About 1.3% of newly diagnosed pancreatic cancers are neuroendocrine tumours of the pancreas, which arise in the insulin-producing islets of Langerhans. Although these are not often as aggressive as the much more common adenopancreatic tumours, they are frequently diagnosed late and their prognosis is poor. Most patients are diagnosed with distant metastases and live for only about two years, and treatment options are limited. Only one drug, streptozocin, is licensed for this tumour type in the US. Recently, however, clinical trials of several targeted therapies for this cancer have shown promising results. One of these is everolimus, an inhibitor of a serine-threonine kinase known as mammalian target of rapamycin (mTOR) that stimulates the growth and proliferation of cell types that include pancreatic neuroendocrine tumour cells.

Following positive Phase II results, the RAD001 in Advanced Neuroendocrine Tumors (RADIANT-3) Phase III study was set up to evaluate everolimus in adult patients with advanced pancreatic neuroendocrine tumours [1, 2, 3]. A total of 410 patients from 18 countries were randomized to receive either 10 mg everolimus daily or a matched dose of placebo. All patients had been diagnosed with low- or intermediate-grade metastatic pancreatic neuroendocrine tumours, had experienced disease progression in the year preceding randomization, and had WHO performance status of 2 or less. Prior therapy with any drug other than another mTOR inhibitor was allowed.

Thirty-four percent of patients receiving everolimus were alive and progression-free 18 months after initiating treatment, compared to 9% of those in the placebo group, and the median progression-free survival was 11 months in the everolimus group compared to 4.6 months for placebo. This significant difference was seen in all subgroups of patients studied, with no significant difference in results when the patients were stratified by age, sex, race, WHO performance status, tumour grade or prior chemotherapy. Adverse effects were generally mild or moderate, with the most common side effects in the everolimus group being stomatitis (observed in 64% of patients), rash (49%), diarrhea and fatigue. However, one death of a patient receiving everolimus was attributed to the study drug.

Once the difference in outcome became apparent, patients receiving placebo were offered the opportunity to cross over to receive everolimus, and 73% of the patients initially randomized to receive placebo did cross over. Therefore, no significant difference in overall survival could be observed between the two initial arms, which limited the power of the study. Furthermore, most differences in progression free survival arose from tumour stabilization rather than objective responses. Nevertheless, these results do suggest that everolimus therapy may be effective in controlling this tumour.

Studies of rare genetic cancer syndromes have implicated two genes in the mTOR pathway, tuberin (TSC2) and phosphatase and tensin homologue (PTEN), in the development of sporadic pancreatic neuroendocrine tumours. The researchers in the RADIANT-3 study group now hope to evaluate mutations in these genes as biomarkers for everolimus response, and to test it in combination with other drugs including sunitinib, an oral drug that inhibits many tyrosine kinases but not mTOR and that has also shown some efficacy against this tumour type.

Articles:

[1]: Yao, J.C., Shah, M.H., Ito, T. and 14 others (RADIANT-3 Study Group) (2011), Everolimus for Advanced Pancreatic Neuroendocrine Tumors. N. Engl. J. Med. 364: 514-23.

[2]: Kirk, R. (2011). Hope for pancreatic neuroendocrine tumors. Nature Reviews Clinical Oncology 8: 191. doi:10.1038/nrclinonc.2011.33

[3] http://www.clinicaltrials.gov/ct2/show/NCT00510068