Background: Cabozantinib is a tyrosine kinase inhibitor approved as monotherapy for aRCC in the USA, and as first-line therapy for patients with intermediate or poor risk aRCC, or after previous VEGF-targeted therapy in Europe. In the METEOR trial, a substantial proportion of patients required cabozantinib dose modifications. We report a real-world study of cabozantinib use for aRCC. Methods: CASSIOPE was a non-interventional prospective cohort study (conducted Apr 2018–May 2022; NCT03419572). Enrollment spanned 11 European countries (91 sites) where cabozantinib is marketed for aRCC. Patients had aRCC and had received ≥ 1 prior VEGF-targeted therapy (excluding cabozantinib). Decision to initiate cabozantinib was made prior to enrolment. The primary endpoint was cabozantinib usage (dose interruptions, reductions or discontinuations due to AEs) in the second- (2L) or later- (≥ 3L) line settings. Secondary endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and tolerability. Data were analyzed descriptively for patients with safety follow-up after ≥ 1 cabozantinib dose. Results: In total, 679 patients were included (73.0% male; median [range] age 67.0 [29–93] yrs; 85.7% clear-cell aRCC; 80.3% prior nephrectomy). Median (range) observation period was similar for 2L (n = 335; 8.51 [0.2–15.4] mo) and ≥ 3L cabozantinib (n = 343; 9.26 [0.0–15.0] mo). Usage data are shown. For the overall population, ORR (95% CI) and median (95% CI) PFS according to local assessment were 21.9% (17.5%–26.9%) and 7.8 (6.3–8.7) mo for 2L cabozantinib, and 38.0% (32.7%–43.5%) and 8.7 (7.6–9.6) mo for ≥ 3L cabozantinib. Median OS (95% CI) was 13.0 (12.6–not calculated [NC]) mo for 2L, and 17.1 (13.8–NC) mo for ≥ 3L cabozantinib. Most patients (90.4%) reported treatment-related AEs (Grade 1, 71.1%; Grade 2, 70.3% of patients), most commonly any grade diarrhea (52.4%), palmar-plantar erythrodysesthesia syndrome (27.2%), decreased appetite (25.5%), hypertension (21.9%), asthenia (21.6%), fatigue (20.5%) and nausea (20.3%). Conclusions: In this real-world study, tolerability of ≥ 2L cabozantinib was consistent with the METEOR trial safety profile: cabozantinib dose modifications due to AEs were common, but discontinuation rates due to AEs were substantially less frequent. Cabozantinib activity was maintained across lines. Clinical trial information: NCT03419572.