A phase 2 open-label study of belzutifan (a HIF-2α inhibitor) monotherapy in patients with advanced/metastatic pheochromocytoma/paraganglioma or pancreatic neuroendocrine tumors

#3405

Introduction: Patients with advanced pheochromocytoma/paraganglioma (PPGL) or pancreatic neuroendocrine tumor (panNET) are in need of novel targeted therapies. Hypoxia-inducible factor 2α (HIF-2α) is one of the key oncogenic drivers in neuroendocrine tumors like PPGL and somatostatinomas. Hypoxia signaling pathway alterations or other mechanisms that stabilize HIFs are common in some PPGLs and panNETs. Belzutifan (MK-6482), a HIF-2α inhibitor, has shown antitumor activity in advanced renal cell carcinoma and von Hippel-Lindau (VHL) disease–associated tumors, including panNET.

Aim(s): To evaluate efficacy and safety of belzutifan in patients with advanced PPGL or panNET.

Materials and methods: This open-label, multicenter, single-arm, phase 2 study (NCT04924075) is enrolling patients aged ≥12 y (body weight ≥40 kg if aged 12–17 y) with histopathologically documented, unresectable, locally advanced/metastatic PPGL (BP ≤150/90 mm Hg [≤135/85 mm Hg if adolescent]) (cohort A1) or histopathologically documented, advanced/metastatic well-differentiated G1/G2 (2017 WHO criteria) panNET with progression on prior targeted therapy (cohort A2). Other eligibility criteria include PD ≤12 months from screening, measurable disease per RECIST v1.1 by blinded independent central review (BICR), ECOG PS ≤1, and archival/new tumor sample for biomarker analysis. Approximately 140 patients (70/cohort) will be enrolled and receive belzutifan 120 mg QD until PD or unacceptable toxicity. Tumor imaging occurs initially at week 9, then Q8W through week 49, and Q12W thereafter. The primary study endpoint is ORR per RECIST v1.1 by BICR. Secondary endpoints are duration of response, time to treatment response, disease control rate, PFS, OS, and safety. Enrollment began in August 2021.

Conference:

Presenting Author:

Authors: Jimenez C, Hadoux J, Del Rivero J, Das S, Iliopoulos O,

Keywords: pheochromocytoma, paraganglioma, pancreatic neuroendocrine tumor, belzutifan, MK-6482, metastatic,