Multikinase Inhibitor Prolongs Progression-Free Survival in MTC

Manisha Shah, MD

Cabozantinib, a multikinase inhibitor, significantly prolonged progression-free survival in medullary thyroid cancer (MTC) compared with placebo among patients with radiographically confirmed progressive disease at study onset, results from a randomized, phase III trial show. The subgroup analysis of data from the EXAM study was presented during the 82^nd Annual Meeting of the American Thyroid Association.

Manisha Shah, MD, associate professor of Oncology at Ohio State University Medical Center in Columbus, along with multi-center colleagues, reported that the median progression-free survival (PFS) rate among patients randomized to 140 mg per day of cabozantinib was 11.2 months compared with 4.0 months for placebo controls (HR 0.28, 0.19-0.40; P < 0.0001). At 1 year, 47.3% of patients remained free of progression in the multikinase inhibitor arm compared with 7.2% in the placebo arm. The median duration of response was 14.6 months, the doctor reported.

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

As Shah pointed out, up to 65% of patients with sporadic MTC express somatic RET mutations and >95% of hereditary cases are characterized by germline RET mutations. She noted that both MET and VEGFR2 are also overexpressed in MTC. Cabozantinib inhibits all three of these mutations.

At baseline, approximately 40% of the patients in both arms had received prior systemic therapy; 21% had prior tyrosine kinase inhibitor (TKI) exposure, including about 10% who had been treated with vandetanib, another multikinase inhibitor. A total of 219 patients were randomized to the cabozantinib arm, while 111 patients received placebo.

At the time of analysis, 45% of patients on the multikinase inhibitor arm were continuing treatment, versus 13% of placebo patients; 60% of placebo controls had discontinued treatment due to progressive disease, compared with 26% of patients on active therapy, Shah said. Subgroup analysis also showed that objective response rates (ORRs) of between 25% and 32% were seen with cabozantinib regardless of RET mutational status; the ORR was 21% for patients with bone metastases or prior treatment with TKI. In contrast, no ORRs were seen in comparable placebo subgroups.

Grade ≥3 adverse events seen with cabozantinib were those commonly associated with inhibition of the VEGF pathway, and included hypertension (8% vs 0.9% for placebo); hemorrhage (3% vs 0.9% for placebo); and venous thrombosis (6% vs 2% for placebo), Shah reported. Death for reasons other than progressive disease, and within 30 days of the cessation of treatment, occurred in 5.6% of patients in the cabozantinib arm vs 2.8% of placebo controls; some of the deaths in those taking cabozantinib were attributed to causes associated with VEGF inhibition, she said.

However, as investigators pointed out, adverse events, while common, are generally manageable with dose modification, allowing patients to receive cabozantinib for extended periods of time.

“This is the first randomized phase III study in MTC patients with confirmed radiographic progressive disease (at study entry),” investigators concluded. “If approved, cabozantinib may be an important new treatment option for MTC.”

Exelixis, Inc, the California-based developer of the drug, announced in July that the FDA had accepted its New Drug Application for cabozantinib under the agency’s priority review program. The requested indication is for patients with progressive, unresectable, locally advanced, or metastatic MTC. The FDA is expected to render a decision on the application by Nov. 29, 2012, according to Exelixis.