The optimal treatment strategy for advanced non-clear cell renal cell carcinoma (nccRCC) remains unclear. This study compares the efficacy of pembrolizumab plus lenvatinib (Pem+Len), nivolumab plus cabozantinib (Nivo+Cabo), and cabozantinib monotherapy (Cabo) for advanced nccRCC.A systematic literature search was conducted to identify clinical trials investigating the 3 treatment regimens for advanced nccRCC. Individual patient data (IPD) were reconstructed from Kaplan-Meier curves for progression-free survival (PFS) and overall survival (OS) using the IPDfromKM package. The outcomes were compared across treatment regimens. A subgroup analysis was conducted for papillary RCC (pRCC).Three clinical trials (NCT02761057, NCT03635892, and NCT04704219) were included; 242 patients were analyzed, including 158/40/44 patients receiving Pem+Len/Nivo+Cabo/Cabo, respectively. Patients with pRCC accounted for 59%/80%/100% of each treatment cohort, respectively. Pem+Len yielded significantly superior PFS (HR = 0.52, 95% CI, 0.34-0.81, P < .01) and OS (HR = 0.50, 95% CI, 0.28-0.89, P = .02) compared with Cabo. Nivo+Cabo showed potential superiority over Cabo in PFS (HR = 0.73, 95% CI, 0.44-1.20, P = .21) and OS (HR = 0.64, 95% CI, 0.35-1.16, P = .14), although these differences did not reach statistical significance. Our analysis did not reveal a clear superiority/inferiority between Pem+Len and Nivo+Cabo. The subgroup analysis for pRCC demonstrated significantly better PFS with Pem+Len (HR = 0.48, 95% CI, 0.29-0.77, P < .01) compared with Cabo, while the benefit of Nivo+Cabo was not significant (HR = 0.66, 95% CI, 0.37-1.15, P = .14). Limitations included its retrospective design and inconsistent follow-up periods among the trials.The IPD reconstruction analysis suggested better PFS and OS with Pem+Len and Nivo+Cabo compared with Cabo, supporting the use of these combination therapies for advanced nccRCC. Further comparative studies are needed to validate these findings.Copyright © 2025 Elsevier Inc. All rights reserved.