479 Background: Cabozantinib is approved as a subsequent therapy for patients with metastatic renal cell carcinoma (mRCC) based on the METEOR trial. However, only 5% of patients in this trial received prior immunotherapy. Methods: We identified patients with mRCC from the IMDC who were treated with cabozantinib in the second-line (2L) setting from 2010 to 2023. These patients were stratified by IMDC risk groups and first-line (1L) treatment. We analyzed overall response rate (ORR), time to next treatment (TTNT), treatment duration (TD), overall survival (OS) and performed a multivariable analysis adjusted by IMDC criteria at 2L. Results: A total of 603 patients were identified. Baseline characteristics are summarized in the table. For the entire cohort, the ORR was 25.7%, TTNT was 10.1 months (mo), TD was 8.9 mo and mOS was 19 mo. Among patients treated with 1L ipilimumab/nivolumab (n=190), anti-PD1 + TKI (n=148), and TKI alone (n=207), cabozantinib showed an ORR of 27.2%, 26.4%, and 25%, respectively; a median TTNT of 9.9, 10.3, and 9.7 mo; a median TD of 9.4, 8.2, and 8.3 mo. Median OS was 18.6, 17.6, and 21.3 mo, respectively. A multivariable analysis was unable to demonstrate that first-line ORR (CR/PR vs SD vs PD) or TTNT (< 12 vs ≥ 12 mo) predicts for second-line cabozantinib ORR in the overall cohort and by first-line therapy type. Specifically, patients with stable disease or with partial and complete response in 1L were associated with an OR for a response of 0.99 (95% CI 0.52-1.92) or 1.23 (95% CI 0.61-2.49), respectively. Similarly, a first-line TTNT of ≥12 months had an OR for response of 1.04 (95% CI 0.59-1.82). Conclusions: This study demonstrates that cabozantinib maintains efficacy comparable to that observed in the METEOR trial in a real-world setting, including in patients with prior immunotherapy combination therapies. Efficacy of 1L treatment does not predict efficacy of 2L cabozantinib. Baseline characteristics. Variable Overall (N = 603) IO-IO (N = 190) IO-TKI (N = 148) TKI Alone (N = 207) Other (N = 58) p-value Non clear cell histology 107 (17.7) 33 (17.4) 26 (17.6) 28 (13.5) 20 (34.5) 0.003 Nephrectomy 416 (69.0) 97 (51.1) 110 (74.3) 166 (80.2) 43 (74.1) <0.001 1st line IMDC Risk Fav/Int/Poor 83 (13.8)/296 (49.1)/101 (16.7) 10 (5.3)/100 (52.6) /46 (24.2) 37 (25)/62 (41.9) /20 (13.5) 29 (14)/99 (47.8)/27 (13) 7 (12.1)/35 (60.3)/8 (13.8) <0.001 2nd line IMDC risk Fav/Int/Poor 56 (9.3)/269 (44.6)/108 (17.9) 7 (3.7)/90 (47.4)/45 (23.7) 25 (16.9)/63 (42.6)/24 (16.2) 19 (9.2)/87 (42.0)/32 (15.5) 5 (8.6)/29 (50.0)/7 (12.1) 0.002 Greater than 1 site of Metastasis 473 (78.4) 146 (76.8) 114 (77.0) 161 (77.8) 45 (77.6) 0.722 Brain Metastasis 36 (6.0) 18 (9.5) 5 (3.4) 13 (6.3) 0 (0.0) 0.022 Bone Metastasis 221 (36.7) 74 (38.9) 60 (40.5) 70 (33.8) 17 (29.3) 0.326 Liver Metastasis 106 (17.6) 32 (16.8) 26 (17.6) 39 (18.8) 9 (15.5) 0.926