Data from the phase III ZETA trial show that vandetanib (Zactima), a selective tyrosine kinase inhibitor, significantly slows the progression of advanced medullary thyroid carcinoma (MTC), a rare disease more diffi cult to treat than common thyroid cancers. In an interview with Oncology & Biotech News
, Peter Langmuir, MD, executive director of medical science with AstraZeneca, which manufactures vandetanib, explained the rationale behind investigating vandetanib in this setting. “These patients can be cured with surgery, but it is ineffective or the disease recurs or they develop metastatic disease. There’s no effective treatment that is available.” Vandetanib inhibits tumor cell growth and migration by selectively targeting RET, vascular endothelial growth factor receptor, and epidermal growth factor receptor signaling, all of which are active in MTC.
In ZETA, 331 people (median age, 50.7 y) with unresectable locally advanced or metastatic MTC were randomized 2:1 to receive vandetanib versus placebo between December 2006 and November 2007, with progression-fr ee survival (PFS) as the primary endpoint. Placebo was used as a comparator because there are no standard treatments for these patients. Patients in the vandetanib arm (n = 231) received 300-mg daily oral doses for a median of 90.1 weeks. At progression, patients in the placebo arm (n = 100) were allowed to cross over to the vandetanib arm, and the median duration on placebo was 39.9 weeks.
Samuel A. Wells, MD, head of the Thyroid Clinical Research Program at the National Cancer Institute and lead author of the study abstract, presented findings during an oral session. He reported that median PFS was 19.3 months in the placebo arm, but this was not reached in the vandetanib arm at the point of data cutoff . Wells said this was statistically significant (hazard ratio, 0.46; 95% confidence interval, 0.31-0.69) and made vandetanib the first agent to demonstrate efficacy in advanced MTC in a phase III trial.
Langmuir said PFS was not reached in the vandetanib arm because <50% of patients taking vandetanib (32%) had progressed at the time of cutoff compared with 51% of patients on placebo. Statistical modeling computed a probable median PFS of 30 months for vandetanib, indicating an 11-month advantage for the drug. “We see a similar magnitude of advantages for the secondary endpoints as well,” said Langmuir, noting that the overall response rate reached 45% in the vandetanib arm. “What’s more important is the duration of response,” he added. “What we see with vandetanib is a median duration of response close to 2 years.” Wells said the data on overall survival (OS) are “immature at this point.” Investigators decided not to evaluate OS until at least half the patients had died, and the mortality rate at the July 31, 2009, data cutoff date was only 15%.
Wells said OS is a very important endpoint, but the fact that one-third of patients responded to vandetanib aft er crossing over fr om placebo could confound the OS outcome.
Adverse events (AEs) of any grade were more common in the vandetanib arm than the placebo group, with diarrhea (56% vs 26%, respectively), rash (45% vs 11%, respectively), and nausea (33% vs 16%, respectively) as the most frequently reported AEs. These were generally manageable, said Wells. The discontinuation rate was only 12%, aft er a median duration of treatment of 1 year and 9 months.
Langmuir noted that the prolonged duration of treatment suggests adverse effects were manageable. He said it was interesting that a study of vandetanib in lung cancer also had a 12% rate of discontinuation, but those patients had taken the drug for only 8 to 9 weeks.
Langmuir said AstraZeneca plans to file for regulatory approval as soon as possible. “We’d like to make this drug available for patients because they don’t have options at this point and hopefully this drug will provide that need.” Abstract 5503.