Cabozantinib Prolongs Progression-free Survival in Advanced Medullary Thyroid Cancer

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Cabozantinib prolonged progression-free survival in patients with unresectable, locally advanced, or metastatic medullary thyroid cancer with documented disease progression in the phase III EXAM trial. Based on these results, Exelixis submitted a New Drug Application to the FDA in May 2012. The full data from the trial were presented at the 2012 ASCO Annual Meeting. Final overall survival analysis is expected in 1 to 2 years.

Key Findings

Cabozantinib resulted in clinically meaningful and statistically significant prolongation of progression-free survival in this setting. The Kaplan-Meier estimates of the proportions of subjects alive and progression-free at 1 year are 47.3% for the cabozantinib arm and 7.2% for the placebo arm. The drug achieved durable tumor responses for a median of 14.6 months. In addition, the study demonstrated that serum calcitonin could be used as a marker of response, as serum calcitonin levels decreased with documented tumor shrinkage.

“Patients with medullary thyroid cancer and their physicians face a tough obstacle when their cancer recurs or progresses,” stated Patrick Schoffski, MD, of University Hospitals, Leuven, Belgium. “Treatment options are limited, and standard chemotherapy has shown disappointing results. The new targeted agent cabozantinib is an oral drug that inhibits genetic abnormalities associated with medullary thyroid cancer. Cabozantinib will be an important new treatment option if approved by regulatory agencies for this orphan disease.”

Study Background

The study, sponsored by Exelixis, involved 90 investigators from 23 countries. Medullary thyroid cancer is a rare endocrine disease accounting for 5% to 8% of all thyroid cancers; 75% are sporadic and 25% are hereditary, Dr. Schoffski explained. Up to 65% of these sporadic cancers have somatic RET mutations, and more than 95% of the hereditary cancers have germline RET mutations.

Cabozantinib is a small-molecule inhibitor of MET, VEGFR2, and RET. The drug had excellent activity in earlier trials and was granted orphan drug status by the FDA in January 2011. The phase III EXAM trial randomly assigned 330 patients with locally advanced or metastatic medullary thyroid cancer and documented disease progression within 14 months of screening in a 2:1 ratio to cabozantinib at 140 mg/d or placebo, with treatment continued until disease progression. The planned sample size was chosen to increase power to evaluate differences in overall survival. Therefore, a relatively high degree of censoring is expected in the event-driven analysis of progression-free survival.

Patients were prestratified by age (< 65 and ≥ 65) and prior exposure to tyrosine kinase inhibitors. Baseline characteristics were well balanced for demographics, gender, and performance status. Prior systemic therapy ranging from 1 to 7 previous lines per patient was administered to 37% of the cabozantinib group and 42% of the placebo group. About 20% of both groups were previously exposed to a tyrosine kinase inhibitor. Tissue samples were available for analysis, and about 50% had RET mutations in either blood or tumor.

Benefits and Toxicities

EXAM met its primary endpoint. Median progression-free survival was 11.2 months for cabozantinib vs 4.2 months for placebo (P < .0001), with a 72% reduction in risk of progression favoring cabozantinib.

Prespecified subgroup analysis showed superiority of cabozantinib in all subgroups, regardless of prior anticancer regimens, prior tyrosine kinase inhibitor exposure, prior radiotherapy, and presence of bone metastasis at baseline.

Overall response rate was 28% with cabozantinib vs 0% for placebo (P < .0001). Most patients in the cabozantinib group (94%) had some evidence of tumor regression in target lesions vs 27% of the placebo group.

Common grade 3 toxicities more frequently observed in the cabozantinib arm included diarrhea, hand-foot skin reactions, and fatigue. Most adverse events were grade 2. Deaths unrelated to cancer progression were reported in 5.6% of the cabozantinib arm vs 2.8% in the placebo arm. About 2% of the deaths in the cabozantinib arm were due to causes associated with VEGF inhibition, including hemorrhage, venous thrombosis, and gastrointestinal perforation.

Potential Biomarker

Serum calcitonin levels decreased by a mean of 45% in the calcitonin arm but increased by 57% in placebo recipients. These changes correlated with tumor regression. “This study provides evidence that inhibition of RET can decrease calcitonin expression,” Dr. Schoffski said.

If cabozantinib is approved for treatment of medullary thyroid cancer, it will join vandetanib (Caprelsa) as the second tyrosine kinase inhibitor to be indicated for this orphan disease. It is not clear how these agents will be sequenced. ■

Disclosure: Dr. Schoffski has received research funding from Exelixis.


1. Schoffski P, Elisei R, Müller S, et al: An international double-blind, randomized, placebo-controlled phase III (EXAM) of cabozantinib (XL184) in medullary thyroid cancer patients with documented RECIST progression at baseline. 2012 ASCO Annual Meeting. Abstract 5508. Presented June 4, 2012.

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