Following the advice of its Oncologic Drugs Advisory Committee, FDA has limited the indication for Novartis' mTOR inhibitor Afinitor in pancreatic neuroendocrine tumors (PNET) to those patients with progressive disease.

FDA approved a PNET indication for Afinitor (everolimus) on May 5. Labeling states the drug is indicated for treatment of progressive PNET that is unresectable, locally advanced or metastatic. The indication is more restrictive than that originally proposed by Novartis, which sought approval merely for advanced PNET.

PNET is a rare disease, with fewer than 1,000 new cases in the U.S. each year, FDA said.

PNET is the third approved indication for Afinitor: the drug is also labeled for advanced renal cell carcinoma and subependymal giant cell astrocytoma. Everolimus also is approved under the brand name Zortress for prophylaxis of kidney transplant rejection.

Final labeling on the PNET indication conforms with views expressed by ODAC members at an April 12 meeting. The committee voted unanimously, 10-0, that everolimus' risk/benefit profile in PNET was favorable after finding that progression-free survival data from the pivotal study were robust under multiple analyses (Also see "Afinitor In Pancreatic Tumors: ODAC Sees Consistent Efficacy, But Favors Limits On Use" - Pink Sheet, 18 April, 2011.).

During a same-day review, ODAC voted 8-2 in favor of adding a PNET claim to the label of Pfizer's tyrosine kinase inhibitor Sutent (sunitinib), although complexities resulting from the pivotal study's early termination dampened the panel's enthusiasm for the drug (Also see "Sutent Pancreatic Tumor Study Shows Regulatory Pitfalls Of Stopping Early" - Pink Sheet, 18 April, 2011.).

Better Efficacy In More Progressive Disease

In their review of Afinitor, panelists said the efficacy data and drug-related toxicities support reserving everolimus for those patients with progressive disease or symptoms that require treatment (Also see "Pfizer's Sutent, Novartis' Afinitor Earn ODAC Backing For Pancreatic Tumors" - Pink Sheet, 12 April, 2011.).

Novartis's subgroup analyses suggested everolimus had a more favorable impact on patients with worse performance status, older patients and those with high-grade tumors.

The drug also was associated with serious safety concerns in the pivotal trial. There were seven deaths due to adverse events in the everolimus arm during the double-blind portion of the study, compared with one in the placebo group. These data are reflected in Afinitor's labeling for PNET.

Everolimus also was associated with a more than three-fold increase in the number of adverse event-related discontinuations and a greater incidence of pneumonitis, opportunistic infections and renal failure.

Multiple Efficacy Analyses Reflected In Labeling ...

The pivotal trial enrolled more than 400 patients with advanced low- or intermediate-grade disease who had radiologic evidence of progression within the preceding 12 months. The original endpoint of PFS assessed by independent radiology committee was changed during the study to PFS as determined by local investigator.

At the ODAC meeting there was extensive discussion about the impact of censoring on the efficacy analysis. Ultimately, panelists concluded that the efficacy data were robust no matter which analysis was used.

FDA apparently agreed. Three different efficacy analyses - investigator review, central radiological review and adjudicated review - all showed a statistically significant benefit with everolimus and are all included in labeling. According to the investigator-assessed analysis, the study's primary endpoint, everolimus was associated with a 65% reduced risk of progression and a median PFS improvement of 6.4 months.

...Along With Negative Carcinoid Tumor Study Results

Novartis had originally filed for both a PNET indication and a claim for advanced NET of gastrointestinal and lung origin. However, it withdrew the GI/lung indication request after receiving FDA's negative review, included in the agency's ODAC briefing book, of the pivotal carcinoid study upon which the claim was based.

The carcinoid trial showed no significant PFS benefit with everolimus, and the overall survival trend favored placebo. These summary results are included in the Afinitor label, and the Indications section states that safety and effectiveness in treating carcinoid tumors have not been established.

Interim analyses of the PNET study also showed no benefit on overall survival. FDA's approval of the PNET indication includes a post-marketing requirement for Novartis to submit final analyses of overall survival data from the PNET and carcinoid studies, the company said.

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

Afinitor's Pancreatic Tumor Indication Limited To Progressive Disease

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