On Tuesday, an Oncologic Drugs Advisory Committee (ODAC) recommended that the FDA approve sunitinib (Sutent) and everolimus (Afinitor) for patients with advanced pancreatic neuroendocrine tumors (pNETs). Whereas the incidence of most cancers has been declining steadily over the years, cases of pNET are increasing and new, more effective therapies are desperately needed.
Everolimus was reviewed first, and the 10-member panel voted unanimously that the drug’s benefits outweigh its risks. Wyndham Wilson, MD, chief of the Lymphoma Therapeutics Section at the National Cancer Institute, chaired the ODAC panel. “This is a drug that does have serious side effects…. It’s also a drug that has effectiveness, as well.” He recommended that the FDA restrict the new indication for everolimus to patients with pNET who have the poorest risk scores, noting that the drug seemed to benefit these patients the most.
Everolimus is a mammalian target of rapamycin (mTOR) inhibitor made by Novartis and is already approved for the treatment of subependymal giant cell astrocytoma, advanced renal cell carcinoma in patients treated previously with sunitinib or sorafenib (Nexavar), and to prevent organ rejection in some kidney transplant patients. Novartis originally requested approval for everolimus to treat neuroendocrine tumors originating in the gastrointestinal tract, pancreas, or lungs, but limited its application to pNET at the FDA’s request.
Everolimus was evaluated in a large, international, double-blind trial (RADIANT-3), which enrolled 410 patients with varying grades of pNET. Patients were randomized to receive 10 mg of everolimus or placebo. The study design allowed patients who experienced progression to cross over to the everolimus arm, and nearly three-quarters (72.9%) of patients did so. RADIANT-3 showed that that, compared with placebo, everolimus was associated with a 65% decrease in the risk of progression and an increase in median progression-free survival (4.6 months to 11 months, respectively).
Nearly 20% of patients discontinued everolimus because of adverse effects. Grade 3/4 adverse events were observed in 61.8% of patients treated with everolimus compared with 40.4% of patients given placebo. The most common serious adverse effects are anemia, hyperglycemia, diarrhea, stomatitis, hypophosphatemia, and fatigue.
ODAC spent Tuesday morning reviewing the results of RADIANT-3 before voting. The committee did express concern about the serious adverse events associated with everolimus but concluded that they were “necessary risks” given the drug’s demonstrated efficacy in treating pNET, where there is high unmet need.
The same panel later voted 8 to 2 in favor of approving sunitinib for patients with advanced pNET. The committee expressed a lack of confidence in how the trial used to support the new indication was conducted, with Wilson noting that it was "kind of a poster child for everything that should not have happened in a trial."
The multicenter, phase 3 trial enrolled 171 patients and randomized them to 37.5 mg daily of sunitinib or to placebo until progression, death, or withdrawal. Patients in the sunitinib arm had longer median PFS compared with patients given placebo (11.4 months vs 5.5 months; P = .0001). The study was halted prior to reaching the secondary end point of overall survival because of the higher number of deaths and serious adverse events in the placebo arm, and patients were allowed to cross over to the sunitinib arm. No follow-up was conducted on the patients who crossed over.
Most panel members expressed confidence that the drug did benefit patients, but they said the way the trial was conducted left doubt about the extent of that benefit. Like everolimus, sunitinib is currently approved for renal cell carcinoma. It is also indicated for the second-line treatment of patients with gastrointestinal stromal tumors who progress on or are intolerant of imatinib (Gleevec).
Few drugs are available to treat pNET, and no new ones have been approved for the disease in the past 30 years. Having everolimus and sunitinib as treatment options for pNET would represent a major step forwardin the standard of care for patients with this disease.