Monday, April 11, 2011

D-Day approaches for revolutionary treatments of pancreatic cancer

The Oncology Drugs Advisory Committee will meet to decide on whether to recommend approval of everolimus (Afinitor) and Sunitinib (Sutent) for the treatment of advanced pancreatic neuroendocrine tumors (PNET).

Pancreatic neuroendocrine tumors (PNET) are a rare subgroup of tumors found in the pancreas. Although pNET is rare, its incidence is rising. It is reported in between 2 million to 4 million people each year, and accounts for 9% of neuroendocrine tumors. PNET can be either functional or non-functional. Patients with functional tumours usually present with syndromes induced by secreted hormones including insulin, gastrin, glucagon, somatostatin, vasoactive intestinal polypeptide.

PNET are normally non-functional and have usually already metastasised (to the liver) by the time they are diagnosed explaining why most PNET patients are advanced stage at the time of diagnosis. PNET have a 5-year survival that can range from 97% in benign insulinomas to as low as 30% in non-functional metastatic PNET.

Surgery with curative intent is the mainstay of treatment for localized or loco-regional disease. Surgery as well as other forms of local treatment like transarterial chemoembolization or radiofrequency ablation can also improve prognosis in patients with liver metastases. Unfortunately however patients with pNET have few therapeutic options, and up untill recently no new drug has been approved for the disease for over 25 years.

Sutent became the first new treatment of PNET in December 2010 when it was approved by the EMA.

For further information on PNET see our recently featured report: Pipeline Insight: Cancer Overview Malignant Melanoma, Neuroendocrine Tumors and Thyroid Cancer

If recommended for approval tomorrow, everolimus (Afinitor) and Sunitinib (Sutent) should offer much needed hope to sufferers of this rare cancer. Afinitor probably stands the greatest chance of approval.

Afinitor is an mTOR inhibitor that has already been approved for the treatment of patients with advanced renal cell carcinoma after failure of treatment with Sutent. Pivotal studies reported that progression-free survival (PFS) more than doubled in patients with pNET treated with everolimus (Afinitor) versus placebo with best supportive care.

Novartis was seeking approval of everolimus for treatment of neuroendocrine tumors that are gastrointestinal, lung or pancreatic origin. But the FDA asked Novartis to update its new drug application to to seek approval only for treatment of tumors that begin in the pancreas, according to a press release from the company which was highlighted on today's issue of DailyUpdates-Oncology.

In briefing documents released ahead of Tuesday's advisory committee hearing, FDA reviewers analyzed the Novartis' large, international clinical trial that randomized patients with pNET to everolimus in addition to best supportive care or to placebo and best supportive care.

The final analyses included 274 patients, and found that patients treated with everolimus had a median progression-free survival (PFS) of 11 months, compared with 4.6 months among patients randomized to placebo (P<0.001).

Like Afinitor, Sutent was also able to dramatically increase PFS, doubling it to 11.4 months, versus 5.5 months in the placebo arm. Patients treated with sunitinib had a 71.3% probability of being alive and free of disease at six months, compared with 43.2% of the placebo group. Overall survival had not been reached after a median follow-up of 10-11 months.

Sutent is an oral multi-kinase inhibitor approved for the treatment of advanced/metastatic renal cell carcinoma and unresectable and/or metastatic malignant gastrointestinal stromal tumor (GIST) after failure of imatinib mesilate treatment. Sutent works by blocking multiple molecular targets implicated in the growth, proliferation and spread of cancer including VEGFR and PDGFR.

Despite promissing data, the FDA reviewers have expressed major concern that the trial was closed early. The trial was stopped after there were 81 progression-free survival events, which was just 31% of the events that the study design planned for. As a result the reviewers were concerned that the magnitude of PFS is uncertain and hence the benefit:risk assessment may also be uncertain.

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