August 15, 2012 — The targeted agent vandetanib (Caprelsa, AstraZeneca) has shown benefit in differentiated thyroid cancer (DTC), which is the most common presentation of the disease, accounting for 90% of cases of thyroid cancer. The drug is already approved for use in medullary thyroid cancer (MTC), the other form of this disease.
The results of the phase 2 trial showing benefit in DTC were published online August 14 in the Lancet Oncology.
In 72 patients, median progression-free survival nearly doubled with oral vandetanib 300 mg/day— from 5.9 months with placebo to 11.1 months (hazard ratio, 0.63; P = .008).
There was also a significant improvement in disease control rate, which includes complete and partial response and stable disease.
However, there was no difference in overall survival between the 2 groups.
A previous phase 3 trial of vandetanib for MTC (J Clin Oncol. 2012;30:134-141) also found no difference in overall survival. However, there was improvement in progression-free survival in that trial, which led to approval for that indication.
In an accompanying comment, Keith Bible, MD, from the Mayo Clinic in Rochester, Minnesota, points out that in both the DTC and MTC trials, there was crossover from placebo to active drug. This would have confounded the assessment of treatment effects on overall survival, he notes.
Predictably, in the DTC trial, there were more adverse events of grade 3 or higher in the vandetanib group than in the placebo group, including QTc prolongation (14% vs 0%), diarrhea (10% vs 0%), asthenia (7% vs 4%), and fatigue (5% vs 0%).
Three deaths (2 in the vandetanib group and 1 in the placebo group) were considered to be treatment related, so there was an excess mortality of 1.5% in the drug-treated group. Dr. Bible points out that this is consistent with treatment-related mortality reported for other kinase inhibitors.
Hence, this study "leaves the important issue of the effects of vandetanib on overall survival unanswered," he concludes.
Few Other Treatment Options
The DTC trial was conducted in Europe by a group of researchers headed by Martin Schlumberger, MD, from the Institute Gustave Roussy in Villejuif, France. All patients in the trial had locally advanced or metastatic DTC, which comprises papillary, follicular, and poorly differentiated carcinomas.
All trial participants were unsuitable for radioiodine therapy, either because of disease progression after previous radioiodine treatment or because they had 1 lesion or more without detectable radioiodine uptake.
"Present therapies are largely ineffective" for such patients, note the study authors. "To the best of our knowledge, vandetanib is the first targeted agent to demonstrate improved [progression-free survival]," they add.
"These results are potentially good news for patients with aggressive DTC who currently have few treatment options," Dr. Schlumberger said in a statement.
He noted that the significant improvement in progression-free survival (and in the disease control rate), compared with placebo, suggests that vandetanib is an effective treatment option for the long-term stabilization of patients with advanced DTC.
The drug might be particularly useful for a subset of patients with papillary thyroid cancer, he explained. There was a greater improvement in median progression-free survival in this subgroup (comprising 38% to 40% of the total population) with vandetanib than with placebo (16.2 vs 5.9 months) than in patients with other types of cancer, including follicular thyroid cancer and poorly differentiated thyroid cancer (7.7 vs 5.6 months).
In his comment, Dr. Bible writes that the "time has come to individualize treatment approaches in differentiated thyroid cancer."
This study is "a step in the right direction," he explains, "although more work is needed to better clarify which patients with DTC might have the greatest net benefits from kinase inhibitors."
Thyroid cancer is increasing worldwide, with a doubling in incidence in the past decade. Although most patients with thyroid cancer have an excellent prognosis, with an overall mortality rate of only 3% in the United States, there are few treatment options for patients with aggressive disease, he notes.
The trial was sponsored by AstraZeneca. Dr. Schlumberger and several coauthors report serving on advisory boards and receiving payment for lecturers from AstraZeneca, Bayer, Eisai, Exelixis, Genzyme, and Roche. Two of the study coauthors are employees of AstraZeneca. Dr. Bible has disclosed no relevant financial relationships.
Lancet Oncol. Published online August 14, 2012. Abstract, Comment
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