On May 14, the U.S. Food and Drug Administration approved the oral hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor belzutifan (Welireg) for patients aged 12 years and older with locally advanced, unresectable, or metastatic pheochromocytoma or paraganglioma (PPGL). This represents the first FDA approval of an oral therapy for PPGL.
LITESPARK-015
Efficacy was evaluated in LITESPARK-015 (ClinicalTrials.gov identifier NCT04924075), an open-label, multicohort trial. Cohort A1 was conducted in 72 patients with measurable disease verified by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, documented histopathological PPGL diagnosis, and locally advanced or metastatic disease not amenable to surgery or curative treatment. Patients with concomitant hypertension with adequately controlled blood pressure were required to have no change in antihypertensive medications for at least 2 weeks prior to study initiation. Patients with carcinomatous meningitis were excluded.
The major efficacy outcome measure was objective response rate by BICR using RECIST v1.1. Additional efficacy outcome measures were duration of response and the number of patients who had a reduction in at least one antihypertensive medication by at least 50% maintained for at least 6 months. The objective response rate was 26% (95% confidence interval [CI] = 17%–38%). Median duration of response was 20.4 months (95% CI = 8.3 months to not reached). Of the 60 patients on baseline antihypertensive medications, 19 (32%; 95% CI = 20%–45%) had a reduction in at least one antihypertensive medication by at least 50% for at least 6 months.
The most common adverse reactions (occurring in ≥ 25% of patients), including laboratory abnormalities, were anemia, fatigue, musculoskeletal pain, decreased lymphocytes, increased alanine aminotransferase, increased aspartate aminotransferase, increased calcium, dyspnea, increased potassium, decreased leukocytes, headache, increased alkaline phosphatase, dizziness, and nausea.
The recommended belzutifan dose for adults is 120 mg administered orally once daily; the recommended dose for pediatric patients 12 years and older is based on body weight. For pediatric patients weighing ≥ 40 kg, the dose is 120 mg orally once daily, for those weighing < 40 kg, the dose is 80 mg orally once daily. Continue belzutifan until disease progression or unacceptable toxicity.
This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. This application was granted Priority Review.
