Conference Coverage

Cabozantinib boosts survival for some patients with RET+ medullary thyroid cancer


AT ITC 2015


LAKE BUENA VISTA, Fla. – The tyrosine kinase inhibitor cabozantinib significantly extended overall survival for patients with RET-M918T–positive medullary thyroid cancer.

The placebo-controlled EXAM trial did not show any significant differences in overall survival among the entire group, Dr. Steven Sherman said at the International Thyroid Congress. But in a subgroup analysis, those with RET-M918T mutations who received the drug had the best outcomes by far, with a mean overall survival 2 years longer than that of similar patients who received placebo (44 vs. 19 months; HR 0.60; P = .026).

Dr. Steven Sherman

Dr. Steven Sherman

Cabozantinib (COMETRIQ) delivers a three-way punch to thyroid tumors, said Dr. Sherman of MD Anderson Cancer Center, Houston. It inhibits tyrosine kinase, vascular endothelial growth factor receptors, and mutant RET. But EXAM does not provide any clues about the exact mechanism by which it subdued this particular class of tumors.

“We may well be targeting mutant RET as well as tyrosine kinase and VEGF-R. But the other possibility is that these RET tumors are highly dependent on VEGF for angiogenesis and that inhibiting that is the key element. The data from this study don’t allow us to speculate on which is the most important,” said Dr. Sherman.

The 2-year trial randomized 330 patients with progressive medullary thyroid cancer to cabozantinib (140 mg per day) or placebo. If patients taking placebo progressed, they were not allowed to cross over to cabozantimib. The primary endpoint was progression-free survival (PFS); results were published in 2013 in the Journal of Clinical Oncology (doi: 10.1200/JCO.2012.48.4659).

Dr. Sherman presented the final results on overall survival at the meeting, which was held by the American Thyroid Association, Asia-Oceania Thyroid Association , European Thyroid Association, and Latin American Thyroid Society.

Almost half of the cohort had received prior therapy, and 21%, a prior tyrosine kinase inhibitor. About half had RET mutations; 12% were RET negative, and genomic status was unknown in the remainder. M918T was the predominant RET mutation (74%). The main sites of metastasis were lymph nodes, liver, lung, and bone.

PFS was significantly better in those taking the study drug (11 vs. 4 months; HR 0.28; P equal to or less than .01). Significant PFS benefits were seen regardless of age, prior treatment, and RET status.

In the overall survival analysis, however, cabozantinib conferred no significant benefit over placebo across the entire cohort (26.6 vs 21 months; HR 0.85; P = .24).

RET mutation profiles were available for 65% of patients. The drug did not confer significant overall survival benefit to all those with RET mutations (31.6 vs. 24.8 months; HR 0.79; P = .24). However, those with the M918T mutation who took cabozantinib survived significantly longer than did those who took placebo.

A small number of patients (16) had RAS mutations, and those who took cabozantinib did have better overall survival than did those who took placebo, although the difference was not statistically significant.

Adverse events were more common in the cabozantinib arm and included pneumonia (4.2%), pulmonary embolism (3.3%), mucosal inflammation (2.8%), hypocalcemia (2.8%), hypertension, dysphagia, dehydration, and lung abscess (2.3% each).

The EXAM study was sponsored by Exelixis. Dr. Sherman had no financial disclosures.

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