FDA Panel Backs Sunitinib for Pancreatic Neuroendocrine Tumors

SILVER SPRING, MD. – The benefits of treatment with the oral tyrosine kinase inhibitor sunitinib outweigh the risks as a treatment for patients with metastatic pancreatic neuroendocrine tumors, according to the majority of a Food and Drug Administration advisory panel.

The FDA’s Oncologic Drugs Advisory Committee voted 8 to 2 on April 12 that the drug’s risk-benefit profile was favorable for patients with this rare cancer, despite uncertainty over the magnitude of the drug’s effect on progression-free survival in a pivotal trial that was terminated early.

The panel did not vote specifically on whether to recommend approval.

Pfizer Inc. has proposed that sunitinib malate capsules, marketed as Sutent, be approved for the treatment of unresectable pancreatic neuroendocrine tumors (PNET). Panelists cited the rarity of the disease and the few treatment options available among the reasons for their positive votes on the risk-benefit question. Several noted that the drug’s labeling should indicate that most patients in the pivotal phase III study had metastatic disease, and that sunitinib should not be used to treat patients with indolent forms of the disease.

Sunitinib was approved in 2006 in the United States for treating locally advanced or metastatic renal cell carcinoma and for imatinib-refractory or -intolerant gastrointestinal stromal tumor (GIST). It was approved for treating PNET in 2010 in Europe.

The pivotal PNET trial compared 37.5 mg of sunitinib daily with placebo in patients with locally advanced or metastatic, well-differentiated, unresectable PNET with progressive disease within the past year. It was stopped early in February 2009, after benefits were identified favoring the treatment group. Based on a review of data on 154 patients, the data-safety monitoring board recommended that the study be terminated because of differences in progression-free survival events (49 on placebo vs. 24 on sunitinib), deaths (15 on placebo vs. 5 on sunitinib) and severe adverse events (28 on placebo vs. 20 on sunitinib).

In an intention-to-treat analysis of 86 patients on sunitinib and 85 patients on placebo, the median progression-free survival was 11.4 months among those on sunitinib, compared with 5.5 months among those on placebo, which represented a 68% reduction in risk, a highly statistically significant difference. Overall survival, a secondary end point, was higher among the treated patients, but the difference was not statistically significant.

There were no new or unexpected adverse events. Adverse events and toxicities associated with treatment were similar to the known safety profile of sunitinib, and included diarrhea and stomatitis. Two of the patients on sunitinib died of cardiac failure.

Panelists agreed there was evidence of benefit, but acknowledged FDA reviewers’s concerns that early termination of the study could have overestimated the magnitude of the treatment difference on progression-free survival, the primary end point of the study. FDA reviewers also raised concerns about possible unblinding because of well-known adverse effects of sunitinib, such as hypertension and changes in hair color.

A decision on approval is expected by the end of 2011, according to a company spokesperson.

The FDA usually follows the recommendations of its advisory panels. Panel members have been cleared of potential conflicts of interest by the FDA prior to meetings; occasionally, the agency grants a waiver to a panelist with a conflict, but this did not occur at this meeting.

SILVER SPRING, MD. – The benefits of treatment with the oral tyrosine kinase inhibitor sunitinib outweigh the risks as a treatment for patients with metastatic pancreatic neuroendocrine tumors, according to the majority of a Food and Drug Administration advisory panel.

The FDA’s Oncologic Drugs Advisory Committee voted 8 to 2 on April 12 that the drug’s risk-benefit profile was favorable for patients with this rare cancer, despite uncertainty over the magnitude of the drug’s effect on progression-free survival in a pivotal trial that was terminated early.

The panel did not vote specifically on whether to recommend approval.

Pfizer Inc. has proposed that sunitinib malate capsules, marketed as Sutent, be approved for the treatment of unresectable pancreatic neuroendocrine tumors (PNET). Panelists cited the rarity of the disease and the few treatment options available among the reasons for their positive votes on the risk-benefit question. Several noted that the drug’s labeling should indicate that most patients in the pivotal phase III study had metastatic disease, and that sunitinib should not be used to treat patients with indolent forms of the disease.

Sunitinib was approved in 2006 in the United States for treating locally advanced or metastatic renal cell carcinoma and for imatinib-refractory or -intolerant gastrointestinal stromal tumor (GIST). It was approved for treating PNET in 2010 in Europe.

