Phase I LITESPARK-018: Dose escalation study of belzutifan in advanced pretreated clear cell renal cell carcinoma (ccRCC)

BackgroundBelzutifan, a first-in-class HIF-2α inhibitor, is approved at a dose of 120 mg QD for certain patients (pts) with VHL disease and advanced RCC. Belzutifan is primarily metabolized by UGT2B17 and CYP2C19, but polymorphisms in UGT2B17 and CYP2C19 results in a loss of enzymatic activity (poor metabolizers [PMs]) or reduced activity (intermediate metabolizers [IMs]) that may impact belzutifan exposure. LITESPARK-018 (NCT04846920) was designed to evaluate the safety of escalating belzutifan doses for UGT2B17 IMs and extensive metabolizers (EMs) and at 120 mg QD for UGT2B17 PMs with pretreated advanced ccRCC.MethodsPts with previously treated advanced ccRCC were nonrandomly allocated to either arm A (UGT2B17 IMs/EMs sequentially enrolled into 3 escalating dose groups [160 mg BID, 160 mg TID, 200 mg TID] or arm B (UGT2B17 PMs [including UGT2B17/CYP2C19 PMs] at belzutifan 120 mg QD). Primary objectives were safety, tolerability, and MTD. Pharmacokinetics (PK) was a secondary objective. ORR and DOR were exploratory.ResultsOverall, 26 pts were assigned to arm A (160 mg BID n = 6; 160 mg TID n = 10; 200 mg TID n = 10) and 3 pts to arm B (120 mg QD). Median follow-up was 14.4 mo (range, 4.1-24.6). All-cause AEs occurred in all 29 pts, most commonly anemia (93%). The most common grade 3-5 AEs were anemia (48%) and hypoxia (31%). In arm A, the MTD was not reached (NR). A grade 3 DLT (treatment-related hypoxia) occurred in each dose group. 1 pt in the 200 mg TID group died from acute cardiac failure unrelated to treatment. In arm B, no dose reductions occurred. Belzutifan exposure increased with higher doses and more frequent administration (table). In all pts, ORR was 7% (95% CI, 1-23; 2 PR) and median DOR was NR (14.8 mo-NR).ConclusionsBelzutifan was generally tolerable at all doses evaluated. Based on limited PK data, individual belzutifan exposures were comparable or higher than the anticipated exposure in dual UGT2B17/CYP2C19 PM pts receiving belzutifan 120 mg QD. Table. Table: 1695P Pharmacokinetics Arm ABelzutifan160 mg BID n = 6 Arm ABelzutifan160 mg TID n = 10 Arm A Belzutifan200 mg TID n = 10 Arm B Belzutifan 120 mg QD n = 3 AUC0-24,SS geometric mean (%CV) [min-max], μg·hr/mL 52.93 (27.75) [41.90-86.80] 54.50 (41.45) [29.00-99.80] 59.47 (40.79) [33.20-97.10] 43.30 (52.61) [24.50-59.50] Clinical trial identificationNCT04846920. Release date: April 15, 2021.Editorial acknowledgementMedical writing and/or editorial assistance was provided by Obinna Ezeokoli, PhD, and Robert Steger, PhD, of ApotheCom (Yardley, PA, USA).Legal entity responsible for the studyMerck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.FundingMerck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.DisclosureU.N. Vaishampayan: Financial Interests, Personal, Advisory Board, consultant: BMS; Financial Interests, Personal, Advisory Board: Bayer, Gilead, Pfizer, Merck, Exelixis, Novartis; Financial Interests, Institutional, Research Grant, Investigator initiated trial supported by Merck: Merck; Non-Financial Interests, Member of Board of Directors: Michigan Society of Hematology/Oncology. A.J. Zurita Saavedra: Financial Interests, Personal, Advisory Board: Pfizer, Astellas, Incyte, Bayer, Exelixis, Dendreon, Janssen, HIKMA; Financial Interests, Personal, Research Funding: Pfizer, AstraZeneca, Astellas, X4 Pharma, Infinity, Merck, ABX, Curium, Clarity, Fusion. K. Beckermann: Other, Institutional, Research Grant: IASLC-BMS-LCFA, Pionyr, Aravive, Arsenal Bio; Financial Interests, Personal, Advisory Board: Aravive, Avevo, AstraZeneca, Alpine Bioscience, BMS, Exelixis, Merck, Eisai, Arcus, Nimbus, Sanofi, Seagen, Xencor, Adicet. A. Chain: Financial Interests, Personal, Full or part-time Employment: Merck & Co. Inc; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc. D. Vickery, Y. Zhang: Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc.; Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc. R. Perini: Financial Interests, Personal, Stocks/Shares: Merck & Co. Inc; Financial Interests, Personal, Full or part-time Employment: Merck & Co. Inc. D.F. McDermott: Financial Interests, Personal, Advisory Board: Pfizer, Merck, BMS, Alkermes, Iovance, werewolf therapeutics, Calithera, Eisai; Financial Interests, Personal, Advisory Board, Scientific Advisory Board Members: Cullinan; Financial Interests, Institutional, Coordinating PI: BMS.