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The FDA approved belzutifan, the first oral treatment for pheochromocytoma and paraganglioma, offering a new treatment pathway for patients with these rare tumors.
The FDA has announced the regulatory approval of belzutifan (Welireg, Merck & Co), an oral hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor, for the treatment of adult and pediatric patients 12 years and older with locally advanced, unresectable, or metastatic pheochromocytoma or paraganglioma (PPGL), becoming the first oral therapy approved for the treatment of PPGL, according to the FDA.1,3
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In LITESPARK-015 (NCT04924075), an open-label, multi-cohort trial, patients with PGGL demonstrated positive objective response rate (ORR) and duration of response (DOR) when treated with belzutifan. According to the investigators, ORR was 26% (95% CI, 17-38), while median DOR was 20.4 months (95% CI, 8.3-NR). Importantly, of the 60 patients on baseline antihypertensive medications, 19 (32%; 95% CI, 20-45) had a reduction in at least 1 antihypertensive medication by at least 50% for at least 6 months.1,2
Earlier this year, belzutifan was granted priority review by the FDA based on the positive LITESPARK-015 trial results. “Pheochromocytoma and paraganglioma are rare tumors that form in and around the adrenal glands, and currently, there are no approved therapies available in the US for patients with this rare disease,” said Marjorie Green, MD, senior vice president and head of oncology, global clinical development at Merck Research Laboratories, in a news release upon the FDA’s granting of priority review. “We look forward to working with the FDA to…provide this critical option to these patients who urgently need new innovative therapies.”3
Trial Name: Belzutifan/MK-6482 for the Treatment of Advanced Pheochromocytoma/Paraganglioma (PPGL), Pancreatic Neuroendocrine Tumor (pNET), Von Hippel-Lindau (VHL) Disease-Associated Tumors, Advanced Gastrointestinal Stromal Tumor (wt GIST), or Solid Tumors With HIF-2α Related Genetic Alterations (MK-6482-015)
ClinicalTrials.gov ID: NCT04924075
Sponsor: Merck Sharp & Dohme LLC
Estimated Completion Date: June 4, 2029
Cohort A1 of the LITESPARK-015 trial featured 72 patients with measurable disease—verified by blinded independent central review—documented histopathological PPGL diagnosis, and locally advanced or metastatic disease that was not amenable to curative treatment or surgery. For patients with concomitant hypertension with adequately controlled blood pressure, they were required to not change their antihypertensive medication regimen for at least 2 weeks before initiating the trial.1
Common adverse events—those with an incidence of 25% or more—observed by the investigators included anemia, fatigue, musculoskeletal pain, increased calcium, headache, dizziness, increased potassium, and nausea. Belzutifan is recommended to be administered at a dose of 120 mg orally, once daily, for adults; recommended dosing for pediatric patients depends on their weight, according to the investigators. Those weighing 40 kg or more should be given 120 mg orally once daily, while for those below 40 kg, 80 mg orally once daily should be administered.1
Belzutifan has numerous other indications; most prominently, it is the first and only HIF-2α inhibitor to be approved in the United States for the treatment of adults with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system hemangioblastomas, or pancreatic neuroendocrine tumors (pNETs) not requiring immediate surgery. These indications were based in part on positive results from another study in the LITESPARK family, LITESPARK-004 (NCT03401788). In that trial, investigators determined that belzutifan showed antitumor activity in patients with VHL-disease-related neoplasms at a median follow-up of 29.3 months.4,5
The FDA has also approved belzutifan for the treatment of advanced renal cell carcinoma following PD-1 or PD-L1 inhibitor treatment. It became the first treatment option specifically for patients in this population whose disease has progressed following therapeutic alternatives, further expanding its portfolio.6
Health care providers and pharmacists utilizing belzutifan in their practice should closely monitor patients treated with the medication and report any serious adverse events to regulatory authorities. The FDA advises belzutifan to be continued until disease progression or unacceptable toxicity. In this vein, pharmacists should work with other members of a patient’s specialty care team to properly evaluate them regarding their condition and the feasibility of therapy continuing.1
