Cabozantinib (XL184) showed activity in patients with Medullary Thyroid Cancer (MTC) and had an acceptable safety profile, reports a phase I study in the Journal of Clinical Oncology.

While the development of antiangiogenic agents targeting vascular endothelial growth factor (VEGF) and VEGFR signalling pathways have led to key advances in the treatment of cancer, survival improvements have been modest.

It is now thought that agents targeting the VEGF signalling pathways may be promoting tumour aggressiveness through up regulation of MET, a pro invasive receptor tyrosine kinase (RTK) implicated in tumour growth, metastasis and angiogenesis. Cabozantinib is a potent inhibitor of RTKs, including MET, VEGFR2, and RETI, with preclinical studies showing that cabozantinib exhibited significant antiangiogenic and antitumor activity in a broad range of tumour models, including a model of MTC .

In the current study Razelle Kurzrock and colleagues from MD Anderson Cancer Center (Houston, Texas) undertook a phase 1 dose escalating study of cabozantinib in 85 patients with advanced solid tumours, including 37 patients (44%) with MTC.

Results show that of the 35 patients with MTC with measurable disease an objective response was achieved in 10 (29%, 95% CI, 15% to 45%). Five of the 10 responders had a partial response at the first radiologic assessment and responses occurred most commonly at the 175-mg dose level. Stable disease of at least 6 months duration (range, 6.4 to 31.1 months) was observed in 15 (41%) of the 37 patients with MTC.

Dose-limiting toxicities were grade 3 palmar plantar erythrodysesthesia (PPE), mucositis, and AST,

ALT, and lipase elevations and grade 2 mucositis that resulted in dose interruption and reduction.

"This phase I study of cabozantinib demonstrated that the drug is active in MTC, with an acceptable spectrum of toxicity," wrote the authors, adding that future studies will evaluate the need for administration of the drug in a fasting stage. An international phase III study of cabozantinib is currently ongoing in patients with progressive MTC.

Reference

R Kurzrock, S Sherman, D Ball, et al. Activity of XL184 (Cabozantinib), an Oral Tyrosine Kinase Inhibitor, in Patients With Medullary Thyroid Cancer, JCO, Doi/10.1200/JCO.2010.32.4145