Cabozantinib Improves Disease-Free Survival in Progressive Medullary Thyroid Cancer 


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Cabozantinib (Cometriq) is an inhibitor of hepatocyte growth factor receptor (MET), vascular endothelial growth factor receptor 2 (VEGFR2), and rearranged during transfection (RET) tyrosine kinases. In a phase III trial reported in Journal of Clinical Oncology, Rossella Elisei, MD, of University of Pisa, Italy, and colleagues found that cabozantinib significantly prolonged progression-free survival compared with placebo in patients with progressive medullary thyroid cancer.1 This trial provided the basis for U.S. Food and Drug Administration approval of cabozantinib in progressive metastatic medullary thyroid cancer.

Study Details

In the trial, 330 patients with documented radiographic progression of metastatic medullary thyroid cancer were randomly assigned 2:1 to oral cabozantinib at 140 mg/d (n = 219) or placebo (n = 111). There was no limit on prior therapy, including exposure to other tyrosine kinase inhibitors. The primary endpoint was progression-free survival.

The cabozantinib group and placebo group were generally well matched for age (median, 55 years in both), sex (69% and 63% male), Eastern Cooperative Oncology Group (ECOG) performance status (0 in 56% and 51%), RET mutation status (positive in 46% and 52%, M918T-positive in 34% and 39%), disease type (sporadic in 87% and 85%), prior anticancer therapy (39% and 43%), prior systemic therapy for medullary thyroid cancer (37% and 42%), ≥ 2 prior systemic therapies (24% and 28%), prior thyroidectomy (92% and 94%), prior tyrosine kinase inhibitor treatment (20% and 22%), number of organs/anatomic locations involved (≥ 2 in 87% of both), and main sites of metastatic disease (eg, lymph nodes in 80% and 78%, liver in 70% and 60%). Cross-over of patients in the placebo group to cabozantinib was not allowed.

Prolonged Progression-Free Survival

At the database cutoff date, 45% of patients in the cabozantinib group and 14% of patients in the placebo arm were receiving study treatment. After a median follow-up of 13.9 months, median progression-free survival was 11.2 months in the cabozantinib group vs 4.0 months in the placebo group (hazard ratio [HR] = 0.28, P < .001). Kaplan-Meier estimates of the proportions of patients alive and progression-free at 1 year were 47.3% for the cabozantinib group and 7.2% for the placebo group.

Progression-free survival was significantly prolonged with cabozantinib in subgroup analyses by age, sex, ECOG performance status, number of prior anticancer regimens, prior tyrosine kinase inhibitor treatment, RET mutation status (positive, unknown, hereditary, sporadic), M918T mutation status (positive, negative), and presence of bone metastases at baseline. The only subgroups for which the hazard ratio was not significant were the RET mutation–negative and M918T mutation status unknown subgroups.

The response rate was 28% in the cabozantinib group and 0% in the placebo group, with responses observed irrespective of RET mutation status. An interim analysis of overall survival, performed when 44% of events required for final analysis had occurred, showed no difference between the cabozantinib and placebo groups (HR = 0.98, 95% confidence interval = 0.63–1.52). At the interim analysis, 30% of patients in the cabozantinib group and 28% in the placebo group had died, with 77% and 80% of deaths being attributed to disease progression.

Toxicities

Grade 3 or 4 adverse events occurred in 69% of cabozantinib patients and 33% of placebo patients, with the most frequent in cabozantinib patients being diarrhea (16%), palmar-plantar erythrodysesthesia (13%), and fatigue (9%). Adverse events associated with VEGF pathway inhibition were more common in cabozantinib patients, including grade 3 or 4 hypertension (8.4% vs 0.9%), venous thrombosis (3.7% vs 1.8%), hemorrhage (3.3% vs 0.9%), and gastrointestinal perforation (3.3% vs 0%).

Laboratory abnormalities more common in cabozantinib patients included increased AST, increased ALT, increased alkaline phosphatase, hypocalcemia, hypophosphatemia, hyperbilirubinemia, hypomagnesemia, hypokalemia, hyponatremia, lymphopenia, neutropenia, and thrombocytopenia. No drug-induced severe liver injury was observed. Thyroid-stimulating hormone levels above normal were observed in 57% of cabozantinib patients and 19% of placebo patients.

Adverse events led to dose reduction in 79% of cabozantinib patients and 9% of placebo patients, dose interruption in 65% and 17%, and treatment discontinuation in 16% and 8%. Grade 5 adverse events occurred within 30 days of the last dose of study treatment in 7.9% and 7.3% of patients. Serious adverse events occurred in 42% and 23%; those occurring with a frequency ≥ 2% greater in the cabozantinib group consisted of mucosal inflammation (2.8% vs 0%), hypocalcemia (2.8% vs 0%), pulmonary embolism (2.3% vs 0%), and hypertension (2.3% vs 0%).

The investigators concluded, “Cabozantinib (140 mg per day) achieved a statistically significant improvement of [progression-free survival] in patients with progressive metastatic [medullary thyroid cancer] and represents an important new treatment option for patients with this rare disease. This dose of cabozantinib was associated with significant but manageable toxicity.” ■

Disclosure: The study was supported by Exelixis. For full disclosures of the study authors, visit jco.ascopubs.org.

Reference

1. Elisei R, Schlumberger MJ, Müller SP, et al: Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol. September 3, 2013 (early release online).


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Medullary thyroid cancer is derived from parafollicular C cells in the thyroid gland. The disease is sporadic in about 75% of cases and hereditary in the remaining 25%.1 Oncogenic mutations in the gene for tyrosine kinase receptor rearranged during transfection (RET) are driver genetic alterations...


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