Introduction:

The first-in-class hypoxia-inducible factor-2α (HIF-2α) inhibitor belzutifan is approved in the United States for the treatment of adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system hemangioblastomas, or pancreatic neuroendocrine tumors not requiring immediate surgery and for adult patients with advanced RCC following a PD-(L)1 inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor. Belzutifan has a unique mechanism of action and a distinct adverse event profile that includes anemia and hypoxia. We characterized the safety profile of belzutifan monotherapy and associated adverse events (AE) management strategies in a post hoc pooled analysis of patients with previously treated advanced clear cell RCC who participated in the phase 1 LITESPARK-001 (NCT02974738), phase 3 LITESPARK-005 (NCT04195750), and phase 2 LITESPARK-013 (NCT04489771) trials and patients with VHL disease-associated RCC enrolled in the phase 2 LITESPARK-004 trial (NCT03401788).

Methods:

All patients who received ≥1 dose of belzutifan 120 mg by mouth once daily across the 4 trials were included in the pooled population. AE severity was graded per the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03 or 5.0, and was descriptively summarized.

Results:

Overall, 576 patients were included (LITESPARK-001, n=58 [3 patients had non-RCC advanced solid tumors]; LITESPARK-005, n=381; LITESPARK-013, n=76; and LITESPARK-004, n=61). Of 576 patients, 99.3% experienced ≥1 all-cause AE and 61.6% experienced ≥1 grade 3-5 AE. AEs led to dose modification (reduction/interruption/discontinuation) in 50.0% of patients; 6.4% discontinued treatment due to AEs. The most common AEs were anemia (including decreased hemoglobin; 84.2%; grade 3 or 4, 28.8%) and fatigue (42.7%; grade 3, 2.8%). Hypoxia occurred in 16.3% of patients (grade 3 or 4, 12.2%). Adverse drug reactions (AEs considered associated with belzutifan) are summarized in the table. Among patients with anemia or decreased hemoglobin, 22.9% were treated with erythropoiesis-stimulating agents (ESA) only, 17.5% with blood transfusions only, and 12.8% with ESA and blood transfusions. Among patients with hypoxia, 70.2% received supplemental oxygen. Grade 3-5 treatment-related AEs occurred in 37.7% of patients (grade 5, n=1 [multiple organ dysfunction syndrome]).

Conclusion:

This post hoc pooled analysis showed that belzutifan monotherapy had a generally manageable safety profile in patients with advanced RCC; few patients discontinued treatment due to AEs. Median time to first onset occurred within the first 3 months of treatment. As expected, anemia and hypoxia were among the most frequent AEs and were generally manageable with dose modification and/or treatment with ESA/blood transfusions for anemia and supplemental oxygen for hypoxia. To date, this is the largest pooled safety dataset for a HIF-2α inhibitor.

Funding: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA