Toxicity of Vandetanib Is Expected Focus for FDA Advisory Committee

The Food and Drug Administration plans to ask its Oncologic Drugs Advisory Committee on Dec. 2 whether the "substantial toxicity" associated with AstraZeneca’s investigational medullary thyroid cancer drug Zictifa (vandetanib) warrants limiting the proposed indication to only those patients with progressive, symptomatic disease.

In meeting briefing documents released Nov. 30, the agency also leaves the door open to a post-marketing study requirement that would determine the optimal dose of vandetanib, potentially reducing the drug’s toxic effects.

Although the agency’s briefing documents do not appear to raise any major efficacy concerns, issues surrounding pivotal trial protocol violations and the large proportion of vandetanib patients that were censored in the agency’s phase III study analysis could impact the advisory committee’s interpretation of the efficacy data.

Salvaging Vandetanib for Thyroid Cancer

AstraZeneca is seeking an indication for treatment of unresectable, locally advanced or metastatic medullary thyroid cancer, a rare disease with approximately 2,000 new cases per year in the United States. Submitted in July, the NDA is undergoing a priority review, with a Jan. 7, 2010 user fee date. The application has orphan drug designation.

Vandetanib is an oral, multi-tyrosine kinase inhibitor that acts on the VEGF, EGFR and RET pathways. The RET pathway is understood to be the key driver in medullary thyroid cancer; RET mutations occur in most hereditary forms of the disease and in the tumors of 50%-80% of patients who have the sporadic, non-hereditary version, the FDA’s briefing documents say. Patients with early-stage disease can be treated surgically with curative intent; for patients with distant metastases, the five-year survival rate is approximately 40%.

AstraZeneca is hoping that vandetanib can find a niche role in thyroid cancer after failing to demonstrate an overall survival benefit, and showing only modest improvement in progression-free survival, in the far more lucrative indication of non-small cell lung cancer.

The company initially filed vandetanib (under the proposed name Zactima) for advanced NSCLC in the United States and Europe in June 2009. However, it withdrew the applications a mere four months later after preliminary feedback from regulators indicated that PFS data would not be sufficient to support approval). Data presented at the 2010 American Society of Clinical Oncology annual meeting also showed that vandetanib failed to improve overall survival in NSCLC.

While the PFS data may have been insufficient for approval in NSCLC, thyroid cancer is a different story.

The FDA’s briefing documents state that although the agency and sponsor did not reach agreement on a special protocol assessment for the pivotal phase III trial in thyroid cancer, the agency agreed that PFS assessed through blinded, independent review was an acceptable endpoint for full approval.

The NDA is supported by one phase III trial in 331 patients and two open-label phase II studies in a total of 49 patients.

In the phase III study, patients were randomized 2:1 to once-daily administration of either vandetanib 300 mg (the maximum tolerated dose) or placebo. Patients were treated until investigator-determined progression, and subjects in either arm could receive vandetanib after that determination. Imaging was performed at baseline and then every 12 weeks, and the results were assessed by the investigator and an Independent Review Committee (IRC).

AstraZeneca’s analysis showed a significant 54% reduction in risk of progression with vandetanib. "The benefit represents an approximately 11-month delay to the median PFS for patients receiving vandetanib (not reached in the vandetanib arm with median follow-up for 24 months, but estimated at 30 months, compared to 19 months for placebo)," the company’s briefing documents state.

Doubts About Overall Survival

Although the PFS findings appear robust, AstraZeneca is hedging its bets that a similar effect will not be seen on overall survival.

At the time of the primary PFS analysis, only 14% and 16% of vandetanib and placebo patients had died, respectively, and there was no significant difference in overall survival. The protocol calls for final survival analysis to be conducted when at least 50% of patients have died, which is projected to occur in 2012 or later.

"The survival comparison between vandetanib and placebo will likely be affected by the cross-over design of the study," AstraZeneca’s briefing documents state. "Furthermore, following review of the PFS analysis results, the study was unblinded on 06 January 2010 with FDA’s agreement and understanding of the potential for further confounding the planned survival update."

The FDA’s analysis of the PFS data also suggests robust, though different, results. The agency’s primary analysis found a significant 65% reduction in risk of progression with vandetanib, but said median PFS with the drug could not be estimated.

Calling the hazard ratio of 0.35 "remarkable," FDA reviewers nevertheless express concern about the number of censored events and the difference in percentage of censored events between the two groups. The FDA’s analysis employed different patterns of censoring than that of AstraZeneca, with the result being that 74.5% of vandetanib patients were censored, compared with 59% in the placebo arm.

