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 RCC

( The European Society of Medical Oncology (ESMO) 2021 annual meeting’s non-prostate cancer mini-oral session included a presentation by Dr. David McDermott discussing results of a phase 2 study of belzutifan + cabozantinib for the treatment of advanced clear cell renal cell carcinoma (RCC). HIF transcription activates several genes associated with clear cell RCC, including VEGF. Cabozantinib, a VEGF, AXL, and MET inhibitor, is approved for advanced clear cell RCC, with VEGF blockade leading to tumor hypoxia and HIF activation. Belzutifan is a potent, selective small molecular inhibitor, thus targeting both the HIF-2alpha and the VEGF pathways may improve outcomes for patients with advanced clear cell RCC:



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

Patients for this trial had advanced clear cell RCC and had previously received immunotherapy and ≤2 systemic treatment regimens. Initially, a safety review committee evaluated the first 6 patients enrolled in either cohort for 21 days to determine the recommended phase II dose. The schema for this trial is as follows:


The primary endpoint was ORR (complete response + partial response) per RECIST v1.1 by investigator review. Secondary endpoints were durable control rate (complete response + partial response + stable disease), duration of response, PFS, and OS. For this preliminary analysis, efficacy was evaluated in patients who received ≥1 dose of treatment and had an opportunity for ≥6 months of follow-up. Additionally, safety was evaluated in all patients.

In the first 6 patients enrolled, 1 had dose-limiting toxicity (hand-foot syndrome); belzutifan 120 mg plus cabozantinib 60 mg was determined to be the recommended phase II dose. Overall, 52 patients were enrolled in cohort 2 and were included in the safety analysis set. The median age was 63 years of age (range: 43-79), 73.1% were male, and 78.8% were IMDC intermediate/poor risk. In all patients, 28 (54%) previously received 1 line of therapy and 24 (46%) previously received 2 lines of therapy. Median time from enrollment to data cutoff was 15.4 months (range, 8.7-30.6).

The ORR was 28.8% (all confirmed partial responses) and durable control rate was 92.3%, with no appreciable differences across IMDC risk category and prior anticancer therapy: 


Overall, 86.5% of patients had a reduction in target lesion size. Median duration of response was not reached (range, 3.7+ to 14.8+ months) and all responses were ongoing as of the data cutoff date. Median PFS was 16.8 months (95% CI, 9.2 to not reached), and PFS rate at 12 months was 65%; OS rate at 12 months was 81%. In all patients, 98% had a treatment-related adverse event, with most events (92%) being grade 1 or 2. The incidence of grade 3 treatment-related adverse events ≥10% were hypertension (23%), anemia (12%), and fatigue (12%). Two (4%) patients experienced grade 3 hypoxia. There were no grade 4 or 5 treatment-related adverse events. Discontinuations owing to treatment-related adverse events occurred in 6 patients (12%) for belzutifan and 8 patients (15%) for cabozantinib.

Dr. McDermott concluded his presentation with the following take-home messages:

  • With a median follow-up of 15.4 months, belzutifan + cabozantinib showed promising activity in all patients with previously treated metastatic clear cell RCC who were enrolled in cohort 2
  • Belzutifan + cabozantinib side effects were manageable
  • Targeting the underlying pathology of the disease through HIF-2alpha and VEGF inhibition may be effective treatment for patients with metastatic clear cell RCC
  • The study is ongoing in patients who received prior systemic treatment, with an additional cohort of untreated patients (cohort 1) actively recruiting
  • A phase 3 study of belzutifan + lenvatinib versus cabozantinib is recruiting patients with advanced clear cell RCC who received prior immunotherapy and up to two prior systemic regimens

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

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2021 European Society for Medical Oncology (ESMO) Annual Congress 2021, Thursday, Sep 16, 2021 – Tuesday, Sep 21, 2021.