ODAC approves everolimus for treatment of pancreatic neuroendocrine tumors

Issue: May 10, 2011

The FDA’s Oncologic Drugs Advisory Committee voted unanimously today to approve a supplemental new drug application from Novartis to use everolimus for the treatment of pancreatic neuroendocrine tumors.

The vote was 10-0.

Everolimus (Afinitor) is approved for the treatment of advanced renal cell carcinoma in patients who have received prior treatment with sunitinib or sorafenib and for the treatment of subependymal giant cell astrocytoma.

In voting to approve the measure, Wyndham Wilson, MD, chief of the NCI lymphoma therapeutics section and committee chair said he would like the indication limited only to the highest-risk patients because of the high incidence of toxicity and because the drug appears to have the most benefit in that subgroup.

“This is a drug that does have serious side effects,” he said. “It’s also a drug that has effectiveness, as well. This is a drug where the risk/benefit is going to be greatest in people who going to need therapy — it seems to benefit those who are at a higher risk.”

Novartis submitted data from the randomized phase-3 studies PNET and Carcinoid to support the application. In PNET, 410 patients with unresectable or metastatic PNET were recruited at 82 centers in 18 countries. Patients were assigned to 10 mg daily everolimus (n=204) or daily placebo (n=203).

Almost 73% of patients in the placebo group crossed over to everolimus upon investigator-determined progression.

At cutoff, median PFS was 11.0 months in the everolimus arm compared with 4.6 months for placebo as determined by local investigator (HR=0.35). An independent review committee determined PFS was 13.4 months vs. 5.7 months in favor of the experimental arm (HR=0.38)

At the time of the interim analysis of OS, 72.9% of the placebo arm had crossed over to everolimus. About one-quarter of patients in both groups had died at the time of analysis (adjusted HR=0.97; 95% CI, 0.66-1.41). Median OS had not been reached.

The investigator-determined response rate was 4.8% in the everolimus arm and 2.0% in the placebo arm. The independent-review committee found a response rate of 2.4% in the everolimus arm and 0.5% in the placebo arm.

About 20% of patients assigned to everolimus discontinued treatment due to adverse events compared with 5.9%. Researchers observed that 61.8% of patients assigned to everolimus experienced grade-3/grade-4 adverse events compared with 40.4% for placebo. Most common grade-3/grade-4 adverse events include anemia, hyperglycemia, somatitis, hypophosphatemia, diarrhea and fatigue.

In the Carcinoid study, patients with advanced carcinoid tumors, primarily gastrointestinal or lung NETs, and a history of secretory symptoms were enrolled at 93 centers in 15 countries. Patients were assigned to everolimus in conjunction with depot octreotide (n=216) or placebo plus depot octreotide (n=213).

Everolimus was associated with a 5.10 month improvement in median PFS compared with placebo (16.43 months vs. 11.33 months) as determined by independent adjudicated central assessment.

The adjudication committee determined that HR was 0.67 (95% CI, 0.47-0.97) for PFS for patients assigned to everolimus with a baseline performance status of 0; HR=0.74 0.74 (95% CI; 0.55-0.99) for patients with well-differentiated tumors and HR=0.72 (95% CI, 0.31-1.68) for patients with a lung as the primary site of disease.

According to independent central radiology review for PFS, HR=0.93 (95% CI, 0.71-1.22) while HR=0.78 (95% CI, 0.62-0.98) according to the investigator assessment.

Committee members cited informative censoring as a potentially important confounding factor in the PFS results based on the independent central radiology review and may have caused the discrepancy in the interim results. Informative censoring also the affected the independent adjudicated central assessment.

However, committee members determined that the benefits were strong enough to warrant approval and that there was a serious unmet need for treatment in this disease. – by Jason Harris

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