"Censoring is primarily due to the lack of correlation between investigator and IRC-read scans," the agency says. "Only 88/174 (50.6%) scans were read as progression by both the investigator and IRC."

Clinical Trial Conduct Under Review

In addition to the censoring issue, the agency hints at concerns about study conduct that could cast a shadow on the efficacy findings. Protocol violations occurred in 21.2% of vandetanib-treated patients and 27% of subjects in the placebo arm. "These included the absence of measurable disease by investigator in 14 patients, the absence of a confirmed histological diagnosis in one patient and one patient who received the incorrect treatment," the FDA says. "Inspection of the clinical sites has resulted in several observations that are under review."

The phase II trials assessed response rates (complete response plus partial response). In one study that evaluated an initial daily dose of 300 mg vandetanib, investigator and IRC-assessed response rates were 20% and 16.7%, respectively. A second study evaluated a 100 mg dose, and the investigator response rate was15.8%.

The phase II study response rates were considerably lower than those seen in the phase III study, where the investigator and IRC response rates for vandetanib were 39% and 44.6%, respectively.

Adverse Event Concerns Could Tip Risk/Benefit

Dose reductions and interruptions due to adverse events were a prominent issue in all three studies. In the phase III trial, 35.9% of vandetanib patients required a dose reduction and 47.2% required a dose interruption.

Serious adverse events occurred in 30.7% of vandetanib-treated patients in the phase III trial, with the most common events being diarrhea, pneumonia, and hypertension.

The agency expresses particular concerns about AE signals from the 3,000-patient vandetanib safety database relating to QT interval prolongation, cerebrovascular events, interstitial lung disease/pneumonia, and serious skin conditions.

"Vandetanib at a dose of 300 mg is associated with a substantial (mean effect 35 ms) and concentration-dependent prolongation in QTc," the FDA says. "This increase in mean QTc does not lessen over time and the half-life of vandetanib (19 days) makes this prolongation in QTc interval particularly problematic. In addition to QTc prolongation, the majority of the severe adverse events seen with both EGFR and VEGFR inhibitors have been reported with vandetanib. This includes Stevens-Johnson syndrome, some ischemic arterial events, and interstitial lung disease."

The safety profile is raised in the FDA’s one voting question for ODAC: "Given the substantial toxicity observed with vandetanib and the long natural history of the disease, is the risk-benefit profile acceptable for the proposed indication or should the indication be limited to patients with progressive, symptomatic medullary thyroid cancer?" The agency also seeks the committee’s views on other subgroups that may be appropriate for treatment.

On the issue of dosing, AstraZeneca proposes "dosing to tolerance," starting with an initial daily dose of 300 mg, with reductions as necessary to manage side effects and avoid discontinuation in most patients "to maintain the maximum possible derived clinical benefit and engagement with molecular targets over many months to years." However, the FDA is asking ODAC whether additional doses should be explored as a post-marketing study requirement to determine the optimal dose and potential study designs for accomplishing this.

Used with permission from "The Pink Sheet." Internal Medicine News Digital Network and "The Pink Sheet" are owned by Elsevier.

The Food and Drug Administration plans to ask its Oncologic Drugs Advisory Committee on Dec. 2 whether the "substantial toxicity" associated with AstraZeneca’s investigational medullary thyroid cancer drug Zictifa (vandetanib) warrants limiting the proposed indication to only those patients with progressive, symptomatic disease.

In meeting briefing documents released Nov. 30, the agency also leaves the door open to a post-marketing study requirement that would determine the optimal dose of vandetanib, potentially reducing the drug’s toxic effects.

Although the agency’s briefing documents do not appear to raise any major efficacy concerns, issues surrounding pivotal trial protocol violations and the large proportion of vandetanib patients that were censored in the agency’s phase III study analysis could impact the advisory committee’s interpretation of the efficacy data.

Salvaging Vandetanib for Thyroid Cancer

AstraZeneca is seeking an indication for treatment of unresectable, locally advanced or metastatic medullary thyroid cancer, a rare disease with approximately 2,000 new cases per year in the United States. Submitted in July, the NDA is undergoing a priority review, with a Jan. 7, 2010 user fee date. The application has orphan drug designation.

Vandetanib is an oral, multi-tyrosine kinase inhibitor that acts on the VEGF, EGFR and RET pathways. The RET pathway is understood to be the key driver in medullary thyroid cancer; RET mutations occur in most hereditary forms of the disease and in the tumors of 50%-80% of patients who have the sporadic, non-hereditary version, the FDA’s briefing documents say. Patients with early-stage disease can be treated surgically with curative intent; for patients with distant metastases, the five-year survival rate is approximately 40%.

