Panel Supports Vandetanib for Medullary Thyroid Cancer

SILVER SPRING, MD – A Food and Drug Administration panel voted Dec. 2 that the risk-benefit profile of vandetanib is acceptable for at least some patients with medullary thyroid cancer, but that postmarketing evaluation of alternative dosing should be required by the agency as part of its approval.

The Oncologic Drugs Advisory Committee also was asked by the FDA to comment on whether the drug’s indication should be limited to patients with progressive, symptomatic medullary thyroid cancer, given concerns about the safety of the drug. The majority of panel members agreed that some restrictive language should be added to the indication in light of toxicity concerns, particularly the possibility of QTc prolongation.

"The risk-benefit profile is acceptable, from my perspective, for this drug to be approved for this indication. ... I think that there is enough of a signal at lower doses, which presumably would lead to less toxicity, that they should be explored," said panel member Dr. Mikkael Sekeres, who is a professor medicine at the Cleveland Clinic.

Dr. Wyndham Wilson of the National Cancer Institute, Rockville, Md., who is the panel chair, agreed. "It’s all about steady state levels, not about dose. ... The pharmacology data would suggest that you could probably get reasonable steady-state levels with a somewhat lower dose rate and still have equal effectiveness."

Vandetanib is an oral, multiple-tyrosine kinase inhibitor that acts on the vascular endothelial growth factor, epidermal growth factor receptor, and rearranged during transfection pathways. Medullary thyroid cancer patients with early-stage disease can be treated surgically with curative intent; for patients with distant metastases, the 5-year survival rate is approximately 40%.

AstraZeneca, the developer of vandetanib, is seeking an indication for patients with locally advanced or metastatic medullary thyroid cancer.

The drug was previously under investigation for the treatment of non–small cell lung cancer. However, the treatment with vandetanib did not improve overall survival benefit and only modestly improved progression-free survival (PFS) in this patient group.

In the phase III study, 331 patients with unresectable locally advanced or metastatic medullary thyroid cancer were randomized 2:1 to once-daily administration of either vandetanib 300 mg (the maximum tolerated dose) or placebo. AstraZeneca’s analysis showed a significant 54% reduction in risk of progression with vandetanib, improving median PFS by 11 months.

Dose reductions and interruptions because of adverse events in the phase III study and in two phase II studies were troubling, however. In the phase III trial, 36% of vandetanib patients required a dose reduction and 47% required a dose interruption.

Grade 3 or greater adverse events occurred in 55% of vandetanib-treated patients in the phase III trial, compared with 24% in the placebo group. The most common adverse events overall were diarrhea, rash, nausea, and hypertension.

The FDA and the panel were both particularly concerned about adverse event signals from the vandetanib safety database relating to QT interval prolongation, cerebrovascular events, interstitial lung disease/pneumonia and serious skin conditions. Of the total of 3,019 patients in safety database, 319 were treated with 300 mg vandetanib for medullary thyroid cancer.

According to the FDA, the incidence of grade 3-4 QTc prolongation in those patients was 8%. When ECGs were reviewed, more than 35% of patients experienced QTc prolongation greater than 60 ms – a grade 4 toxicity.

The panel was also concerned about events that occurred among the 3,019 patients in the overall safety database, which included sudden death (0.4%), torsade de pointes (less than 0.1%), grade 3-5 interstitial lung disease (0.8%), and Stevens-Johnson syndrome (0.7%).

QT prolongation is dose dependent with a mean prolongation of 35 ms in patients receiving 300 mg vandetanib, according to the FDA.

Given these adverse events, many panel members expressed concern about treating asymptomatic patients with medullary thyroid cancer, which has a long natural history that can involve periods of disease indolence, given the toxicity of the drug. Many panel members cited this as reason for the necessity of postmarketing evaluation of other doses.

The FDA usually follows the recommendations of its advisory panels. Panel members are cleared of potential conflicts of interest by the FDA before a meeting, but it occasionally grants a waiver to a panelist with a conflict of interest.

