AbstractIntroductionRechallenge with antibodies targeting programmed cell death protein‐1 or its ligand (PD‐1/L1) after discontinuation or disease progression in solid tumors following a prior PD‐1/L1 treatment is often practiced in clinic. This study aimed to investigate if adding PD‐1/L1 inhibitors to cabozantinib, the most used second‐line treatment in real‐world patients with metastatic clear cell renal cell carcinoma (mccRCC), offers additional benefits.MethodsUsing de‐identified patient‐level data from a large real‐world US‐based database, patients diagnosed with mccRCC, who received any PD‐1/L1‐based combination in first‐line (1L) setting, followed by second‐line (2L) therapy with either cabozantinib alone or in combination with PD‐1/L1 inhibitors were included. Patients given a cabozantinib‐containing regimen in 1L were excluded. The study end points were real‐world time to next therapy (rwTTNT) and real‐world overall survival (rwOS) by 2L.ResultsOf 12,285 patients with metastatic renal cell carcinoma in the data set, 348 patients met eligibility and were included in the analysis. After propensity score matching weighting, cabozantinib with PD‐1/L1 inhibitors versus cabozantinib (ref.) had similar rwTTNT and rwOS in the 2L setting. Hazard ratios and 95% confidence interval (CI) for rwTTNT and rwOS are 0.74 (95% CI, 0.49–1.12) and 1.15 (95% CI, 0.73–1.79), respectively.ConclusionIn this study, the results align with the phase 3 CONTACT‐03 trial results, which showed no additional benefit of adding PD‐L1 inhibitor to cabozantinib compared to cabozantinib alone in 2L following PD‐1/L1–based therapies in 1L. These results from real‐world patients strengthen the evidence regarding the futility of rechallenge with PD‐1/L1 inhibitors.