New Kinase Inhibitor Prolongs PFS in Thyroid Cancer

September 25, 2012 — Targeting multiple oncogenic signaling pathways with cabozantinib, a new multikinase inhibitor, significantly prolongs progression-free survival, compared with placebo, in patients with progressive medullary thyroid cancer (MTC), new research shows.

In their study, Manisha Shah, MD, from Ohio State University Medical Center in Columbus, and colleagues report longer progression-free survival with cabozantinib than with placebo (11.2 vs 4.0 months; P < .0001).

More patients in the cabozantinib group than in the placebo group were alive and free of disease progression at 1 year (47.3% vs 7.2%), the investigators note. Median duration of response was 14.6 months.

"Patients had locally advanced or metastatic MTC with documented disease progression within 14 months prior to study entry, and about half had boney metastasis," Dr. Shah said. "Radiographically documented progressive MTC is an unmet medical need not previously studied in a phase 3 trial," she added.

She presented the study results here at the American Thyroid Association 82nd Annual Meeting.

MTC Mutations

Recent studies have identified a number of mutations associated with MTC, including RET mutations, which have been seen in up to 65% of sporadic cases, Dr. Shah pointed out.

In hereditary MTC, more than 95% of cases have germline RET mutations, but other mutations, including MET and VEGFR2, are overexpressed in the same malignancy.

It has been shown that activation of the MET pathway promotes angiogenesis, tumor invasion, and metastasis, and that cabozantinib inhibits MET, VEGFR2, and RET kinase activity.

In this study, 219 patients (mean age, 54 years) were initially randomized to cabozantinib (140 mg/day for 12 months or until treatment discontinuation) and 111 were randomized to placebo.

In the study population, approximately 40% of patients had been treated with systemic therapy; approximately 20% had been treated with a tyrosine kinase inhibitor (TKI), and approximately 10% had been treated with vandetanib, another multikinase inhibitor.

At the time of the analysis, 26% of patients in the cabozantinib group had discontinued treatment because of progressive disease and 16% had discontinued treatment because of adverse events.

On subgroup analysis, mutational status, previous anticancer treatment, and previous TKI therapy did not significantly affect objective response rate (ORR) in the cabozantinib group: the ORR was 32% in RET-positive patients, 25% in RET-negative patients, 28% in patients who received no previous anticancer treatment, 26% in patients who received 1 previous anticancer treatment, 30% in patients who received at least 2 previous anticancer treatments, 21% in patients who received previous TKI treatment, and 30% in patients who had not received previous TKI treatment.

Adverse Events

Adverse events were common, and included hypertension, hemorrhage, and venous thrombosis, which is frequently associated with inhibition of the VEGF pathway.

However, rates of grade 3 or higher adverse events were relatively modest, at 8% for hypertension, 3% for hemorrhage, and 4% for venous thrombosis.

"Overall deaths for any reason were balanced between treatment arms," the investigators note.

"This is the first randomized phase 3 study in MTC patients with confirmed radiographic progressive disease [at study entry] and, if approved, cabozantinib may be an important new treatment option for MTC," they report.

Katherine Thornton, MD, from the Johns Hopkins Sidney Kimmel Cancer Center at Sibley Memorial Hospital in Washington, DC, told Medscape Medical News that the study results look "promising."

She said Dr. Shah and colleagues are "to be commended for completing this relatively large phase 3 study in a rare tumor like MTC, because conducting randomized trials in rare tumors is challenging."

The safety-profile data of the drug will be interesting to review down the road, Dr. Thornton explained. Because "this is a drug that patients could theoretically be on chronically, the short-term and long-term side effects will be important to consider," she said.

Dr. Shah reports receiving research support from Exelixis, Bayer, and Eisai; and being on the advisory board for Exelixis. Dr. Thornton reports reviewing the vandetanib phase 3 trial for the US Food and Drug Administration, but otherwise reports no relevant financial disclosures.

American Thyroid Association (ATA) 82nd Annual Meeting. Oral abstract 17. Presented September 21, 2012.