SILVER SPRING, MD – A Food and Drug Administration panel voted Dec. 2 that the risk-benefit profile of vandetanib is acceptable for at least some patients with medullary thyroid cancer, but that postmarketing evaluation of alternative dosing should be required by the agency as part of its approval.

The Oncologic Drugs Advisory Committee also was asked by the FDA to comment on whether the drug’s indication should be limited to patients with progressive, symptomatic medullary thyroid cancer, given concerns about the safety of the drug. The majority of panel members agreed that some restrictive language should be added to the indication in light of toxicity concerns, particularly the possibility of QTc prolongation.

"The risk-benefit profile is acceptable, from my perspective, for this drug to be approved for this indication. ... I think that there is enough of a signal at lower doses, which presumably would lead to less toxicity, that they should be explored," said panel member Dr. Mikkael Sekeres, who is a professor medicine at the Cleveland Clinic.

Dr. Wyndham Wilson of the National Cancer Institute, Rockville, Md., who is the panel chair, agreed. "It’s all about steady state levels, not about dose. ... The pharmacology data would suggest that you could probably get reasonable steady-state levels with a somewhat lower dose rate and still have equal effectiveness."

Vandetanib is an oral, multiple-tyrosine kinase inhibitor that acts on the vascular endothelial growth factor, epidermal growth factor receptor, and rearranged during transfection pathways. Medullary thyroid cancer patients with early-stage disease can be treated surgically with curative intent; for patients with distant metastases, the 5-year survival rate is approximately 40%.

AstraZeneca, the developer of vandetanib, is seeking an indication for patients with locally advanced or metastatic medullary thyroid cancer.

The drug was previously under investigation for the treatment of non–small cell lung cancer. However, the treatment with vandetanib did not improve overall survival benefit and only modestly improved progression-free survival (PFS) in this patient group.

In the phase III study, 331 patients with unresectable locally advanced or metastatic medullary thyroid cancer were randomized 2:1 to once-daily administration of either vandetanib 300 mg (the maximum tolerated dose) or placebo. AstraZeneca’s analysis showed a significant 54% reduction in risk of progression with vandetanib, improving median PFS by 11 months.

Dose reductions and interruptions because of adverse events in the phase III study and in two phase II studies were troubling, however. In the phase III trial, 36% of vandetanib patients required a dose reduction and 47% required a dose interruption.

Grade 3 or greater adverse events occurred in 55% of vandetanib-treated patients in the phase III trial, compared with 24% in the placebo group. The most common adverse events overall were diarrhea, rash, nausea, and hypertension.

The FDA and the panel were both particularly concerned about adverse event signals from the vandetanib safety database relating to QT interval prolongation, cerebrovascular events, interstitial lung disease/pneumonia and serious skin conditions. Of the total of 3,019 patients in safety database, 319 were treated with 300 mg vandetanib for medullary thyroid cancer.

According to the FDA, the incidence of grade 3-4 QTc prolongation in those patients was 8%. When ECGs were reviewed, more than 35% of patients experienced QTc prolongation greater than 60 ms – a grade 4 toxicity.

The panel was also concerned about events that occurred among the 3,019 patients in the overall safety database, which included sudden death (0.4%), torsade de pointes (less than 0.1%), grade 3-5 interstitial lung disease (0.8%), and Stevens-Johnson syndrome (0.7%).

QT prolongation is dose dependent with a mean prolongation of 35 ms in patients receiving 300 mg vandetanib, according to the FDA.

Given these adverse events, many panel members expressed concern about treating asymptomatic patients with medullary thyroid cancer, which has a long natural history that can involve periods of disease indolence, given the toxicity of the drug. Many panel members cited this as reason for the necessity of postmarketing evaluation of other doses.

The FDA usually follows the recommendations of its advisory panels. Panel members are cleared of potential conflicts of interest by the FDA before a meeting, but it occasionally grants a waiver to a panelist with a conflict of interest.

