23 patients (66%), and 14 patients (40%) were classified as International Metastatic RCC Database Consortium poor risk. Median progression-free survival (PFS) and overall survival (OS) from third-line therapy initiation were 7.43 and 15.2 months, respectively, with an objective response rate of 11%. Clear-cell histology (hazard ratio [HR] 0.30, p = 0.0131) and Karnofsky Performance Status ≥80% (HR 0.27, P = .0157) were associated with longer OS after multivariable adjustment. Grade ≥ 3 adverse events occurred in 13 patients (37%). Dose reduction, treatment interruption, and treatment discontinuation were required in 14 (40%), 14 (40%), and 5 (14%) patients, respectively. In the subgroup receiving the most common treatment sequence-first-line nivolumab plus ipilimumab followed by VEGFR-TKIs (n = 25)-median PFS and OS were 10.3 and 17.3 months, respectively. CONCLUSION: Third-line systemic therapy following ICI combinations and sequential VEGFR-TKIs shows feasible clinical effectiveness and manageable toxicity in real-world patients with advanced RCC.