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Inhibition of hypoxia-inducible factor-2α in renal cell carcinoma with belzutifan: a phase 1 trial and biomarker analysis

An Author Correction to this article was published on 27 August 2021

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Abstract

Hypoxia-inducible factor-2α (HIF-2α) is a transcription factor that frequently accumulates in clear cell renal cell carcinoma (ccRCC), resulting in constitutive activation of genes involved in carcinogenesis. Belzutifan (MK-6482, previously known as PT2977) is a potent, selective small molecule inhibitor of HIF-2α. Maximum tolerated dose, safety, pharmacokinetics, pharmacodynamics and anti-tumor activity of belzutifan were evaluated in this first-in-human phase 1 study (NCT02974738). Patients had advanced solid tumors (dose-escalation cohort) or previously treated advanced ccRCC (dose-expansion cohort). Belzutifan was administered orally using a 3 + 3 dose-escalation design, followed by expansion at the recommended phase 2 dose (RP2D) in patients with ccRCC. In the dose-escalation cohort (n = 43), no dose-limiting toxicities occurred at doses up to 160 mg once daily, and the maximum tolerated dose was not reached; the RP2D was 120 mg once daily. Plasma erythropoietin reductions were observed at all doses; erythropoietin concentrations correlated with plasma concentrations of belzutifan. In patients with ccRCC who received 120 mg once daily (n = 55), the confirmed objective response rate was 25% (all partial responses), and the median progression-free survival was 14.5 months. The most common grade ≥3 adverse events were anemia (27%) and hypoxia (16%). Belzutifan was well tolerated and demonstrated preliminary anti-tumor activity in heavily pre-treated patients, suggesting that HIF-2α inhibition might offer an effective treatment for ccRCC.

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Fig. 1: Efficacy results of the ccRCC cohort.

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Merck Sharp & Dohme (MSD), a subsidiary of Merck & Co., Inc., is committed to providing qualified scientific researchers access to anonymized data and clinical study reports from the company’s clinical trials for the purpose of conducting legitimate scientific research. MSD is also obligated to protect the rights and privacy of trial participants and, as such, has a procedure in place for evaluating and fulfilling requests for sharing company clinical trial data with qualified external scientific researchers. The MSD data sharing website (available at http://engagezone.msd.com/ds_documentation.php) outlines the process and requirements for submitting a data request. Applications will be promptly assessed for completeness and policy compliance. Feasible requests will be reviewed by a committee of MSD subject matter experts to assess the scientific validity of the request and the qualifications of the requestors. In line with data privacy legislation, submitters of approved requests must enter into a standard data sharing agreement with MSD before data access is granted. Data will be made available for request after product approval in the United States and European Union or after product development is discontinued. There are circumstances that might prevent MSD from sharing requested data, including country- or region-specific regulations. If the request is declined, it will be communicated to the investigator. Access to genetic or exploratory biomarker data requires a detailed, hypothesis-driven statistical analysis plan that is collaboratively developed by the requestor and MSD subject matter experts; after approval of the statistical analysis plan and execution of a data sharing agreement, MSD will either perform the proposed analyses and share the results with the requestor or will construct biomarker co-variates and add them to a file with clinical data that is uploaded to an analysis portal so that the requestor can perform the proposed analyses.

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Acknowledgements

Editorial assistance was provided by R. Steger and M. Grzywacz of ApotheCom. This assistance was funded by Merck Sharp & Dohme, a subsidiary of Merck & Co., Inc. Funding for this research was provided by Merck Sharp & Dohme, a subsidiary of Merck & Co., Inc. T.K.C. is supported in part by the Dana–Farber/Harvard Cancer Center Kidney Specialized Program of Research Excellence and program, the Kohlberg Chair at Harvard Medical School, the Trust Family, Michael Brigham, and Loker Pinard Funds for Kidney Cancer Research at Dana–Farber Cancer Institute, and by various grants from the National Cancer Institute, Department of Defense, and foundations. Authors were also supported by NCI grants P50 CA101942 and U01 CA236489 to D.F.M. and T.K.C.