SILVER SPRING, MD – A Food and Drug Administration panel voted Dec. 2 that the risk-benefit profile of vandetanib is acceptable for at least some patients with medullary thyroid cancer, but that postmarketing evaluation of alternative dosing should be required by the agency as part of its approval.

The Oncologic Drugs Advisory Committee also was asked by the FDA to comment on whether the drug’s indication should be limited to patients with progressive, symptomatic medullary thyroid cancer, given concerns about the safety of the drug. The majority of panel members agreed that some restrictive language should be added to the indication in light of toxicity concerns, particularly the possibility of QTc prolongation.

"The risk-benefit profile is acceptable, from my perspective, for this drug to be approved for this indication. ... I think that there is enough of a signal at lower doses, which presumably would lead to less toxicity, that they should be explored," said panel member Dr. Mikkael Sekeres, who is a professor medicine at the Cleveland Clinic.

Dr. Wyndham Wilson of the National Cancer Institute, Rockville, Md., who is the panel chair, agreed. "It’s all about steady state levels, not about dose. ... The pharmacology data would suggest that you could probably get reasonable steady-state levels with a somewhat lower dose rate and still have equal effectiveness."

Vandetanib is an oral, multiple-tyrosine kinase inhibitor that acts on the vascular endothelial growth factor, epidermal growth factor receptor, and rearranged during transfection pathways. Medullary thyroid cancer patients with early-stage disease can be treated surgically with curative intent; for patients with distant metastases, the 5-year survival rate is approximately 40%.

AstraZeneca, the developer of vandetanib, is seeking an indication for patients with locally advanced or metastatic medullary thyroid cancer.

The drug was previously under investigation for the treatment of non–small cell lung cancer. However, the treatment with vandetanib did not improve overall survival benefit and only modestly improved progression-free survival (PFS) in this patient group.

In the phase III study, 331 patients with unresectable locally advanced or metastatic medullary thyroid cancer were randomized 2:1 to once-daily administration of either vandetanib 300 mg (the maximum tolerated dose) or placebo. AstraZeneca’s analysis showed a significant 54% reduction in risk of progression with vandetanib, improving median PFS by 11 months.

Dose reductions and interruptions because of adverse events in the phase III study and in two phase II studies were troubling, however. In the phase III trial, 36% of vandetanib patients required a dose reduction and 47% required a dose interruption.

Grade 3 or greater adverse events occurred in 55% of vandetanib-treated patients in the phase III trial, compared with 24% in the placebo group. The most common adverse events overall were diarrhea, rash, nausea, and hypertension.

The FDA and the panel were both particularly concerned about adverse event signals from the vandetanib safety database relating to QT interval prolongation, cerebrovascular events, interstitial lung disease/pneumonia and serious skin conditions. Of the total of 3,019 patients in safety database, 319 were treated with 300 mg vandetanib for medullary thyroid cancer.

According to the FDA, the incidence of grade 3-4 QTc prolongation in those patients was 8%. When ECGs were reviewed, more than 35% of patients experienced QTc prolongation greater than 60 ms – a grade 4 toxicity.

The panel was also concerned about events that occurred among the 3,019 patients in the overall safety database, which included sudden death (0.4%), torsade de pointes (less than 0.1%), grade 3-5 interstitial lung disease (0.8%), and Stevens-Johnson syndrome (0.7%).

QT prolongation is dose dependent with a mean prolongation of 35 ms in patients receiving 300 mg vandetanib, according to the FDA.

Given these adverse events, many panel members expressed concern about treating asymptomatic patients with medullary thyroid cancer, which has a long natural history that can involve periods of disease indolence, given the toxicity of the drug. Many panel members cited this as reason for the necessity of postmarketing evaluation of other doses.

The FDA usually follows the recommendations of its advisory panels. Panel members are cleared of potential conflicts of interest by the FDA before a meeting, but it occasionally grants a waiver to a panelist with a conflict of interest.