AstraZeneca is hoping that vandetanib can find a niche role in thyroid cancer after failing to demonstrate an overall survival benefit, and showing only modest improvement in progression-free survival, in the far more lucrative indication of non-small cell lung cancer.

The company initially filed vandetanib (under the proposed name Zactima) for advanced NSCLC in the United States and Europe in June 2009. However, it withdrew the applications a mere four months later after preliminary feedback from regulators indicated that PFS data would not be sufficient to support approval). Data presented at the 2010 American Society of Clinical Oncology annual meeting also showed that vandetanib failed to improve overall survival in NSCLC.

While the PFS data may have been insufficient for approval in NSCLC, thyroid cancer is a different story.

The FDA’s briefing documents state that although the agency and sponsor did not reach agreement on a special protocol assessment for the pivotal phase III trial in thyroid cancer, the agency agreed that PFS assessed through blinded, independent review was an acceptable endpoint for full approval.

The NDA is supported by one phase III trial in 331 patients and two open-label phase II studies in a total of 49 patients.

In the phase III study, patients were randomized 2:1 to once-daily administration of either vandetanib 300 mg (the maximum tolerated dose) or placebo. Patients were treated until investigator-determined progression, and subjects in either arm could receive vandetanib after that determination. Imaging was performed at baseline and then every 12 weeks, and the results were assessed by the investigator and an Independent Review Committee (IRC).

AstraZeneca’s analysis showed a significant 54% reduction in risk of progression with vandetanib. "The benefit represents an approximately 11-month delay to the median PFS for patients receiving vandetanib (not reached in the vandetanib arm with median follow-up for 24 months, but estimated at 30 months, compared to 19 months for placebo)," the company’s briefing documents state.

Doubts About Overall Survival

Although the PFS findings appear robust, AstraZeneca is hedging its bets that a similar effect will not be seen on overall survival.

At the time of the primary PFS analysis, only 14% and 16% of vandetanib and placebo patients had died, respectively, and there was no significant difference in overall survival. The protocol calls for final survival analysis to be conducted when at least 50% of patients have died, which is projected to occur in 2012 or later.

"The survival comparison between vandetanib and placebo will likely be affected by the cross-over design of the study," AstraZeneca’s briefing documents state. "Furthermore, following review of the PFS analysis results, the study was unblinded on 06 January 2010 with FDA’s agreement and understanding of the potential for further confounding the planned survival update."

The FDA’s analysis of the PFS data also suggests robust, though different, results. The agency’s primary analysis found a significant 65% reduction in risk of progression with vandetanib, but said median PFS with the drug could not be estimated.

Calling the hazard ratio of 0.35 "remarkable," FDA reviewers nevertheless express concern about the number of censored events and the difference in percentage of censored events between the two groups. The FDA’s analysis employed different patterns of censoring than that of AstraZeneca, with the result being that 74.5% of vandetanib patients were censored, compared with 59% in the placebo arm.

"Censoring is primarily due to the lack of correlation between investigator and IRC-read scans," the agency says. "Only 88/174 (50.6%) scans were read as progression by both the investigator and IRC."

Clinical Trial Conduct Under Review

In addition to the censoring issue, the agency hints at concerns about study conduct that could cast a shadow on the efficacy findings. Protocol violations occurred in 21.2% of vandetanib-treated patients and 27% of subjects in the placebo arm. "These included the absence of measurable disease by investigator in 14 patients, the absence of a confirmed histological diagnosis in one patient and one patient who received the incorrect treatment," the FDA says. "Inspection of the clinical sites has resulted in several observations that are under review."

The phase II trials assessed response rates (complete response plus partial response). In one study that evaluated an initial daily dose of 300 mg vandetanib, investigator and IRC-assessed response rates were 20% and 16.7%, respectively. A second study evaluated a 100 mg dose, and the investigator response rate was15.8%.

The phase II study response rates were considerably lower than those seen in the phase III study, where the investigator and IRC response rates for vandetanib were 39% and 44.6%, respectively.

Adverse Event Concerns Could Tip Risk/Benefit

Dose reductions and interruptions due to adverse events were a prominent issue in all three studies. In the phase III trial, 35.9% of vandetanib patients required a dose reduction and 47.2% required a dose interruption.

Serious adverse events occurred in 30.7% of vandetanib-treated patients in the phase III trial, with the most common events being diarrhea, pneumonia, and hypertension.