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Contributions

T. K. C. contributed to the conception and design of the study, data analysis and interpretation, drafting and revising of the manuscript, provision of study patients and administrative, logistical or technical support and provided final approval to submit the manuscript for publication. T. M. B. contributed to the data acquisition and interpretation, drafting and revising of the manuscript and provision of study patients and provided final approval to submit the manuscript for publication. K. P. P. contributed to the conception and design of the study, data analysis and interpretation, drafting and revising of the manuscript and provision of study patients and provided final approval to submit the manuscript for publication. E. R. P. contributed to the data acquisition, analysis and interpretation, drafting and revising of the manuscript and provision of study patients and provided final approval to submit the manuscript for publication. J. R. M. contributed to the data acquisition and interpretation, drafting and revising of the manuscript and provision of study patients and provided final approval to submit the manuscript for publication. D. F. M. contributed to the data acquisition and interpretation, drafting and revising of the manuscript and provision of study patients and provided final approval to submit the manuscript for publication. M. D. M. contributed to the data acquisition, analysis and interpretation, drafting and revising of the manuscript and provision of study patients and provided final approval to submit the manuscript for publication. L. J. A. contributed to the data acquisition, analysis and interpretation, drafting and revising of the manuscript and provision of study patients and provided final approval to submit the manuscript for publication. S. T. contributed to the conception of the study design and data interpretation and drafting and revising of the manuscript and provided final approval to submit the manuscript for publication. R. F. P. contributed to the conception of the study design and data interpretation and drafting and revising of the manuscript and provided final approval to submit the manuscript for publication. N. J. Z. contributed to the conception of the study design, data acquisition, analysis and interpretation and drafting and revising of the manuscript, provided administrative, logistical or technical support and provided final approval to submit the manuscript for publication. E. J. contributed to the conception of the study design, data analysis and interpretation, drafting and revising of the manuscript and provision of study patients and provided final approval to submit the manuscript for publication.

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Correspondence to Toni K. Choueiri or Eric Jonasch.

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Competing interests

T. K. C. has served on advisory boards, provided consultation and received clinical trial grants from AstraZeneca, Bristol Myers Squibb, Exelixis, Pfizer, Janssen, Merck Sharp & Dohme, Eli Lilly, Eisai, Novartis, GlaxoSmithKline, Infinity, Surface Oncology and EMD Serono; has stock ownership in Pionyr and Tempest; has a patent pending and issues related to biomarkers of immuno-oncology; and sits on the National Comprehensive Cancer Network (NCCN) kidney panel. T. K. C. received royalties from Up-To-Date. T. K. C. received fees for continuing medical education (CME)-accredited activities such as Medscape, OncLive, Research to Practice and others. T. M. B. has received research funding from Peloton Therapeutics, a wholly owned subsidiary of Merck & Co., Inc., Daiichi Sankyo, MedPacto, Incyte, Mirati Therapeutics, MedImmune, AbbVie, AstraZeneca, MabVax, Stemline Therapeutics, Merck Sharp & Dohme, Eli Lilly, GlaxoSmithKline, Novartis, Genentech, Deciphera, Merrimack, Immunogen, Phosplatin Therapeutics, Calithera Biosciences, Koltan Pharmaceuticals, Principia Biopharma, Immunocore, Roche, Aileron Therapeutics, Bristol Myers Squibb, Amgen, Onyx, Sanofi, Boehringer Ingelheim, Astellas Pharma, Five Prime Therapeutics, Jacobio, Top Alliance Biosciences, Janssen, Clovis Oncology, Takeda, Karyopharm Therapeutics, Foundation Medicine, ARMO BioSciences, Leap Therapeutics, Ignyta, Moderna Therapeutics, Pfizer, Loxo and Bayer; has been a consultant for Eli Lilly, Bristol Myers Squibb, Foundation Medicine, Leap Therapeutics, Ignyta, Moderna Therapeutics, Pfizer, Loxo, Bayer, Guardant Health, Exelixis and Blueprint Medicines; and served on speaker bureaus for Bayer and Eli Lilly. K. P. P. has received research funding from Merck Sharp & Dohme, ARMO BioSciences, ArQule, Amgen, Calithera Biosciences, Incyte, Jounce, ADC Therapeutics, 3D Medicines, Syros Pharmaceuticals, Mersana, MabSpace Biosciences, Bayer, Daiichi Sankyo, AnHeart, Basilea, F-star, Linnaeus, Mirati and Tempest Therapeutics; and has served on advisory boards for ArQule, Bayer and Basilea. E. R. P. has received research funding from Peloton Therapeutics, a wholly owned subsidiary of Merck & Co., Inc., Acceleron, AstraZeneca, Bristol Myers Squib, Merck Sharp & Dohme, Pfizer, Astellas and Genentech; has been a consultant for Bristol Myers Squibb, Exelixis, Flatiron, Genentech, Incyte, Janssen, Merck Sharp & Dohme and Seattle Genetics; has served on data safety monitoring committees for AstraZeneca, Infinity Pharma and Pfizer; has a patent pending for methods for screening patients with muscle invasive bladder cancer for responsiveness to neoadjuvant chemotherapy; and has received fees for CME-accredited activities for AUA, Clinical Care Options, Fox Chase Cancer Center, Georgetown, GU ASCO, Medscape, Mt. Sinai School of Medicine, NCCN, Ohio State University, Omniprex, OncLive, PER, PriME Oncology, Research to Practice, Spire Learning and the University of Pennsylvania. J. R. M. has received research funding from Peloton Therapeutics, a wholly owned subsidiary of Merck & Co., Inc., Corvus Pharmaceuticals, Silagen, Tizona, Eisai, Genentech, Pfizer, Vyriad, Replimune, Calithera Biosciences, Rexahn Pharmaceuticals, Seattle Genetics, Astellas, Tocagen, Novartis and Eli Lilly; and has served on an advisory board for Exelixis. D. F. M. has received research funding from Bristol Myers Squibb, Merck Sharp & Dohme, Genentech, Pfizer, Exelixis, X4 Pharma and Alkermes; and has been a consultant for Bristol Myers Squibb, Pfizer, Merck Sharp & Dohme, Alkermes, EMD Serono, Eli Lilly and Iovance Biotherapeutics. M. D. M. has received research funding from Merck Sharp & Dohme and has served on advisory boards for Merck Sharp & Dohme, Pfizer, Novartis, Exelixis and Eisai. L. J. A. has nothing to disclose. S. T. is an employee of Peloton Therapeutics, a wholly owned subsidiary of Merck & Co., Inc. R. F. P. is an employee of and has stock ownership in Merck Sharp & Dohme, a subsidiary of Merck & Co., Inc. N. J. Z. was an employee of Merck & Co., Inc. at the time of this analysis. E.J. has received research funding from Arrowhead Pharmaceuticals, research funding and consultation fees from Aravive, Merck, and Novartis, consultation fees from Aveo, Eisai, Ipsen, NiKang and Pfizer, and has received royalties from UpToDate and consultation fees from Elsevier (PracticeUpdate).

