Background: The oral HIF-2α inhibitor belzutifan demonstrated antitumor activity with manageable safety as monotherapy in pts with heavily pretreated ccRCC and in combination with a VEGF-TKI in pts who previously received a PD-1/L1 inhibitor. KEYMAKER-U03B (NCT04626518) is phase 1/2, multicenter, multi-arm, open-label, adaptive umbrella study. We present preliminary results from arm B5 for belzutifan + lenvatinib. Methods: In all arms, adults with histologically confirmed ccRCC, KPS ≥70%, and disease progression on or after PD-1/L1 inhibitor and VEGF-TKI treatment (in sequence or in combination) were enrolled. In arm B5, pts received belzutifan 120 mg PO QD + lenvatinib 20 mg PO QD. The study comprised a safety lead-in phase to establish the recommended phase 2 dose (RP2D), followed by an efficacy phase. Primary end point for the safety lead-in phase was safety and tolerability to establish RP2D; co-primary end points of the efficacy phase were safety and ORR per RECIST v1.1 by blinded independent central review (BICR). Secondary end points include clinical benefit rate (CBR; CR + PR + SD ≥6 mo), DOR and PFS per RECIST v1.1 by BICR. Response will be presented in pts who had an opportunity to receive ≥2 postbaseline scans due to ongoing enrollment. PFS was evaluated in all enrolled pts and safety in all treated pts. End points will be evaluated in each arm separately; no comparisons will be made across arms. Results: As of September 29, 2022, 32 pts were enrolled and 30 received treatment. Median age was 60.5 y, 78% were male and 78% had intermediate/poor IMDC risk. 23 pts were on treatment at data cutoff date. Median follow up was 6.9 mo (range: 0.1-18.2). Safety of belzutifan 120 mg + lenvatinib 20 mg was manageable. Of 10 evaluable pts in the safety lead-in phase, only 1 experienced a dose-limiting toxicity (grade 1 dyspnea). Among pts who had opportunity for ≥2 postbaseline scans (n = 24), ORR was 50% (95% CI, 29-71; all PRs); CBR was 54% (95% CI, 33-74). Median DOR was not reached (NR; range: 1.4+ to 14.0+ mo); 74% of responders remained in response for ≥12 mo by KM estimation. For all enrolled pts, median PFS was 11.2 mo (95% CI, 4-NR); 6-mo rate was 55%. In the safety analysis, 28 pts (93%) experienced a treatment-related AE (TRAE), most commonly (≥40%) anemia (43%), fatigue (43%), and hypertension (43%). Grade 3-4 TRAEs occurred in 15 pts (50%); most commonly hypertension (27%) and anemia (17%). 1 pt experienced grade 2 hypoxia. No pt died due to a TRAE. Conclusions: Preliminary data from the belzutifan + lenvatinib combination exhibited promising antitumor activity in pts with ccRCC that progressed on PD-1/L1 inhibitors and VEGF-TKIs. Safety findings were consistent with individual profiles of each agent. The combination is being further evaluated in the phase 3 LITESPARK-011 study. Clinical trial information: NCT04626518.