Hepatocyte growth factor (HGF) and its tyrosine kinase receptor MET are overexpressed in a wide variety of tumor types, promoting tumor growth, invasion and metastasis. Upregulation of MET occurs in response to multiple therapies including VEGF-pathway inhibition, and promotes resistance.  Additionally, HGF and VEGF cooperate to promote endothelial cell proliferation, tubule formation, and growth of new vessels in vivo.  Cabozantinib was derived through optimization of a lead compound selected for potent MET and VEGFR inhibition.  In preclinical in vivo tumor models cabozantinib has potent anti-tumor and anti-angiogenic activity. Cabozantinib also inhibits additional receptor tyrosine kinases implicated in oncogenesis, including RET.  Activating translocations involving RET occur in subsets of papillary thyroid and lung cancers, and activating RET point mutations, in particular M918T, occur in medullary thyroid cancer (MTC) and may be associated with a poor prognosis. In a phase 1 study in patients with advanced solid tumors, 85 patients (37 with MTC) were enrolled to evaluate safety, pharmacokinetics, and to determine the maximum-tolerated dose. Ten of 37 MTC patients achieved a confirmed partial response.A phase 3 study of cabozantinib vs placebo in patients with progressive, metastatic MTC was conducted. The primary endpoint was progression-free survival (PFS).  Secondary endpoints included objective response rate (ORR) and overall survival (OS). 330 patients were randomized 2:1 to cabozantinib or placebo. Median PFS for cabozantinib was 11.2 months vs 4.0 months for placebo (HR0.28, 95% CI 0.19-0.40, p<0.0001). PFS results favored the cabozantinib group across pre-defined subset analyses. ORR was 28% for cabozantinib vs 0% for placebo (p<0.0001). An interim analysis of OS (44% of the 217 required events) did not show a difference between treatment arms. The most frequent grade =3 adverse events were diarrhea, palmar-plantar erythrodysesthesia, fatigue, hypocalcemia, and hypertension. Additional trials of cabozantinib in multiple tumor types are in progress.

Discovery and development of cabozantinib for the treatment of metastatic medullary thyroid carcinoma

247th National Meeting (2014)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.