Background: Malignant pheochromocytomas and paragangliomas (PPG) are frequently hypervascular and associated with bone metastases. Cabozantinib is a potent anti-angiogenic tyrosine kinase inhibitor that also targets the c-met receptor. Cabozantinib could be an effective treatment for PPG.
Methods: Investigator initiative phase 2 clinical trial with Cabozantinib to treat patients with PPG. The trial has two branches: 1. Patients with measurable disease (n=14); 2. Patients with predominant/exclusive bone metastases (n=8). Patients require histological confirmation and demonstration of disease progression over one year. Patients receive Cabozantinib at initial dose of 60 mg daily with dose reduction to 40-20 mg depending on tolerability. Primary endpoint: objective response rate (ORR); secondary endpoints: progression free-survival (PFS), blood pressure control, quality of life, and safety.
Results: 11 patients have been enrolled. Median age=53 years, (range 37– 78); median number of previous systemic therapy=1 (range 0 – 1). Three patients with measurable disease achieved a partial response (>30% reduction) and three patients achieved moderate responses (15-30% reduction). 4 patients with predominant bone metastases exhibited disease stabilization (as per FDG-PET) and no skeletal related events. One patient had disease progression. ORR=43%; Clinical benefit rate=91%. Tumor shrinkage has been associated with blood pressure improvement and disappearance of diabetes mellitus. Trial PFS=11.1 months (range 0.9-22.1). Toxicity has led to a reduction of the dose of Cabozantinib from a starting dose of 60 mg to 40-20 mg daily in 8 patients. Most common toxicities have been grade 1-2 fatigue, dysgeusia, and hand and foot syndrome. No grade 4 or 5 adverse events related to Cabozantinib have been reported. No molecular predictor of response has been identified.
Conclusions: Preliminary data shows that Cabozantinib causes tumor shrinkage in patients with measurable disease and disease stabilization in patients with bone metastases. Cabozantinib seems a safe medication for patients with PPG.