Everolimus-Octreotide Winning Combo for Neuroendocrine Tumors

Fran Lowry

December 01, 2011

December 1, 2011 — Adding everolimus to octreotide improves progression-free survival, compared with octreotide alone, in patients with advanced neuroendocrine tumors associated with carcinoid syndrome, according to research published online November 25 in the Lancet.

The extra 5.1 months of progression-free survival achieved with the combination represents "a clinically important and relevant advance in terms of treatment of these patients," senior investigator James C. Yao, MD, from the University of Texas M.D. Anderson Cancer Center in Houston, told Medscape Medical News.

"There is currently no US Food and Drug Administration (FDA)-approved treatment for advanced neuroendocrine tumors outside the pancreas," Dr. Yao said. "At the same time, the diagnosed incidence of the disease has been rising in population-based registries such as SEER, so there is definitely an unmet medical need for effective treatment."

It has previously been shown that everolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR), has antitumor activity in patients with advanced pancreatic neuroendocrine tumors. The overaction of mTOR has been implicated in the pathogenesis of neuroendocrine tumors.

A previous phase 2 study conducted by Dr. Yao and colleagues (J Clin Oncol. 2008;26:4311-4318) showed that everolimus had promising anticancer activity in neuroendocrine tumors. A subsequent international randomized phase 3 study (N Engl J Med. 2011;364:514-523) showed that everolimus improved progression-free survival in pancreatic neuroendocrine tumors, a related disease. The results of that phase 3 study, known as RADIANT-3, led to the FDA approval of everolimus for the treatment of advanced pancreatic neuroendocrine tumors in May.

Octreotide, a somatostatin analogue, improves hormone-related symptoms associated with neuroendocrine tumors. The long-acting formulation (octreotide LAR [long-acting repeatable]) has also shown antitumor activity, prolonging time to disease progression in patients with certain types of neuroendocrine tumors.

Results From RADIANT-2

In the current randomized placebo-controlled phase 3 study, dubbed RADIANT-2, Dr. Yao and colleagues sought to assess the effectiveness of the combination of everolimus plus octreotide LAR in patients with low- or intermediate-grade neuroendocrine tumors associated with carcinoid syndrome.

In the study, 429 patients with unresectable locally advanced or distant metastatic neuroendocrine tumors were randomized to receive either oral everolimus 10 mg daily or placebo, both in conjunction with intramuscular octreotide LAR 30 mg every 28 days. Treatment was continued until disease progression, withdrawal from treatment because of adverse effects, or withdrawal of consent.

Of these patients, 357 discontinued study treatment and 1 was lost to follow-up.

The study found that median progression-free survival was 16.4 months (95% confidence interval [CI], 13.7 to 21.2) in the combination group and 11.3 months (95% CI, 8.4 to 14.6) in the monotherapy group (hazard ratio, 0.77; 95% CI, 0.59 to 1.00; P = .026).

The adverse effects were higher in the combination group than in the monotherapy group, although they were manageable. They were mostly grade 1 or 2, and included stomatitis (62% vs 14%), fatigue (31% vs 23%), and diarrhea (27% vs 16%).

"There was a 23% reduction in the risk of progression in the group that got the combination," Dr. Yao reported. "This is a disease that has very few treatment options. In this study, it looks like this combination offers a significant delay in tumor growth. We plan to confirm these findings in future studies."

Worthwhile Advance

The addition of everolimus in patients with carcinoid syndrome seems to be a worthwhile advance, according to an accompanying comment by Guido Rindi, MD, from Università Cattolica-Policlinico A. Gemelli, Rome, Italy, and Martyn Caplin, MD, from Royal Free Hospital, London, United Kingdom. However, they note, the toxic effects related to everolimus are "not insignificant," and they point out that the survival benefit is unknown.

"Everolimus is undoubtedly an important advance for the management of carcinoid tumors, but any new advance creates many new questions about its best use," they write. Does everolimus have any role in the adjuvant setting? What is its effect on overall survival? And "most importantly," what is its effect on quality of life?

"These not-so-rare tumors do deserve more attention to further understand their biology and obtain answers to such crucial therapeutic questions," they conclude.

The study was funded by Novartis Pharmaceuticals. Dr. Yao reports a financial relationship with Novartis. Dr. Rindi and Dr. Caplin report financial relationships with Ipsen, Novartis, and Pfizer.

Lancet. Published online November 25, 2011. Abstract, Comment


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