Clinical efficacy and safety of second-line cabozantinib after first-line immune checkpoint inhibitor-based combinations in metastatic renal cell carcinoma: a multicenter retrospective study

Abstract Background The efficacy of second-line cabozantinib following first-line immune checkpoint inhibitor (ICI)-based combinations, particularly after pembrolizumab plus lenvatinib (Pem + Len), remains uncharacterized. We evaluated real-world outcomes in patients with metastatic renal cell carcinoma (mRCC). Methods This multicenter retrospective study included 96 mRCC patients who initiated second-line cabozantinib between 2021 and 2025, after first-line ipilimumab plus nivolumab (Ipi + Nivo; n = 36), avelumab or pembrolizumab plus axitinib (Ave/Pem + Axi; n = 30), or Pem + Len (n = 30). Endpoints included objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) from cabozantinib initiation and from first-line therapy initiation, prognostic factors, and safety. Results The overall ORR was 36% (Ipi + Nivo: 40%; Ave/Pem + Axi: 43%; Pem + Len: 23%). The median PFS from cabozantinib initiation was 9.4 months (Ipi + Nivo: 9.4; Ave/Pem + Axi: 15.9; Pem + Len: 8.7; P = 0.57), and the median OS was 25.5 months ( P = 0.87). From first-line therapy initiation, the median PFS (27.1 months) and OS (42.2 months) did not differ significantly across groups ( P = 0.70; P = 0.91). On multivariate analysis, only IMDC poor risk was independently associated with PFS. Grade ≥ 3 treatment-related adverse events occurred in 34.4% of patients. Conclusion Second-line cabozantinib provided meaningful efficacy across all approved first-line ICI-based combinations. Cumulative PFS from first-line therapy initiation was similar across regimens, although OS data for the Pem + Len group remain immature. Cabozantinib appears to represent a reasonable second-line option in the ICI era.