EVEROLIMUS AND SUNITINIB FOR PANCREATIC NEUROENDOCRINE TUMORS

July 8, 2010 — Another targeted therapy has had a major impact on pancreatic neuroendocrine tumors in a phase 3 clinical trial, so now everolimus (Afinitor, Novartis) and sunitinib (Sutent, Pfizer) are set to offer new treatment options in these patients.

Both drugs are already marketed for use in kidney cancer and for other indications. The new data for pancreatic neuroendocrine tumors have already been filed with regulatory authorities for sunitinib, and there are plans to file for everolimus for this new indication.

Pancreatic neuroendocrine tumors affect the hormone-producing tissues within the pancreas, and are relatively rare, affecting annually only 2 to 4 people per million worldwide. However, the incidence is rising, and has quadrupled in the past 30 years, according to data from the National Cancer Institute. The most common treatment is surgery, which can be curative, but patients who are not suitable candidates have been treated with chemotherapy. Targeted agents now stand to offer a new treatment option, with lower toxicity and the convenience of oral dosing.

New Data With Everolimus

The latest results, reported at the 12th World Congress on Gastrointestinal Cancer in Barcelona, Spain, show that everolimus significantly increased progression-free survival in a placebo-controlled phase 3 trial of 410 patients, the largest study ever conducted in this tumor type.

The results, presented at the meeting by James Yao, MD, from the University of Texas M.D. Anderson Cancer Center in Houston, showed that everolimus increased progression-free survival to 11 months, compared with 4.6 months for placebo and best supportive care (hazard ratio [HR], 0.35; P < .0001).

This is similar to the improvement in progression-free survival seen with sunitinib in a phase 3 trial reported earlier this year, which was stopped early because of the benefit seen. That trial involved 171 patients, and sunitinib improved progression-free survival to 11.4 months, compared with 5.5 months for placebo and best supportive care (HR, 0.418; P = .0001).

New data from that trial, including results for overall survival, were reported at the Barcelona meeting by the principal investigator, Eric Raymond, MD, professor of medical oncology at Beaujon University Hospital in Clichy, France.

The 1-year median overall survival was 90% in the sunitinib group and 70% in the placebo group, Dr. Raymond reported. The latest data, at 20 months, show that the benefit in the sunitinib group was sustained, with overall survival remaining at 90%, but it fell to below 60% in the placebo group (HR, 0.409; P = .0204).

Because the data for progression-free survival were so similar for sunitinib and everolimus, Dr. Raymond said he was very surprised that there was no overall survival benefit in the everolimus trial. The follow-up was about 2 years, and yet the survival curves were "very similar," he told Medscape Medical News.

David Lebwohl, MD, from Novartis Oncology, said in an interview that there was no difference in the survival curves, and explained that this was to be expected because of the design of the trial, which allowed patients who were on placebo to cross over to everolimus as soon as they progressed. Hence, in effect, the trial was comparing everolimus given initially with everolimus given later, he said. This design was specifically asked for by the investigators involved; it was considered to be the only ethical approach, in view of the benefit that had already been seen with everolimus in pancreatic neuroendocrine tumors in an earlier phase 2 study.

Dr. Lebwohl also said that the design of the sunitinib trial was somewhat different, in that the patients were unblinded and the placebo patients were offered the active drug only after a prespecified period of time had elapsed.

Change in the Way Patients Are Treated

Both Dr. Lebwohl and Dr. Raymond predicted that the new data will lead to a change in the way that patients with pancreatic neuroendocrine tumors are treated. In the past, patients who were unsuitable for surgery had been treated with chemotherapy, including streptozocin, anthracyclines, and fluoropyrimidines, but the data for this come from old studies and do not show a definitive benefit, unlike the new data with the targeted agents. In addition, the targeted agents are less toxic and have the convenience of oral dosing.

These new data "will change the way that these patients are treated," Dr. Lebwohl said.

The targeted agents represent a "major advance" in the treatment of this rare cancer, Dr. Raymond noted.

He also said that he uses sunitinib as his first choice, and is doing so in his patients on a compassionate-use program.

"I may be biased in this opinion, as I conducted the trial and I have more clinical experience with sunitinib," he said, "but I would not jeopardize the chance of a longer overall survival for the patient. It would appear that the earlier you start sunitinib, the greater the benefit, so I would start with sunitinib and then, if the patient progresses, I would try everolimus."

Dr. Raymond said that this is similar to the way he is using these drugs in kidney cancer, where he also starts with sunitinib and then uses everolimus at progression.

"This translates to a very human story," Dr. Raymond said, noting the he has patients who took part in the trial and who have now been on sunitinib for more than 3 years. "They are taking sunitinib continuously and this seems to be keeping the tumor under control," he added.

Previously, the median overall survival for patients with advanced pancreatic neuroendocrine tumors has been 24 months.

Approached for independent comment, Wasif Saif, MD, associate professor of medicine and director of the gastrointestinal cancers program at Yale University School of Medicine in New Haven, Connecticut, said that the phase 3 studies of everolimus and sunitinib both "showed promising and somewhat similar data."

"In my opinion, it's great news, as tolerance can be different in patients" and it is useful to have more than 1 agent to choose from, he added.

"Pancreatic neuroendocrine tumors are generally felt to be indolent, although the majority do present at an advanced stage," Dr. Saif said. "In the past, treatment options have been limited, with hormonal treatment with octreotide being the primary therapeutic approach. Chemotherapeutic agents have been used with limited efficacy; [they are] less effective in well-differentiated tumors," he explained, adding that "targeted therapy has a clear role."

Dr. Saif will be moving soon; after August 1, he will be professor of medicine at Columbia University, director of gastrointestinal cancers at the Herbert Irving Cancer Center, and medical director of the Pancreas Center at the New York Presbyterian Hospital in New York City.

Both phase 3 studies were sponsored by the manufacturers.

12th World Congress on Gastrointestinal Cancer: Abstracts O-0028 and O-0009. Presented on June 30, 2010.