The consistency of the progression-free survival benefit with Novartis’ Afinitor (everolimus) led FDA’s Oncologic Drugs Advisory Committee to support the drug’s approval for treatment of advanced pancreatic neuroendocrine tumors (PNET) despite questions about the statistical treatment of data in the pivotal study.

At its April 12 meeting, ODAC unanimously voted that the risk-benefit profile in PNET was favorable, having found the everolimus PFS data to be robust under multiple analyses.

However, many members did not think everolimus, in light of its toxicities, was appropriate for a broad population of patients with advanced disease. They generally recommended it be reserved for patients with aggressive disease or symptoms in need of treatment (Also see "Pfizer's Sutent, Novartis' Afinitor Earn ODAC Backing For Pancreatic Tumors" - Pink Sheet, 12 April, 2011.).

If FDA follows the panel’s advice on everolimus labeling, it stands to reason the agency would apply the same limitations on a PNET indication for Pfizer’s Sutent (sunitinib), which ODAC reviewed the same day and also endorsed, albeit with less enthusiasm (see related story, Also see "Sutent Pancreatic Tumor Study Shows Regulatory Pitfalls Of Stopping Early" - Pink Sheet, 18 April, 2011.).

ODAC’s deliberations on everolimus were no doubt simplified by Novartis’ decision to pursue only a pancreatic tumor claim, where the PFS evidence was strongest, and to withdraw a claim for advanced NET of gastrointestinal or lung origin.

After seeing FDA’s critical review of the pivotal trial in carcinoid tumors being used to support the GI/lung indications in the agency’s briefing book for the ODAC meeting, which the company saw ahead of time, Novartis notified FDA on April 4 that it no longer sought approval for GI or lung tumors.

While the PNET trial demonstrated significant improvement in PFS, ranging from six to eight months depending upon the analysis 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.).

Advisory Committee Vote

10-0 that everolimus’ benefit-risk profile is favorable for the treatment of patients with advanced neuroendocrine tumors of pancreatic origin

Pursuing Approval In A Fourth Setting

Everolimus, an mTOR inhibitor, is approved as Afinitor for advanced renal cell carcinoma and subependymal giant cell astrocytoma. It is marketed as Zortress for prophlaxis of kidney transplant rejection.

PNET is a rare disease that can be marked by periods of indolence. Survival varies by stage, with median survival for metastatic disease approximately 17 months, according to data presented at the meeting.

Approved treatment options for PNET are limited. Teva Parenteral Medicines' Zanosar (streptozocin) is indicated for treatment of metastatic islet cell carcinoma of the pancreas. Labeling states that due to the drug's inherent renal toxicity, treatment should be limited to patients with symptomatic or progressive metastatic disease. Novartis' Sandostatin (octreotide acetate) is indicated for symptomatic treatment of diarrhea and flushing associated with carcinoid syndrome and vasoactive intestinal peptide tumors.

Novartis’ PNET 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 study employed a crossover design, whereby placebo patients who experienced disease progression could receive everolimus.

Changing The Endpoint

The original endpoint was PFS assessed by an independent radiology committee. However, the endpoint was changed during the trial to PFS as determined by the local investigator.

The change resulted from an interim analysis of the carcinoid study that showed widely divergent results between the PFS evaluations of investigators and the IRC. Novartis attributed the discordant results to the role of informative censoring by the IRC.

The protocol revision for the PNET study also added a review by an adjudication committee, which examined all patients in whom there was a difference in the investigator- or IRC-determined progression and a difference in the timing of determined progression of 126 or more days.

Three separate analyses of the results from the PNET study – based upon investigator assessment, IRC assessment and adjudication – all demonstrated a significant improvement in PFS ranging from six to eight months with consistent hazard ratios of 0.34-0.38. Interim analyses of the study have not shown a benefit in overall survival.

Novartis presented subgroup analysis suggesting a more favorable impact of everolimus on patients with worse performance status, older patients and those with higher grade tumors.

The safety profile was less reassuring. In the double-blind portion of the PNET trial, there were seven deaths due to adverse events in the everolimus arm, compared with one in the placebo group. Everolimus 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.

At the ODAC meeting, much of the discussion centered on the impact of censoring and the appropriate patient population in light of the drug’s toxicities.

Patients were censored for a variety of reasons in the PNET study, for example, when investigator-determined progression was not confirmed by the IRC but the patient had already started on other anticancer therapy. In the IRC-based analysis, half of all patients were censored.

Various analyses showed consistent efficacy results despite inherent biases, ODAC member Logan said.

Committee member Brent Logan, Medical College of Wisconsin, noted there was a lot of inconsistency between progression assessments in the various analyses. While the IRC analysis might have been biased due to informative censoring, the investigator-based analysis might have been biased from inadvertent unblinding due to everolimus’ toxicities, he said.

“Unfortunately it’s very difficult to untangle these potential biases and any attempt to do so relies on a number of assumptions,” Logan said. But “we do see consistency in the PNET study across the analyses … they do suggest a benefit of median PFS of about six months, six to eight months.”

Temporary voting member Tito Fojo, National Cancer Institute, said an investigator’s determination that a patient’s disease had progressed automatically introduced bias into the review of the IRC, which would censor the patient if it disagreed. As a result, the study likely made the drug look more effective than it actually was.

Limiting The Population

FDA Office of Oncology Drug Products Director Richard Pazdur noted that Novartis’ proposed indication for advanced PNET is broad and could include patients with minimal disease. “With any disease there’s a variation in the natural history," he commented, "Would you want to put some caveats on which patients would be reasonable to treat with this?”

Pazdur observed that ODAC had a similar discussion about restricting the patient population in its December review of AstraZeneca’s medullary thyroid cancer treatment Zictifa (vandetanib), which is also associated with harsh adverse reactions.

In that case, a majority of committee members favored limiting vandetanib’s indication to patients with symptomatic or progressive disease to reduce the risk for drug-related toxicities. FDA followed this advice in its approval of vandetanib earlier this month (Also see "AstraZeneca's Vandetanib Approval Includes REMS With Distribution Restrictions" - Pink Sheet, 7 April, 2011.).

ODAC members generally agreed that the PNET patients who had more aggressive disease seemed to reap the greatest benefit from everolimus. Labeling the drug for use in such patients would reduce the risk that newly diagnosed patients, or those who are asymptomatic or have indolent tumors, would be exposed to everolimus’ toxicities.

Everolimus should be limited to patients with clear evidence of disease progression or symptoms that need to be addressed, temporary voting member David Kelsen, Memorial Sloan-Kettering Cancer Center, said. There should be “enough education so that it will not be given to patients right at the time of their first diagnosis.”

“All the hazard ratios are more favorable in the patients that have the worst performance status, who are older, who are the ones that have less well differentiated tumors, indicating that it seems to benefit those that are at higher risk,” ODAC Chairman Wyndham Wilson, National Cancer Institute, said. “I think that if there were some way to label this so it wasn’t quite so open, that we would be enhancing the risk-benefit.”

By Sue Sutter

Afinitor In Pancreatic Tumors: ODAC Sees Consistent Efficacy, But Favors Limits On Use

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