US FDA ODAC backs Novartis’ Afinitor, Pfizer’s Sutent in rare pancreatic cancers
This article was originally published in Scrip
The US FDA's Oncologic Drugs Advisory Committee (ODAC) on 12 April backed approval of Novartis' Afinitor (everolimus) as a treatment for patients with a rare type of cancer, known as pancreatic neuroendocrine tumors (PNETs), voting unanimously that the drug's benefits outweighed its risks based on the medicine's demonstrated efficacy and safety profile.
In a separate afternoon session, the same ODAC also voted 8 to 2 that Pfizer's Sutent (sunitinib malate) had a favorable benefit-risk profile as a treatment for unresectable PNET, despite the unclear magnitude of the treatment effect, because data were based on an early terminated study.
Both drugs already are approved in the US for other cancer indications.
Panelist Dr Peter Choyke, chief of molecular imaging at the National Cancer Institute (NCI), said he was convinced that both drug's showed activity in patients with PNET.
He said he was "moved" to support approval of the drugs by the "argument that there is really nothing else out there" to treat PNETs, a rare cancer with a poor prognosis for metastatic disease and for which there are few therapeutic options.
PNETS, which account for up to 28% of all neuroendocrine tumors (NETs), are different from pancreatic adenocarcinoma, which account for about 95% of all pancreatic cancers. While PNET is typically considered an indolent disease, nearly 90% of patients are initially diagnosed with locally advanced or metastatic disease, explained Matthew Kulke, director of carcinoid and neuroendocrine tumor program at the Dana-Farber Cancer Institute in Boston.
"They clearly are fatal," he said.
Streptozocin, sold by Teva as Zanosar, is the only drug approved in the US to control PNETs, but it is limited to patients with symptomatic or progressive metastatic disease due to its highly toxic nature.
Dr Larry Kvols, head of oncologic sciences section at the Moffitt Cancer Center & Research Institute in Tampa, Florida, noted that streptozocin was approved nearly 30 years ago under "different efficacy standards".
Novartis' Sandostatin (octreotide acetate), which is approved for symptomatic treatment of diarrhea and flushing in patients with metastatic carcinoid tumors – NETS that are not of pancreatic origin – and vasoactive intestinal polypeptide-secreting tumors, also is used off-label for PNETs.
Dr Choyke said that although he backed approval of Afinitor in PNETs, he was "cautious, because the tempo of this disease is variable, from indolent to very aggressive". Afinitor's risk-benefit ratio supports use in patients with more aggressive PNETs, he insisted.
"There's a subgroup of patients that clearly benefit from this drug," said panelist Dr David Kelsen, chief of gastrointestinal oncology at Memorial Sloan-Kettering Cancer Center. "But I don't think it is for the entire group."
He urged the FDA to "take care" in drawing up the labeling for Afinitor in PNETs to ensure the drug is limited to only patients expected to progress on the drug.
Panelist Dr Kelsen insisted that Afinitor should not be given to PNET patients at their first diagnosis.
"Hopefully, the FDA and the sponsor will work very hard to identify the small group of patients who will benefit from this," he said.
Afinitor, a selective inhibitor of mammalian target of rapamycin, already is approved in 68 countries worldwide to treat advanced renal cell carcinoma at a once-daily 10mg dose. The drug also is approved in the US to treat subependymal giant-cell astrocytomas associated with tuberous sclerosis.
In seeking to expand the labeling for Afinitor, Novartis' initial supplemental new drug application (sNDA) for the advanced PNET indication also included gastrointestinal and lung NETs.
But on 8 April, the Basel, Switzerland-based drug maker revealed it would only seek the PNET indication (scripintelligence, 11 April 2011).
Lynne McGrath, US head of drug regulatory affairs for oncology global development at Novartis, acknowledged during the panel meeting that the company determined after reviewing the FDA's briefing documents ahead of the ODAC that there were "difficulties" involved in getting the broader NET indication.
Indeed, regulators questioned the reliability of the firm's data in the carcinoid trial, pointing to the high rate of discordance between the investigator and the central radiological review in the radiologic assessments.
Dr Kristen Snyder, a medical officer in the FDA's Office of Oncology Drug Products, also noted that the carcinoid trial failed to reach its primary endpoint of progression-free survival (PFS), and an interim analysis of overall survival also favored placebo over Afinitor.
With Pfizer's Sutent, which already is approved in the US to treat imatinib-refractory or intolerant gastrointestinal stromal tumors and locally advanced or metastatic renal cell carcinoma, the panel was grappling with how to judge the magnitude of the PFS benefit of the drug in PNET when dealing with data from a prematurely terminated single small Phase III study.
Pfizer's study of Sutent, a multikinase inhibitor, was stopped early in March 2009 at 73 PFS events based on the recommendations of the study's independent data monitoring committee after an analysis showed a greater PFS observed in the Sutent arm, while there was a higher number of deaths and serious adverse events in the placebo arm.
But Dr Gideon Blumenthal, a medical officer in the FDA's Division of Drug Oncology Products, said “Stopping trials prematurely for efficacy may overestimate the magnitude of the treatment effect”.
ODAC chairman Dr Wyndham Wilson, chief of lymphoma therapeutics at the NCI's Metabolism Branch, said it was a "glass half full or glass half empty" matter before the panel, which he said had to decide whether the data were so "encumbered" by the early study termination "that we don't have confidence in the overall totality of it."
But, he determined, "In a setting like this, I tend to look at it as the glass is half full".
But panelist Dr Tito Fojo, program director of medical oncology at the NCI, said, in this case, the glass was "only a quarter full, at best".
"But for a rare disease, it is OK to be a quarter full," Dr Fojo said. If the FDA approves Sutent for unresectable PNET, it will be left to "the community to sort out," he said.