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Exelixis Gains European Cometriq Nod with Note about Low Response in Non-RET Mutated MTC Patients

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Originally published March 25.

The European Commission has approved Cometriq (cabozantinib) as a treatment for medullary thyroid cancer (MTC) patients.

The drug is indicated for patients with progressive, unresectable, locally advanced disease. In its approval, the EC cautions that medullary thyroid cancer patients whose RET mutation status is unknown or negative may experience limited response to the agent compared to those with known RET mutations. As such, this information should be taken into account when making treatment decisions with Cometriq for a particular patient, the EC advises.

When the EC approved AstraZeneca's Caprelsa (vandetanib) in 2012 for aggressive and symptomatic MTC, there was similar language regarding the possibility of low efficacy in patients negative for RET mutations or in whom mutation status is unknown.

Cometriq is a tyrosine kinase inhibitor that blocks the activity of RET, MET, and VEGFR2, and a number of other receptors. Exelixis has a commercialization and distribution agreement with Swedish Orphan Biovitrum, which will support marketing efforts for Cometriq in the EU through 2015.

The approval language for Cometriq is in line with the December recommendation from the European Committee for Medicinal Products for Human Use (CHMP). In its proposed indication for Cometriq to CHMP, Exelixis noted that MTC patients negative for the RET mutation or patients for whom the mutation status is not known, “possible lower benefit should be taken into account before individual treatment decisions.” The drug has also been granted orphan drug designation by European regulators.

The US Food and Drug Administration approved Cometriq as an orphan drug for the treatment of progressive, metastatic MTC in November 2012. Exelixis submitted data from the randomized, double-blind Phase III EXAM study to support the marketing approvals for Cometriq in the US and Europe. In that 330-patient trial, Cometriq significantly improved progression-free survival compared to placebo in progressive, unresectable locally advanced or metastatic MTC patients (median PFS 11.2 months versus 4 months).

In the trial, 48 percent of patients were RET mutation positive according to research-use assays, the FDA-approved label states. However, the US label for the drug doesn't include a cautionary note about the possibility of low response in those without RET mutations.

Researchers involved in the EXAM study presented a detailed analysis of patients' response to Cometriq based on their RET mutations status at the American Society of Clinical Oncology's annual meeting last year. RET-positive patients had median PFS of 60 weeks with Cometriq compared to 20 weeks for patients receiving placebo. Patients with RETM918T mutations appeared to have a slightly better outcome on Cometriq, 61 weeks median PFS versus 17 weeks on placebo.

RET-negative patients did not experience a significant survival advantage compared to those on placebo, 26 weeks versus 23 weeks median PFS. For patients who had unknown RET status, they had a median PFS of 48 weeks on Cometriq compared to 13 weeks on placebo.

MTC develops in cells in the thyroid gland that make a hormone called calcitonin, which helps maintain a healthy level of calcium in the blood, the FDA said in its approval announcement. Patients may get this type of cancer spontaneously or as a result of a familial genetic mutation that causes endocrine system-related cancers. Out of nearly 56,000 newly diagnosed thyroid cancer patients each year in the US, approximately 4 percent will get MTC.

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