Exelixis announced positive top-line results from its ongoing Phase 3 EXAM trial of cabozantinib in patients with advanced medullary thyroid cancer (MTC). EXAM is an international, randomized, placebo-controlled, double-blinded study of cabozantinib in patients with progressive, unresectable, locally advanced, or metastatic MTC. Patients were randomized in a 2:1 ratio to receive cabozantinib or placebo administered at a daily dose of 175mg. The study did not allow for cross-over from the placebo arm to cabozantinib. With an enrollment target of 315 patients and a planned event-driven analysis, the trial provides 90% power to detect a 75% increase in progression-free survival (PFS), the primary endpoint of the study.

The trial met its primary endpoint compared with placebo and substantially exceeded the threshold of a 75% increase in PFS originally assumed when the trial was designed. Cabozantinib significantly improved median PFS by 7.2 months compared with placebo. The median PFS on the cabozantinib arm was 11.2 months versus 4 months on the placebo arm (P<0.0001).

Cabozantinib is a potent inhibitor of MET, RET and VEGFR2 that inhibits tumor growth, metastasis and angiogenesis in preclinical models. MET is up-regulated in many tumor types, and promotes tumor cell survival, invasion and metastasis. Further up-regulation of MET occurs under hypoxic conditions, which are often exacerbated by VEGF-pathway inhibitors, promoting increased tumor cell invasion and metastases. Activation of RET is a frequent occurrence in both medullary and papillary thyroid cancers. The therapeutic role of cabozantinib is currently being investigated across multiple tumor types.

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