Background: Belzutifan (MK-6482) inhibits HIF-2α and demonstrated antitumor activity and favorable safety as monotherapy in a phase 1 study of patients (pts) with metastatic ccRCC. Current study (NCT03634540) investigates belzutifan plus cabozantinib for pts with advanced ccRCC who were either treatment naive (cohort 1) or previously treated, including immunotherapy and TKIs (cohort 2). This preliminary analysis presents data from cohort 2. Methods: Pts had metastatic ccRCC and received no more than 2 prior systemic treatment regimens. Initially, 6 pts in either cohort 1 or 2 were treated with belzutifan 120 mg and cabozantinib 60 mg orally once daily for 21 days and a safety review committee performed an initial evaluation. For purpose of this preliminary analysis, efficacy was evaluated in pts who received ≥1 dose of treatment and had an opportunity of ≥6 mo of follow-up. Primary end point: objective response rate (ORR; RECIST v1.1 by investigator review). Secondary end points: progression free survival (PFS), overall survival (OS), and duration of response (DOR). Safety was evaluated for all cohort participants. Results: Evaluation of safety and tolerability of belzutifan 120 mg plus cabozantinib 60 mg was performed in the first 6 pts. Only 1 participant experienced a dose-limiting toxicity of hand-foot syndrome, therefore belzutifan 120 mg plus cabozantinib 60 mg was determined to be the recommended phase 2 dose. 53 pts were included in the safety analysis population. Median age was 64 yrs, 73.6% were male, 54.7% had ECOG PS 1. Twenty-eight (52.8%) received prior first-line and 24 (45.2%) prior second-line therapies. Median (range) time from enrollment to data cutoff was 11.3 mo (5.6-24.0) for pts with ≥6 mo of follow-up (n=41). The confirmed ORR was 22.0% (9 PRs) and 90.2% had any tumor shrinkage. Disease control rate (CR+PR+SD) was 92.7%. Median (range) DOR was not reached (3.7+ to 14.8+ mo); all responses were ongoing. Median (95% CI) PFS was 16.8 mo (9.2-not reached); PFS rate at 6 mo was 78.3%. OS rate at 6 mo was 95.0%. While 52 of 53 (98.1%) pts experienced a treatment-related adverse event (TRAE), 92% of events were grade 1 and 2. Most common (≥30%) TRAEs were anemia (75.5%), fatigue (67.9%), hand-foot syndrome (52.8%), diarrhea (45.3%), hypertension (43.4%), nausea (35.8%), and ALT/AST increase (32-34%). Incidence of grade 3 TRAEs >5% were hypertension (22.4%), anemia (11.3%), fatigue (11.3%), and ALT increase (5.7%). 2 pts experienced grade 3 hypoxia (3.8%). There were no grade 4 TRAEs or deaths. Discontinuations due to TRAEs occurred in 6 pts (11.3%) for belzutifan and 8 pts (15.1%) for cabozantinib. Conclusions: In this preliminary analysis, belzutifan in combination with cabozantinib demonstrated promising antitumor activity in previously treated pts with metastatic ccRCC. Safety was consistent with individual profiles of each agent. Clinical trial information: NCT03634540.