Cabozantinib is a
receptor tyrosine kinase inhibitor with activity against MET, VEGFR2, FLT3, c-KIT, and RET. Activity of
cabozantinib toward a broad range of
tumor models could be detected in several preclinical studies. Of note,
cabozantinib decreases
metastasis potential and
tumor invasiveness when compared with placebo or agents that target VEGFR and have no activity against MET. Clinical phase I and II studies with
cabozantinib have been conducted in various
malignancies including
medullary thyroid cancer (MTC), NSCLC, breast, ovarian, pancreatic, and
prostate cancer. In MTC, gain of function mutations of RET are central for
tumorigenesis. Hereditary forms of MTC (
MEN II) are caused by germline mutations of RET, in sporadic MTC in up to 50% of cases RET mutations occur. Additionally, activating molecular changes in VEGFR and MET pathways have also been implicated in MTC progression. Clinical responses with
cabozantinib in MTC could be observed in early clinical trials, and following confirmation of clinical benefit in a randomized phase III trial,
cabozantinib gained FDA approval for first-line treatment of advanced MTC in 2012. In
prostate cancer models, MET expression increases with
androgen ablation and
clinical progression of bone and
lymph node metastasis. A phase II trial with
cabozantinib also showed very promising response rates in patients with metastatic
prostate cancer. Therefore, randomized phase III studies are currently ongoing to validate the efficacy of
cabozantinib in heavily pretreated
prostate cancer patients.