The agency expresses particular concerns about AE signals from the 3,000-patient vandetanib safety database relating to QT interval prolongation, cerebrovascular events, interstitial lung disease/pneumonia, and serious skin conditions.

"Vandetanib at a dose of 300 mg is associated with a substantial (mean effect 35 ms) and concentration-dependent prolongation in QTc," the FDA says. "This increase in mean QTc does not lessen over time and the half-life of vandetanib (19 days) makes this prolongation in QTc interval particularly problematic. In addition to QTc prolongation, the majority of the severe adverse events seen with both EGFR and VEGFR inhibitors have been reported with vandetanib. This includes Stevens-Johnson syndrome, some ischemic arterial events, and interstitial lung disease."

The safety profile is raised in the FDA’s one voting question for ODAC: "Given the substantial toxicity observed with vandetanib and the long natural history of the disease, is the risk-benefit profile acceptable for the proposed indication or should the indication be limited to patients with progressive, symptomatic medullary thyroid cancer?" The agency also seeks the committee’s views on other subgroups that may be appropriate for treatment.

On the issue of dosing, AstraZeneca proposes "dosing to tolerance," starting with an initial daily dose of 300 mg, with reductions as necessary to manage side effects and avoid discontinuation in most patients "to maintain the maximum possible derived clinical benefit and engagement with molecular targets over many months to years." However, the FDA is asking ODAC whether additional doses should be explored as a post-marketing study requirement to determine the optimal dose and potential study designs for accomplishing this.

Used with permission from "The Pink Sheet." Internal Medicine News Digital Network and "The Pink Sheet" are owned by Elsevier.

The Food and Drug Administration plans to ask its Oncologic Drugs Advisory Committee on Dec. 2 whether the "substantial toxicity" associated with AstraZeneca’s investigational medullary thyroid cancer drug Zictifa (vandetanib) warrants limiting the proposed indication to only those patients with progressive, symptomatic disease.

In meeting briefing documents released Nov. 30, the agency also leaves the door open to a post-marketing study requirement that would determine the optimal dose of vandetanib, potentially reducing the drug’s toxic effects.

Although the agency’s briefing documents do not appear to raise any major efficacy concerns, issues surrounding pivotal trial protocol violations and the large proportion of vandetanib patients that were censored in the agency’s phase III study analysis could impact the advisory committee’s interpretation of the efficacy data.

Salvaging Vandetanib for Thyroid Cancer

AstraZeneca is seeking an indication for treatment of unresectable, locally advanced or metastatic medullary thyroid cancer, a rare disease with approximately 2,000 new cases per year in the United States. Submitted in July, the NDA is undergoing a priority review, with a Jan. 7, 2010 user fee date. The application has orphan drug designation.

Vandetanib is an oral, multi-tyrosine kinase inhibitor that acts on the VEGF, EGFR and RET pathways. The RET pathway is understood to be the key driver in medullary thyroid cancer; RET mutations occur in most hereditary forms of the disease and in the tumors of 50%-80% of patients who have the sporadic, non-hereditary version, the FDA’s briefing documents say. Patients with early-stage disease can be treated surgically with curative intent; for patients with distant metastases, the five-year survival rate is approximately 40%.

AstraZeneca is hoping that vandetanib can find a niche role in thyroid cancer after failing to demonstrate an overall survival benefit, and showing only modest improvement in progression-free survival, in the far more lucrative indication of non-small cell lung cancer.

The company initially filed vandetanib (under the proposed name Zactima) for advanced NSCLC in the United States and Europe in June 2009. However, it withdrew the applications a mere four months later after preliminary feedback from regulators indicated that PFS data would not be sufficient to support approval). Data presented at the 2010 American Society of Clinical Oncology annual meeting also showed that vandetanib failed to improve overall survival in NSCLC.

While the PFS data may have been insufficient for approval in NSCLC, thyroid cancer is a different story.

The FDA’s briefing documents state that although the agency and sponsor did not reach agreement on a special protocol assessment for the pivotal phase III trial in thyroid cancer, the agency agreed that PFS assessed through blinded, independent review was an acceptable endpoint for full approval.

The NDA is supported by one phase III trial in 331 patients and two open-label phase II studies in a total of 49 patients.

In the phase III study, patients were randomized 2:1 to once-daily administration of either vandetanib 300 mg (the maximum tolerated dose) or placebo. Patients were treated until investigator-determined progression, and subjects in either arm could receive vandetanib after that determination. Imaging was performed at baseline and then every 12 weeks, and the results were assessed by the investigator and an Independent Review Committee (IRC).

