Belzutifan for Advanced Pheochromocytoma or Paraganglioma

BACKGROUND Pheochromocytoma and paraganglioma are neoplasms originating in the adrenal medulla and extraadrenal paraganglia, respectively. Most cases of metastatic pheochromocytoma and paraganglioma are driven by dysregulation of the hypoxia-inducible factor 2α (HIF-2α) pathway. Belzutifan is a HIF-2α inhibitor that may provide antitumor activity in patients with advanced pheochromocytoma or paraganglioma. METHODS We conducted a phase 2, international, single-group trial involving 72 participants with locally advanced or metastatic pheochromocytoma or paraganglioma that was not amenable to surgery or curative-intent treatment. Participants received belzutifan at a dose of 120 mg once daily until the occurrence of progression, unacceptable toxic effects, or withdrawal from the trial. The primary end point was confirmed objective response (complete or partial response) as assessed by blinded independent central review. Secondary and other key end points included the duration of response, disease control, progression-free survival as assessed by blinded independent central review, overall survival, safety, and a reduction from baseline in antihypertensive medication. RESULTS At a median follow-up of 30.2 months (range, 23.3 to 37.6), the percentage of participants with a confirmed objective response was 26% (95% confidence interval [CI], 17 to 38) and the percentage of participants with disease control was 85% (95% CI, 74 to 92). The median duration of response was 20.4 months (95% CI, 8.3 to not reached), with a median duration of progression-free survival of 22.3 months (95% CI, 13.8 to not reached). Overall survival was 76% at 24 months. Among the 60 participants who were receiving antihypertensive medications, 19 (32%) had a reduction of at least 50% in the total daily dose of at least one antihypertensive medication for at least 6 months after starting treatment with belzutifan. Treatment-related adverse events occurred in 71 participants (99%); anemia of grade 3 was noted in 22% of the participants. Eight participants (11%) had treatment-related serious adverse events. CONCLUSIONS Belzutifan showed antitumor activity with durable responses in participants with advanced pheochromocytoma or paraganglioma.