Background: Clear cell RCC (ccRCC) accounts for ~70% of kidney cancer cases in the US. Several first-line therapies are approved for ccRCC, but few patients respond completely and most progress within 5-11 mo. A key oncogenic driver in RCC is the transcription factor hypoxia-inducible factor 2α (HIF-2α). MK-6482 is a small molecule HIF-2α inhibitor that blocks the heterodimerization of HIF-2α with HIF-1β, inducing tumor regression in mouse xenograft RCC models. Updated data presented here include additional follow-up from the expansion cohort of patients with ccRCC from the first-in-human phase 1/2 study of MK-6482 in advanced solid tumors (NCT02974738). Methods: Patients were aged ≥18 y with advanced ccRCC, received ≥1 prior therapy, and had RECIST v1.1 measurable disease, ECOG status 0 or 1, adequate organ function, and life expectancy ≥6 mo. They received 120 mg of MK-6482 orally once daily. Tumors were assessed at baseline, within 7 days before week 9, and then every 8 weeks; response was assessed using RECIST v1.1. The primary end point was safety. Secondary end points included ORR, duration of response (DOR), and PFS. Results: Fifty-five patients with ccRCC were treated with MK-6482 120 mg (52 in expansion and 3 in dose-escalation cohorts). The median number of prior therapies was 3 (range 1-9). Forty-two patients (81%) previously received PD-1/L1 inhibitors and 48 (92%) previously received VEGF inhibitors. Thirteen patients (24%) were classified as favorable risk and 42 (76%) as intermediate or poor risk per IMDC criteria. With a median follow-up of 28 mo, the most common all-grade, all-cause AEs >30% were anemia (76%), fatigue (71%), dyspnea (49%), nausea (36%), cough (31%), and hypoxia (31%). Anemia (27%) and hypoxia (16%) were the most common grade 3 AEs. Two patients (4%) experienced grade 4 AEs, and 4 patients (7%) experienced grade 5 AEs. No grade 4 or 5 AEs were related to treatment. ORR was 25%, with 14 confirmed PRs. Thirty patients (55%) had SD, with a disease control rate (CR+PR+SD) of 80%. Median DOR was not reached; 77% had a response ≥6 mo. By IMDC risk, 4 of 13 patients with favorable risk had PR (ORR = 31%) and 10 of 42 with intermediate or poor risk had PR (ORR = 24%); disease control rate was 92% and 76%, respectively. Median PFS for the total population was 14.5 mo; 51% had a PFS of 12 mo. As of June 1, 2020, 33 patients (60%) discontinued because of PD and 2 (4%) because of AEs; 11 patients (20%) had ongoing treatment. Conclusions: MK-6482 remained well tolerated with a favorable safety profile and promising single-agent activity in patients with ccRCC for all IMDC risk groups after further follow-up. A phase III trial in a similar population is underway. Clinical trial information: NCT02974738.