656MO - Phase II study of belzutifan (MK-6482), an oral hypoxia-inducible factor 2α (HIF-2α) inhibitor, plus cabozantinib for treatment of advanced clear cell renal cell carcinoma (ccRCC)

Background

Belzutifan monotherapy has shown antitumor activity and favorable safety in advanced ccRCC. This ongoing, open-label, phase II study (NCT03634540) investigates belzutifan plus cabozantinib for pts with advanced ccRCC who were either treatment naive (cohort 1) or previously treated with immunotherapy (cohort 2). This analysis presents data from cohort 2.

Methods

Pts had advanced ccRCC and had previously received immunotherapy and ≤2 systemic treatment regimens. Initially, a safety review committee evaluated the first 6 pts enrolled in either cohort for 21 days to determine the recommended phase II dose (RP2D). The primary end point was ORR (CR + PR) per RECIST v1.1 by investigator review. Secondary end points were DCR (CR + PR + SD), DOR, PFS, and OS. For this preliminary analysis, efficacy was evaluated in pts who received ≥1 dose of treatment and had an opportunity for ≥6 mo of follow-up. Safety was evaluated in all pts.

Results

In the first 6 pts enrolled, 1 had a DLT (hand–foot syndrome); belzutifan 120 mg plus cabozantinib 60 mg was determined to be the RP2D. Overall, 52 pts were enrolled in cohort 2 and were included in the safety analysis set. In all pts, 28 (54%) previously received 1 line therapy and 24 (46%) previously received 2 lines of therapy. Median time from enrollment to data cutoff was 8.9 mo (range, 2.2-24.0). In the efficacy analysis set (N = 41), ORR was 22% (9 PRs) and DCR was 90%; 88% of pts had tumor shrinkage. Median DOR was not reached (range, 3.7+ to 14.8+ mo); all responses were ongoing as of the data cutoff date. Median PFS was 16.8 mo (95% CI, 9.2 to not reached); PFS rate at 12 mo was 65%; OS rate at 12 mo was 81%. In all pts, 98% had a treatment-related adverse event (TRAE); most events (92%) were grade 1 or 2. Incidence of grade 3 TRAEs ≥10% were hypertension (23%), anemia (12%), and fatigue (12%). Two (4%) pts experienced grade 3 hypoxia. There were no grade 4 or 5 TRAEs. Discontinuations owing to TRAEs occurred in 6 pts (12%) for belzutifan and 8 pts (15%) for cabozantinib.

Conclusions

In this preliminary analysis, belzutifan plus cabozantinib had manageable safety and showed promising antitumor activity in previously treated pts with advanced ccRCC.

Clinical trial identification

NCT03634540, August 16, 2018.

Editorial acknowledgement

Medical writing and/or editorial assistance was provided by Matthew Grzywacz, PhD, of ApotheCom (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Legal entity responsible for the study

