Inhibition of hypoxia-inducible factor-2α in renal cell carcinoma with belzutifan: a phase 1 trial and biomarker analysis
| العنوان: | Inhibition of hypoxia-inducible factor-2α in renal cell carcinoma with belzutifan: a phase 1 trial and biomarker analysis |
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| المؤلفون: | Rodolfo F. Perini, M. Dror Michaelson, David F. McDermott, Eric Jonasch, Todd M. Bauer, Jaime R. Merchan, Toni K. Choueiri, Leonard Joseph Appleman, Kyriakos P. Papadopoulos, Sanjay Thamake, Elizabeth R. Plimack, Naseem J. Zojwalla |
| المصدر: | Nature Medicine. 27:802-805 |
| بيانات النشر: | Springer Science and Business Media LLC, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | medicine.medical_specialty, business.industry, Anemia, General Medicine, Hypoxia (medical), medicine.disease, Gastroenterology, General Biochemistry, Genetics and Molecular Biology, Clear cell renal cell carcinoma, Pharmacokinetics, Hypoxia-inducible factors, Erythropoietin, Renal cell carcinoma, Internal medicine, Pharmacodynamics, Medicine, medicine.symptom, business, medicine.drug |
| الوصف: | 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. A first-in-human trial of hypoxia-inducible factor (HIF)-2α inhibitor belzutifan (MK-6482) has a favorable safety profile and shows promising clinical activity for the treatment of patients with renal cell carcinoma who have been heavily pre-treated. |
| تدمد: | 1546-170X 1078-8956 0297-4738 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_________::f3bc1061878d1e832ec6d6b3cadebcfbTest https://doi.org/10.1038/s41591-021-01324-7Test |
| حقوق: | CLOSED |
| رقم الانضمام: | edsair.doi...........f3bc1061878d1e832ec6d6b3cadebcfb |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 1546170X 10788956 02974738 |
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