Chapter 21 – Cabozantinib

Cabozantinib (Cometriq, Exelixis) is a quinoline derivative tyrosine kinase inhibitor. After recognizing the orphan status in 2010, the Food and Drug Administration (FDA) granted approval in 2012 for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC). In 2014, the European Medicines Agency (EMA) granted conditional approval for the treatment of adult patients with progressive, unresectable locally advanced or metastatic MTC. Cabozantinib resulted particularly active on VEGFR2 (IC50 0.035 nM), followed by MET (1.8 nM), KIT (4.6 nM), VEGFR-3 (6.0 nM), AXL (7 nM), TRKB (7 nM), RET (9.8 nM), VEGFR-1 (12.2 nM), TIE2 (14.3 nM), and FLT3 (14.4 nM). All of these receptor tyrosine kinases are affected within the range of concentrations clinically achievable. Cabozantinib is the first molecule in the class of RET/VEGFR2 inhibitors to inhibit MET. The initial safety assessment was conducted on 323 MTC patients of the Phase III Study XL184-301 (214 exposed to 140 mg/d; 109 placebo). The safety profile of cabozantinib in MTC patients, as well as in a number of off-label investigations, was remarkably consistent across studies and had all the typical hallmarks of an angiogenic inhibitor. Cutaneous disorders (hand-foot skin reaction, rash), GI toxicities (diarrhea, mucositis, perforation/fistula, abscess), hemorrhage, and hypertension are the prominent adverse event (AE) categories. A black box warning for perforation, fistulas, and hemorrhage was issued at approval. Other common events include decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, abdominal pain, and constipation. Hematologic (lymphopenia, neutropenia, thrombocytopenia) and biochemistry (AST/ALT/bilirubin/ALP elevations, hypocalcemia, hypophosphatemia) abnormalities are also common. The most common experienced severe AEs are pneumonia, mucosal inflammation, hypocalcaemia, dysphagia, dehydration, and hypertension. Other concerning events are arterial thromboembolic events (cardiac, cerebral, pulmonary), wound complications, proteinuria (nephrotic syndrome), osteonecrosis of the jaw, reversible posterior leukoencephalopathy syndrome, and potential embryotoxicity.