Background: Hypoxia-inducible factor 2α (HIF-2α) is a key oncogenic driver in RCC. Antitumor activity of the HIF-2α inhibitor belzutifan has been observed in RCC and is approved for treatment in patients (pts) with VHL disease who require therapy for associated RCC, CNS hemangioblastomas, or pNETs not requiring immediate surgery. Previous data from the phase 1 LITESPARK-001 trial (NCT02974738) designed to evaluate belzutifan in heavily pretreated RCC showed durable antitumor activity and an acceptable safety profile. After more than 3 years of follow-up for pts with ccRCC still receiving treatment, updated data are presented. Methods: Pts enrolled in the ccRCC cohort were previously treated with ≥1 therapy, had RECIST-measurable disease, ECOG PS score of 0 or 1, adequate organ function, and life expectancy of ≥6 months. Pts received oral belzutifan 120 mg once daily. The primary end point was safety. Secondary end points were ORR, DCR (CR + PR + SD), PFS, and DOR per RECIST v1.1 by investigator. The data cutoff date was July 15, 2021. Results: Of 55 pts enrolled in the ccRCC cohort, 9 (16%) remain on treatment as of the data cutoff date of July 15, 2021; the primary reason for discontinuation was progressive disease (n = 34; 62%). Pts received a median of 3 prior therapies (range, 1-9); 39 (71%) received prior VEGF and immunotherapy. Pts were followed while on treatment and for 30 days after the last dose for a median of 41.2 months (range, 38.2-47.7). Twenty-two pts (40%) experienced grade 3 TRAEs. The most common (≥10%) grade 3 TRAEs were anemia (n = 13; 24%) and hypoxia (n = 7; 13%). There were no grade 4 or 5 TRAEs. ORR was 25%, with 1 confirmed CR (2%) and 13 PRs (24%); DCR was 80%. Median DOR was not reached (range, 3.1+ to 37.9+ months); 8 of 14 responding pts (57%) remain in response as of the data cutoff date. Per IMDC risk, 4 of 13 pts with favorable risk achieved response (ORR = 31%; all PRs) and 10 of 42 pts with intermediate/poor risk achieved response (ORR = 24%; 1 CR, 9 PRs). DCR was 92% for pts with favorable risk and 76% for pts with intermediate/poor risk. For pts who received prior VEGF and immunotherapy, 8 of 39 pts achieved response (ORR = 21%; 1 CR; 7 PR); DCR was 74%. For the 16 pts who did not receive prior VEGF/immunotherapy, 6 achieved response (ORR = 38%; all PRs); DCR was 94%. Median PFS for the total cohort was 14.5 months (95% CI, 7.3-22.1); PFS rate at 156 weeks (̃36 months) was 34%. Conclusions: As seen after a median follow-up of > 3 years for pts still receiving treatment, belzutifan monotherapy continued to show a high rate of disease control and durable responses in previously treated pts with advanced ccRCC. Belzutifan exhibited a favorable safety profile, and no new safety signals were observed. In several phase 3 studies, belzutifan is being evaluated as monotherapy and combined therapy for ccRCC. Clinical trial information: NCT02974738.