ODAC approves indication for sunitinib in treatment of PNET

The FDA’s Oncologic Drugs Advisory committee voted 8-2 today in support of the use of Pfizer’s sunitinib in the treatment of unresectable pancreatic neuroendocrine tumors.

ODAC approved everolimus (Afinitor, Novartis) for use in pancreatic neuroendocrine tumors and advanced carcinoid tumors earlier in the day.

Committee members grilled Pfizer representatives on their reasons for closing the trial after only 28% of planned PFS events had been observed, and researchers took multiple early looks at data.

“There is no doubt there is a signal here,” said. Wyndham Wilson, MD, chief of the NCI lymphoma therapeutics section and committee chair. “The question is: How much is the early stoppage overestimating that signal?”

In the end, the committee decided that the risk/benefit associated with sunitinib, and the lack of treatment options available for this disease, were reason enough to grant the indication.

“This is a population that has limited options and this drug was already approved,” said Virginia Mason, RN, who voted an “unenthusiastic yes.” “Clearly, there are people who felt sunitinib had useful purposes in other areas. Hopefully, it proves useful in this area as well.”

Pfizer submitted results from A6181111, a randomized, double-blind, placebo-controlled, multinational trial in support of the request. From June 2007 to April 2009, 171 patients with locally advanced or metastatic well-differentiated pancreatic islet cell tumor at 42 centers in 11 countries were assigned to 37.5 mg daily oral sunitinib (Sutent) or placebo (n=85).

Pfizer said progression-free survival (PFS) was 11.4 months for patients assigned to sunitinib (n=86) compared with 5.5 months for patients assigned to placebo (HR=0.418; 95% CI, 0.263 - 0.662). The company performed an FDA-request reanalysis and found that median PFS was 12.6 months in the sunitinib arm vs. 5.4 months in the placebo arm (HR=0.401; 95% CI, 0.252-0.640).

An FDA analysis of PFS, however, found a median PFS of 10.2 months for sunitinib vs. 5.4 months for placebo (HR=0.427; 95% CI, 0.271 to 0.673). Additionally, the agency recorded 32 events for sunitinib compared with 22 events in the A6181111 study.

“The early signal of improved PFS with sunitinib did not cross a pre-specified efficacy boundary,” FDA staffers wrote. “Stopping trials prematurely for efficacy may overestimate the magnitude of the observed treatment effect.”

Jean Grem, MD, professor of internal medicine in the department of hematology/oncology at the University of Nebraska Medical Center, voted in favor of the indication, despite serious questions about the efficacy of sunitinib.

“There’s no evidence there’s a survival advantage to this drug. On a small study, the separation of survival curves could be just due to chance,” she said. “We’re left with the progression-free survival and, as a number of speakers have pointed out, sunitinib improved progression-free survival but we’re not sure how much. That’s the bottom line.”

The study was not powered to detect overall survival (OS), but as of the study termination date (April 15, 2009), OS was 10.2 months in the sunitinib arm and 11.1 months in the placebo arm, according to the FDA. At the December 2009 cut-off, HR for OS was 0.594 (95% CI, 0.340-1.038). The most recent OS cut-off, June 1, 2010, showed an HR of 0.737 (95% CI, 0.465-1.168).

Nine patients in the sunitinib group had died at study termination compared with 21 patients assigned to placebo (HR=0.409; 95% CI, 0.187-0.894). Seven patients died of disease progression while two died of cardiac failure.

There was no statistically significant difference in OS, which the FDA said was complicated by a 69% rate of crossover.

FDA said treatment-related grade-3/grade-4 adverse events were observed in 26.5% of patients in the sunitinib group vs. 41.5% of patients treated with placebo. Most common serious adverse events recorded in the sunitinib group were neutropenia (12.0%), hypertension (9.6%), palmar-plantar erythrodysesthesia syndrome (6.0%) and leukopenia (6.0%).

Twelve patients discontinued treatment with sunitinib due to toxicity. – by Jason Harris

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