The pivotal PNET trial compared 37.5 mg of sunitinib daily with placebo in patients with locally advanced or metastatic, well-differentiated, unresectable PNET with progressive disease within the past year. It was stopped early in February 2009, after benefits were identified favoring the treatment group. Based on a review of data on 154 patients, the data-safety monitoring board recommended that the study be terminated because of differences in progression-free survival events (49 on placebo vs. 24 on sunitinib), deaths (15 on placebo vs. 5 on sunitinib) and severe adverse events (28 on placebo vs. 20 on sunitinib).

In an intention-to-treat analysis of 86 patients on sunitinib and 85 patients on placebo, the median progression-free survival was 11.4 months among those on sunitinib, compared with 5.5 months among those on placebo, which represented a 68% reduction in risk, a highly statistically significant difference. Overall survival, a secondary end point, was higher among the treated patients, but the difference was not statistically significant.

There were no new or unexpected adverse events. Adverse events and toxicities associated with treatment were similar to the known safety profile of sunitinib, and included diarrhea and stomatitis. Two of the patients on sunitinib died of cardiac failure.

Panelists agreed there was evidence of benefit, but acknowledged FDA reviewers’s concerns that early termination of the study could have overestimated the magnitude of the treatment difference on progression-free survival, the primary end point of the study. FDA reviewers also raised concerns about possible unblinding because of well-known adverse effects of sunitinib, such as hypertension and changes in hair color.

A decision on approval is expected by the end of 2011, according to a company spokesperson.

The FDA usually follows the recommendations of its advisory panels. Panel members have been cleared of potential conflicts of interest by the FDA prior to meetings; occasionally, the agency grants a waiver to a panelist with a conflict, but this did not occur at this meeting.

SILVER SPRING, MD. – The benefits of treatment with the oral tyrosine kinase inhibitor sunitinib outweigh the risks as a treatment for patients with metastatic pancreatic neuroendocrine tumors, according to the majority of a Food and Drug Administration advisory panel.

The FDA’s Oncologic Drugs Advisory Committee voted 8 to 2 on April 12 that the drug’s risk-benefit profile was favorable for patients with this rare cancer, despite uncertainty over the magnitude of the drug’s effect on progression-free survival in a pivotal trial that was terminated early.

The panel did not vote specifically on whether to recommend approval.

Pfizer Inc. has proposed that sunitinib malate capsules, marketed as Sutent, be approved for the treatment of unresectable pancreatic neuroendocrine tumors (PNET). Panelists cited the rarity of the disease and the few treatment options available among the reasons for their positive votes on the risk-benefit question. Several noted that the drug’s labeling should indicate that most patients in the pivotal phase III study had metastatic disease, and that sunitinib should not be used to treat patients with indolent forms of the disease.

Sunitinib was approved in 2006 in the United States for treating locally advanced or metastatic renal cell carcinoma and for imatinib-refractory or -intolerant gastrointestinal stromal tumor (GIST). It was approved for treating PNET in 2010 in Europe.

The pivotal PNET trial compared 37.5 mg of sunitinib daily with placebo in patients with locally advanced or metastatic, well-differentiated, unresectable PNET with progressive disease within the past year. It was stopped early in February 2009, after benefits were identified favoring the treatment group. Based on a review of data on 154 patients, the data-safety monitoring board recommended that the study be terminated because of differences in progression-free survival events (49 on placebo vs. 24 on sunitinib), deaths (15 on placebo vs. 5 on sunitinib) and severe adverse events (28 on placebo vs. 20 on sunitinib).

In an intention-to-treat analysis of 86 patients on sunitinib and 85 patients on placebo, the median progression-free survival was 11.4 months among those on sunitinib, compared with 5.5 months among those on placebo, which represented a 68% reduction in risk, a highly statistically significant difference. Overall survival, a secondary end point, was higher among the treated patients, but the difference was not statistically significant.

There were no new or unexpected adverse events. Adverse events and toxicities associated with treatment were similar to the known safety profile of sunitinib, and included diarrhea and stomatitis. Two of the patients on sunitinib died of cardiac failure.

Panelists agreed there was evidence of benefit, but acknowledged FDA reviewers’s concerns that early termination of the study could have overestimated the magnitude of the treatment difference on progression-free survival, the primary end point of the study. FDA reviewers also raised concerns about possible unblinding because of well-known adverse effects of sunitinib, such as hypertension and changes in hair color.

A decision on approval is expected by the end of 2011, according to a company spokesperson.

The FDA usually follows the recommendations of its advisory panels. Panel members have been cleared of potential conflicts of interest by the FDA prior to meetings; occasionally, the agency grants a waiver to a panelist with a conflict, but this did not occur at this meeting.