ESMO 2021: Phase 2 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)

( VEGF-targeting therapies have been shown to induce hypoxia in preclinical models of renal cell carcinoma (RCC), thus activating signaling through the hypoxia-inducible factors. In this phase 2 study, Dr. McDermott and colleagues tested the hypothesis that dual inhibition of both VEGF and downstream HIF signaling would provide anti-tumor for patients with clear cell RCC.


To do so, they utilized VEGFR blockade with cabozantinib, and the HIF-2alpha inhibitor belzutifan. The study design is indicated below, and this presentation was focused on the results of cohort 2, which included patients who had received prior treatment for their advanced ccRCC. The primary endpoint was overall response rate with combination therapy.


The clinical characteristics of the 52 patient cohort are shown below. Patients were predominantly male with good performance status, with 79% of patients classified as having intermediate or poor-risk by IMDCC criteria. The majority of patients had received only 1 prior line of anti-cancer therapy.



The overall response rate was 28.8% (15 patients), with one patient having a complete response. The overall disease control rate was 92.3%, with 87% of patients experiencing a reduction in target lesion size. The median time to response was 2.1 months, and the median duration of response was not reached. At the 12-month point, 60% of patients had not progressed, and 81.3% of patients were still alive.

Overall, 21.2% of patient had to discontinue trial therapy due to treatment-emergence adverse events, roughly split between belzutifan and cabozantinib. One patient had a grade 5 adverse event of respiratory failure, which was potentially related to therapy by investigator assessment.


Dr. McDermott concluded his presentation by suggesting that combination belzutifan and cabozantinib showed promising clinical activity in pre-treated ccRCC patients, an effect that seemed to be consistent across IMDC risk categories. Overall, the dual pathway targeting of HIF and VEGF is evaluated in a phase 3 study of lenvantinib and belzutifan (NCG04586231).

Presented by: David F. McDermott, MD, Beth Israel Deaconess Medical Center, Boston, MA

Written by: Alok Tewari, MD, PhD – Genitourinary Medical Oncologist, Instructor in Medicine, Dana-Farber Cancer Institute, Harvard Medical School, Twitter: @aloktewar during the 2021 European Society for Medical Oncology (ESMO) Annual Congress 2021, Thursday, Sep 16, 2021 – Tuesday, Sep 21, 2021.