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Funding

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Disclosure

D.F. McDermott: Financial Interests, Personal, Other, Honoraria: BMS, Pfizer, Merck, Alkermes, Inc., EMD, Serono, Eli Lilly and Company, Iovance, Eisai Inc., Werewolf Therapeutics, Calithera Bioscience; Financial Interests, Institutional, Research Grant: BMS, Merck, Genentech, Pfizer, Exelixis, X4 Pharma, Alkermes, Inc., Checkmate Pharmaceuticals. T.K. Choueiri: Financial Interests, Personal, Full or part-time Employment: Dana Farber Cancer Hospital; Financial Interests, Personal, Advisory Role, Consulting or advisory role: Pfizer, Bayer, Novartis, GlaxoSmithKline, Merck, Bristol Myers Squibb, Roche/Genentech, Eisai, Foundation Medicine, Cerulean Pharma, AstraZeneca, Exelixis, Prometheus, alligent, Ipsen, Corvus Pharmaceuticals, Lpath, Alexion Pharmaceuticals, Sanofi/Aventis; Financial Interests, Personal, Leadership Role: Dana Farber Cancer Hospital, NCCN, KidneyCan, ASCO; Financial Interests, Personal, Other, Travel expenses, including accommodations: Pfizer, Bayer, Novartis, GlaxoSmithKline, Merck, Bristol Myers Squibb, Roche/Genentech, Eisai, Foundation Medicine, Cerulean Pharma, AstraZeneca, Exelixis, Prometheus, alligent, Ipsen, Corvus Pharmaceuticals, Lpath, Alexion Pharmaceuticals, Sanofi/Aventis; Financial Interests, Personal, Other: Patent application PCT/US2018/058430; Financial Interests, Personal, Stocks/Shares: Pionyr, Tempest Therapeutics; Financial Interests, Personal, Other, Honoraria: NCCN, UpToDate, Michael J. Hennessey Associates, ASCO, Harborside Press, Analysis Group, Alexion Pharmaceuticals, Sanofi/Aventis, AstraZeneca, Bayer, Bristol Myers Squibb, Genentech/Roche, GlaxoSmithKline, Merck, Novartis, Peloton Therapeutics, Pfizer, Co; Financial Interests, Institutional, Research Grant: Pfizer, Novartis, Merck, Exelixis, TRACON Pharma, GlaxoSmithKline, Bristol Myers Squibb, AstraZeneca, Peloton Therapeutics, Roche/Genentech, Celldex, Agensys, Eisai, Takeda, Prometheus, Ipsen, Corvus Pharmaceuticals, Cerulean Pharma, Seattle Genetics/Aste. T.M. Bauer: Financial Interests, Institutional, Research Grant: Medpacto, Incyte, Mirati Therapeutics, MedImmune, AbbVie, AstraZeneca, MabVax, Stemline Therapeutics, Merck, Lilly, GlaxoSmithKline, Novartis, Genentech, Deciphera, Merrimack, Immunogen, Millennium, Phosplatin Therapeutics, Calithera Biosciences, Kolltan; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Lilly, Bayer; Financial Interests, Personal, Advisory Role: AstraZeneca, Lilly, Bristol Myers Squibb, Foundation Medicine, Pfizer, Loxo, Bayer, Guardant Health, Exelesis, Blueprint Medicines; Non-Financial Interests, Personal, Other, Expense reimbursement: Lilly, Bristol Myers Squibb, Foundation Medicine, Ignyta, Moderna Therapeutics, Loxo, Bayer, Guardant Health; Financial Interests, Institutional, Advisory Role: Leap Therapeutics, Ignyta, Moderna Therapeutics, Pfizer. E. Arrowsmith: Financial Interests, Institutional, Research Grant: AstraZeneca, Onyx, Sarah Cannon Research Institute, Exelixis, Incyte, Modra Pharmaceuticals, Bristol Myers Squibb, Cephalon, Eisai, Lilly, Infinity Pharmaceuticals, Calistoga Pharmaceuticals, Chorus, EMD Serono, Genentech, Cougar Biotechnology, Evelo Bios. A. Roy: Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc.; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc. R. Perini: Financial Interests, Personal, Full or part-time Employment: MSD; Financial Interests, Personal, Stocks/Shares: MSD. D. Vickery: Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc.; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc.; Financial Interests, Personal, Research Grant: Merck & Co., Inc.; Financial Interests, Personal, Other, Travel expenses: Merck & Co., Inc. S.S. Tykodi: Financial Interests, Personal, Advisory Role, Advisory/consultancy: Merck, Intellisphere LLC, Natera, Bristol-Myers Squibb, Exelixis; Financial Interests, Institutional, Research Grant: Genentech, Bristol-Myers Squibb, Merck, Calithera Biosciences, Pfizer, Jounce Therapeutics, Nektar, Exelixis, Clinigen Group; Financial Interests, Personal, Other: Patent Pending - “Binding Proteins Specific for 5T4 and Uses Thereof”.