Cabozantinib in Progressive Medullary Thyroid Cancer

Abstract

A B S T R A C T PurposeCabozantinib, a tyrosine kinase inhibitor (TKI) of hepatocyte growth factor receptor (MET), vascular endothelial growth factor receptor 2, and rearranged during transfection (RET), demonstrated clinical activity in patients with medullary thyroid cancer (MTC) in phase I. Patients and MethodsWe conducted a double-blind, phase III trial comparing cabozantinib with placebo in 330 patients with documented radiographic progression of metastatic MTC. Patients were randomly assigned (2:1) to cabozantinib (140 mg per day) or placebo. The primary end point was progression-free survival (PFS). Additional outcome measures included tumor response rate, overall survival, and safety. ResultsThe estimated median PFS was 11.2 months for cabozantinib versus 4.0 months for placebo (hazard ratio, 0.28; 95% CI, 0.19 to 0.40; P Ͻ .001). Prolonged PFS with cabozantinib was observed across all subgroups including by age, prior TKI treatment, and RET mutation status (hereditary or sporadic). Response rate was 28% for cabozantinib and 0% for placebo; responses were seen regardless of RET mutation status. Kaplan-Meier estimates of patients alive and progression-free at 1 year are 47.3% for cabozantinib and 7.2% for placebo. Common cabozantinibassociated adverse events included diarrhea, palmar-plantar erythrodysesthesia, decreased weight and appetite, nausea, and fatigue and resulted in dose reductions in 79% and holds in 65% of patients. Adverse events led to treatment discontinuation in 16% of cabozantinib-treated patients and in 8% of placebo-treated patients. ConclusionCabozantinib (140 mg per day) achieved a statistically significant improvement of PFS in patients with progressive metastatic MTC and represents an important new treatment option for patients with this rare disease. This dose of cabozantinib was associated with significant but manageable toxicity.

ENDOCRINE TUMOURS: Progressive metastatic medullary thyroid carcinoma: first- and second-line strategies

“…This study indicates that mutationspecific therapies could be beneficial in treating MTC (36). This was also confirmed in two phase III clinical trials, which showed that these TKIs had a significant effect on progression-free survival (37,38). Besides RET, other TKRs, mostly based on overexpression, could also play a role in MTC.…”

RET Aberrations in Diverse Cancers: Next-Generation Sequencing of 4,871 Patients

“…However, none of these inhibitors are FDA approved on the basis of targeting RET aberrations. Meanwhile, there are a series of reports suggesting that matched therapies against RET aberrations can yield significant responses (8,15,(21)(22)(23)(24)(25)(26)(27). Further clinical trials with a focus on RET-aberrant advanced cancer are being conducted to determine impact on outcome (Supplementary Table S1).…”

A comprehensive review on MEN2B

“…Clinical response was also documented by a mean decline of 59% (35-84) in calcitonin levels (Fox et al 2013). Cabozantinib was studied in a randomized, double-blind placebo-controlled phase III study (Elisei et al 2013) of 330 patients, which showed a significant improvement of median progression-free survival (11.2 vs 4.0 months in the cabozantinib and placebo groups, respectively). Sherman and coworkers subsequently reported, in a subgroup analysis of the cabozantinib phase III trial, that patients with a germline or somatic M918T mutation had the greatest progression-free survival benefit vs placebo, in comparison with patients with no identified RET mutation (Sherman et al 2016).…”