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Vandetanib efficacious in medullary thyroid cancer

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International Thyroid Congress

PARIS — Vandetanib, a once-daily selective oral inhibitor of RET, vascular endothelial growth factor receptor and epidermal growth factor receptor signaling, prolonged PFS in patients with medullary thyroid cancer compared with placebo, according to phase 3 data presented at the International Thyroid Congress in Paris.

Samuel A. Wells, MD, of the medical oncology branch of the NCI, and colleagues conducted the study to determine whether once-daily vandetanib 300 mg (Zactima, AstraZeneca) prolonged PFS vs. placebo. The randomized, double blind ZETA study included 331 adults with unresectable, locally advanced or metastatic medullary thyroid cancer (90% sporadic; 95% metastatic; 56% RET mutation positive). Between December 2006 and November 2007, the researchers assigned all patients to vandetanib (n=231) or placebo (n=100) in a 2-1 fashion. Patients were followed until disease progression, at which time they were unblinded and had the option to receive vandetanib in an open-label trial; if they chose open-label vandetanib, they were then followed for survival. The median duration of treatment was 90.1 weeks in the vandetanib arm and 39.9 weeks in the placebo arm.

Two-year follow-up results showed that 37% of the patients had progression and 15% had died.

“The primary endpoint was met — vandetanib demonstrated a statistically significant advantage in progression-free survival vs. placebo,” Wells said during the presentation. The researchers reported an HR of 0.46 (95% CI, 0.31-0.69).

Median PFS was 19.3 months in the placebo group; it had not yet been reached in the vandetanib arm as of the presentation.

Vandetanib was also associated with statistically significant advantages in secondary endpoints such as objective response rate (45% vs. 13%; OR=5.4); disease control rate of 24 weeks or more (OR=2.64); calcitonin biochemical response (OR=72.9); carcinoembryonic antigen biochemical response (OR=52); and time to worsening of pain (HR=0.61). For objective response rate, 12 of 13 responses in the placebo arm occurred after the patients had received open-label vandetanib.

The researchers said overall survival data were “immature” at the time of data cutoff at 24 months. A final survival analysis will take place after 59% of patients have died, they said.

Common adverse events were more common with vandetanib vs. placebo, including diarrhea (56% vs. 26%), rash (45% vs. 11%), nausea (33% vs. 16%), hypertension (32% vs. 5%) and headache (26% vs. 9%).

“Adverse events were generally manageable, permitting treatment with vandetanib for prolonged periods of time,” Wells said.

The phase 3 trial results are important for patients with locally advanced or metastatic medullary thyroid cancer, “a disease for which there is no standard effective therapy,” according to the researchers. Previous phase 2 study data have shown that once-daily vandetanib 300 mg was associated with antitumor activity in patients with advanced hereditary medullary thyroid cancer. – by Katie Kalvaitis

For more information:

• Wells SA. OC-021. Presented at: the 14th International Thyroid Congress; Sept. 11-16, 2010; Paris.

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