Additional information

Peer review information Nature Medicine thanks Ignacio Duran and the other, anonymous reviewers for their contribution to the peer review of this work. Editor recognition statement: Saheli Sadanand was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Extended data

Extended Data Fig. 1 Patient disposition.

AE: adverse event; BID: twice daily; ccRCC: clear cell renal cell carcinoma; DLT: dose-limiting toxicity; QD: once daily; PD: progressive disease.

Extended Data Fig. 2 Mean (SD) plasma concentrations of belzutifan at (a) week 1, (b) week 3, and (c) all weeks.

BID: twice daily; QD: once daily; SD: standard deviation. n includes patients who had a predose assessment and at least one postdose assessment. Data are presented as mean values ± SD.

Extended Data Fig. 3 Mean (SD) plasma concentrations of PT3317 at (a) week 1, (b) week 3, and (c) all weeks.

BID: twice daily; QD: once daily; SD: standard deviation. n includes patients who had a predose assessment and at least one postdose assessment. Data are presented as mean values ± SD.

Extended Data Fig. 4 Mean (SD) percentage change in erythropoietin (mIU/ml) from baseline for the first 8 days.

BID: twice daily; QD: once daily; SD: standard deviation. n includes patients who had a predose assessment and at least one postdose assessment. *Erythropoietin concentration from baseline for the 160-mg QD dose cohort is based on the values after excluding one patient who had a very low erythropoietin baseline measurement of 2.8 mIU/ml, which is lower than the typical lower value of normal physiological reference range (3.5 mIU/ml) and very close to the lower limit of quantitation of 2.5 mIU/ml. This possibly erroneous low baseline value resulted in apparent large increases in percentage change from baseline in all the postbaseline values for this patient.

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Choueiri, T.K., Bauer, T.M., Papadopoulos, K.P. et al. Inhibition of hypoxia-inducible factor-2α in renal cell carcinoma with belzutifan: a phase 1 trial and biomarker analysis. Nat Med 27, 802–805 (2021). https://doi.org/10.1038/s41591-021-01324-7

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