Axitinib in Progressive Metastatic Pheochromocytoma and Paraganglioma: Results of a Phase II Study

Purpose: Metastatic pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine malignancies with limited systemic treatment options. Although inhibition of vascular endothelial growth factor (VEGF) signaling has demonstrated clinical benefit in metastatic PPGL, prospective data evaluating selective VEGF receptor inhibition remain limited. Axitinib is a potent and selective inhibitor of VEGFR-1, -2, and -3 with established activity in several solid tumors. We evaluated the efficacy and safety of axitinib in patients with progressive metastatic PPGL. Methods: Patients with progressive metastatic or unresectable PPGL were enrolled in a prospective, open-label, single-arm, phase II study (NCT03839498). Eligible patients had measurable disease according to RECIST version 1.1 and no prior treatment with a tyrosine kinase inhibitor. Axitinib was administered orally at an initial dose of 5 mg twice daily with protocol-defined dose modifications based on tolerability. The primary endpoints were objective response rate (ORR) and progression-free survival (PFS). Safety was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE). Results: Nineteen patients were enrolled, and 17 received study treatment. A confirmed partial response was achieved in 35.3% of treated patients. Median progression-free survival was 7.9 months (95% CI, 6.1-16.8 months), median duration of response was 7.4 months, median duration of treatment was 9.5 months, and median overall survival was 29 months. Hypertension, the most common treatment-related adverse event, occurring in 79% of patients, was effectively managed with antihypertensive therapy and dose modification. Other common treatment-related adverse events included fatigue, diarrhea, oral mucositis, and palmar-plantar erythrodysesthesia. No patient permanently discontinued treatment because of treatment-related toxicity. Conclusions: In patients with progressive metastatic PPGL, single-agent axitinib demonstrated clinically meaningful antitumor activity with a manageable safety profile. The observed efficacy compares favorably with sunitinib in this rare disease. The ability to maintain treatment despite predictable VEGF-associated toxicities suggests that axitinib represents a viable therapeutic option for patients with metastatic PPGL.