FDA's Oncologic Drugs Advisory Committee on April 12 gave its blessing to both Pfizer's Sutent (sunitinib) and Novartis' Afinitor (everolimus) for treating rare pancreatic tumors, although the panel's enthusiasm for Sutent was tempered by complexities resulting from the pivotal trial's early termination.

ODAC voted that the risk/benefit profiles of sunitinib (8-2) and everolimus (10-0) were favorable for treatment of pancreatic neuroendocrine tumors (PNET). Pfizer is seeking an indication for unresectable PNET, while Novartis' proposed indication is for advanced disease.

Both endorsements were based on Phase III trials demonstrating improvements in progression-free survival ranging from approximately five to eight months, depending upon the analyses applied. Neither drug has yet demonstrated a significant benefit on overall survival.

Confidence Undermined By Data Monitoring Committee Actions

The road to panel endorsement was bumpier for sunitinib, as ODAC members questioned how confident they could be in the magnitude of PFS benefit seen with the tyrosine kinase inhibitor given early termination of the pivotal study.

The Phase III trial was originally designed to enroll 340 patients to observe 260 PFS events, with an interim analysis planned at 130 events. However, the study was terminated for efficacy reasons after only 81 events based upon the advice of the independent Data Monitoring Committee. The DMC's recommendation followed several reviews of interim efficacy data that were not pre-specified.

In meeting briefing documents, FDA raised concerns that the magnitude of PFS benefit seen in the study was uncertain in light of the early termination and the DMC's decision to take multiple looks at the data (Also see "Early Study Termination Is Key Issue In ODAC Review Of Pfizer's Sutent For Pancreatic Cancer" - Pink Sheet, 11 April, 2011.).

While committee members agreed the early halt made it difficult to assess the magnitude of benefit, they nevertheless said the drug had some activity in PNET, which is a rare disease with few approved treatments. Several panelists expressed hesitation that if sunitinib were not approved in PNET now, further study of the drug for this indication would cease.

Temporary voting member Tito Fojo, National Cancer Institute, said he voted yes although "the glass is actually about a quarter full at best. But for a rare disease it's OK to be a quarter full."

Committee members voting in both the majority and minority called on Pfizer to conduct additional studies with sunitinib in PNET, and they floated several design suggestions, including analyzing different dosing regimens of the drug, assessing efficacy against the other approved PNET treatment, Teva Parenteral Medicines' Zanosar (streptozocin), and even pitting sunitinib against everolimus in a head-to-head study.

Reserving Everolimus For Aggressive Disease

While the panel was more forceful in its support for everolimus than sunitinib, there was more discussion about recommending against use of Novartis' mTOR inhibitor for patients with early disease. Everolimus' efficacy data and drug-related toxicities suggest it is best reserved for those patients with more aggressive disease, panelists said.

Temporary voting member David Kelsen, Memorial Sloan-Kettering Cancer Center, said he believed a subgroup of patients would ultimately benefit from everolimus. However, the drug's labeling should recommend use only in patients who have progressed or have symptoms that require treatment. There should be "enough education so it will not be given to patients at the time of their first diagnosis," he said.

The committee's deliberations on everolimus were simplified by Novartis' decision to pursue only an indication in pancreatic tumors. The company notified FDA on April 4 that it no longer sought approval for advanced NET of gastrointestinal and lung origin, saying this decision was based on FDA "feedback."

The sponsor's turnabout apparently followed review of FDA's briefing book for the advisory committee meeting, which the company would have received about two weeks before the ODAC meeting.

FDA's briefing package was publicly released on April 8. In those documents, the agency highlighted the failure of the two pivotal trials - one in PNET, the other in carcinoid tumors - to support each other. While the PNET trial demonstrated significant improvement in PFS, ranging from six to eight months depending upon the analyses used, the carcinoid trial demonstrated no PFS benefit and the overall survival trend favored placebo (Also see "Discordant Trial Results Among Issues FDA Bringing To Advisory Panel Review Of Novartis' Afinitor" - Pink Sheet, 8 April, 2011.)

-Sue Sutter (s.sutter@elsevier.com)

Pfizer's Sutent, Novartis' Afinitor Earn ODAC Backing For Pancreatic Tumors

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