AstraZeneca’s analysis showed a significant 54% reduction in risk of progression with vandetanib. "The benefit represents an approximately 11-month delay to the median PFS for patients receiving vandetanib (not reached in the vandetanib arm with median follow-up for 24 months, but estimated at 30 months, compared to 19 months for placebo)," the company’s briefing documents state.

Doubts About Overall Survival

Although the PFS findings appear robust, AstraZeneca is hedging its bets that a similar effect will not be seen on overall survival.

At the time of the primary PFS analysis, only 14% and 16% of vandetanib and placebo patients had died, respectively, and there was no significant difference in overall survival. The protocol calls for final survival analysis to be conducted when at least 50% of patients have died, which is projected to occur in 2012 or later.

"The survival comparison between vandetanib and placebo will likely be affected by the cross-over design of the study," AstraZeneca’s briefing documents state. "Furthermore, following review of the PFS analysis results, the study was unblinded on 06 January 2010 with FDA’s agreement and understanding of the potential for further confounding the planned survival update."

The FDA’s analysis of the PFS data also suggests robust, though different, results. The agency’s primary analysis found a significant 65% reduction in risk of progression with vandetanib, but said median PFS with the drug could not be estimated.

Calling the hazard ratio of 0.35 "remarkable," FDA reviewers nevertheless express concern about the number of censored events and the difference in percentage of censored events between the two groups. The FDA’s analysis employed different patterns of censoring than that of AstraZeneca, with the result being that 74.5% of vandetanib patients were censored, compared with 59% in the placebo arm.

"Censoring is primarily due to the lack of correlation between investigator and IRC-read scans," the agency says. "Only 88/174 (50.6%) scans were read as progression by both the investigator and IRC."

Clinical Trial Conduct Under Review

In addition to the censoring issue, the agency hints at concerns about study conduct that could cast a shadow on the efficacy findings. Protocol violations occurred in 21.2% of vandetanib-treated patients and 27% of subjects in the placebo arm. "These included the absence of measurable disease by investigator in 14 patients, the absence of a confirmed histological diagnosis in one patient and one patient who received the incorrect treatment," the FDA says. "Inspection of the clinical sites has resulted in several observations that are under review."

The phase II trials assessed response rates (complete response plus partial response). In one study that evaluated an initial daily dose of 300 mg vandetanib, investigator and IRC-assessed response rates were 20% and 16.7%, respectively. A second study evaluated a 100 mg dose, and the investigator response rate was15.8%.

The phase II study response rates were considerably lower than those seen in the phase III study, where the investigator and IRC response rates for vandetanib were 39% and 44.6%, respectively.

Adverse Event Concerns Could Tip Risk/Benefit

Dose reductions and interruptions due to adverse events were a prominent issue in all three studies. In the phase III trial, 35.9% of vandetanib patients required a dose reduction and 47.2% required a dose interruption.

Serious adverse events occurred in 30.7% of vandetanib-treated patients in the phase III trial, with the most common events being diarrhea, pneumonia, and hypertension.

The agency expresses particular concerns about AE signals from the 3,000-patient vandetanib safety database relating to QT interval prolongation, cerebrovascular events, interstitial lung disease/pneumonia, and serious skin conditions.

"Vandetanib at a dose of 300 mg is associated with a substantial (mean effect 35 ms) and concentration-dependent prolongation in QTc," the FDA says. "This increase in mean QTc does not lessen over time and the half-life of vandetanib (19 days) makes this prolongation in QTc interval particularly problematic. In addition to QTc prolongation, the majority of the severe adverse events seen with both EGFR and VEGFR inhibitors have been reported with vandetanib. This includes Stevens-Johnson syndrome, some ischemic arterial events, and interstitial lung disease."

The safety profile is raised in the FDA’s one voting question for ODAC: "Given the substantial toxicity observed with vandetanib and the long natural history of the disease, is the risk-benefit profile acceptable for the proposed indication or should the indication be limited to patients with progressive, symptomatic medullary thyroid cancer?" The agency also seeks the committee’s views on other subgroups that may be appropriate for treatment.

On the issue of dosing, AstraZeneca proposes "dosing to tolerance," starting with an initial daily dose of 300 mg, with reductions as necessary to manage side effects and avoid discontinuation in most patients "to maintain the maximum possible derived clinical benefit and engagement with molecular targets over many months to years." However, the FDA is asking ODAC whether additional doses should be explored as a post-marketing study requirement to determine the optimal dose and potential study designs for accomplishing this.

Used with permission from "The Pink Sheet." Internal Medicine News Digital Network and "The Pink Sheet" are owned by Elsevier.