Belzutifan, an oral, novel hypoxia-inducible factor (HIF)-2α inhibitor, showed encouraging activity as a single agent in heavily pretreated patients with advanced clear-cell renal-cell carcinoma (RCC) associated with von Hippel-Lindau (VHL) disease, as well as impressive tumor shrinkage when used in combination with cabozantinib (Cabometyx) in separate studies presented at the 2021 ASCO Genitourinary Cancers Symposium.
Belzutifan represents a novel approach to RCC, targeting HIF-2α, which impairs hypoxic signaling in cancer cells. Targeting HIF-2α blocks the transcription of several genes involved in cancer-cell growth, proliferation, and abnormal blood vessel formation. This approach has shown promise in the 90% of patients with clear-cell RCC who lack the VHL gene and have an abnormality in HIF.
In March 2021, the FDA granted belzutifan a priority review for the New Drug Application for the treatment of VHL-associated RCC in patients who do not require immediate surgery.
Single-Agent Phase 1/2 Study
Belzutifan achieves continued efficacy over time in patients with VHL-associated clear-cell RCC, according to results of a single-agent phase 1/2 study.
“This study validates the growing preclinical and clinical evidence for HIF-2α inhibition as a promising approach to RCC,” said lead investigator Todd Michael Bauer, MD, Sarah Cannon Research Institute/Tennessee Oncology, Nashville.
“With this drug, we don’t see quick drops in tumor volume, but we often see small tumor shrinkage with each successive scan, and we see great clinical benefit. Belzutifan can work very well over a prolonged period,” Dr Bauer added.
A total of 55 patients with metastatic RCC were included in the expansion cohort; 44 patients stopped treatment (60% because of disease progression), and 11 patients are continuing with the treatment in the study. Treatment with belzutifan was continued until unacceptable side effects or disease progression. Dr Bauer presented efficacy data on 41 patients evaluable for response, with a median follow-up of 27.7 months.
The data are still preliminary, but in these 41 patients, the rate of disease control was 83% in patients who received 160 mg of belzutifan, and 43% in patients who received 200 mg of the drug.
Next, Dr Bauer presented results in all 55 patients in the clear-cell RCC cohort. The median patient age was 62 years. Patients were predominantly male, and all but 1 had Eastern Cooperative Oncology Group performance status 0-1. Most patients had intermediate- or poor-risk disease, most received previous therapies (63% received ≥3 previous lines of therapy), including 91% who received a VEGFR kinase inhibitor and 80% who received an immunotherapy checkpoint inhibitor. A total of 39 (71%) patients received both therapies.
All patients had an adverse event of any grade; 96% had a treatment-related adverse event; 40% had grade 3 adverse events. “Only 2 patients had to discontinue due to a treatment-related adverse event—hypoxia,” Dr Bauer stated.
The objective response rate was 25%, of which 31% were in favorable-risk patients and 24% in intermediate-risk patients. Disease control rates were 92% and 76%, respectively, for the 2 risk categories.
For all risk categories, the median progression-free survival (PFS) was 1.45 months. No median was reached in the favorable-risk patients. For intermediate- and poor-risk patients, the median PFS was 11 months.
A phase 3 study of belzutifan monotherapy in previously treated patients is ongoing.
Belzutifan plus Cabozantinib Combination
In a separate ongoing phase 2 study, the combination of belzutifan and cabozantinib (Cabometyx) achieved 88% tumor shrinkage in target lesions and a 90% disease control rate in patients with previously treated advanced clear-cell RCC, according to preliminary results of 52 patients in cohort 2 of that study. Cohort 1 includes treatment-naïve patients and accrual is not completed.
“These very preliminary, interim results for the combination of belzutifan and cabozantinib showed promising activity in previously treated metastatic clear-cell RCC. We believe that targeting the underlying pathology of clear-cell RCC, targeting the transcription factor HIF-2α with belzutifan, and targeting downstream with the VEGF receptor kinase inhibitor, cabozantinib, could be an effective treatment for patients with metastatic clear-cell RCC,” said lead investigator Toni K. Choueiri, MD, Director, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Boston, MA.
A total of 41 patients received ongoing treatment and were evaluable for efficacy at the time of the meeting, and 9 (22%) patients had a confirmed objective partial response. Another 5 (12%) patients had unconfirmed partial responses. In all, 28 (68%) patients had stable disease as best response. The median duration of response was not reached, and all confirmed responses were still ongoing as of data cutoff on October 15, 2020.
Eligible patients received 120 mg belzutifan plus 60 mg cabozantinib orally, once daily, for 21 days. The efficacy analysis includes patients who received at least 1 dose of the combination and had at least 6 months of follow-up. The PFS rate was 78% at 6 months, and 65% at 12 months. The median PFS was 16.8 months. Dr Choueiri pointed out that the median PFS was “not reliable” at this early time point.
Nearly all (98%) patients had any-grade treatment-related adverse events. Grade 3 events were common (60%).
In all, 6 (12%) patients discontinued belzutifan because of treatment-emergent adverse events and 8 (15%) discontinued cabozantinib treatment; 7 (13%) patients had serious treatment-related adverse events. No deaths were reported from treatment-related adverse events.
“The side effects of belzutifan are manageable. The vast majority were grade 1 or 2. The safety is consistent with the individual profile of each agent,” Dr Choueiri noted.
In July 2020, the FDA granted a breakthrough therapy designation to belzutifan for the treatment of patients with VHL-associated RCC and nonmetastatic RCC tumors <3 cm, unless immediate surgery is required. The FDA also granted belzutifan an orphan drug designation for VHL disease.