1. Everolimus for Advanced Pancreatic Neuroendocrine Tumors N Engl J Med 2011;364:514-23. R4. 박선희 / Prof. 동석호

2. BACKGROUND Pancreatic neuroendocrine tumors Incidence & prevalence ↑ Frequently diagnosed at a late stag e 65% patients : unresectable or metastatic dis.  poor prognosis Median survival time : 24 months  limited treatment options Streptozocin (CTx) Sunitinib Everolimus (RAD001) : oral inhibitor of mTOR

3. Mammalian target of rapamycin (mTOR) Insulin-like growth factor 1 (IGF-1)

4. METHODS Patients Eligible criteria : ≥18 yrs, low~intermediate grade advanced pancrearic NET, radiologic documentation of PD, prior CTx, presence of measurable dis. (RECIST), WHO performance status ≤2, adequate bone marrow & renal & hepatic function, controlled lipid & glucose Exclusion criteria : hepatic-artery embolization within 6mo., cryoablation or radiofrequency ablation of hepatic metastasis within 2mo., any severe or uncontrolled medical conditions, prior therapy hx of mTOR inhibitor, long-term tx c glucocorticoid or immunosuppressive agents.

5. Study design and treatment International, multicenter, double-blind, phase 3 study 2007.7~2009.5, 82 centers in 18 countries 2 treatment group : randomly assigned -Oral everolimus, 10mg once daily -Placebo Progression of the disease, unacceptable toxic effect, drug interruption for ≥ 3wks, withdrawal of consent PD(according to RECIST)  switch to open-label Tx Adverse events  dose reduction (5mg daily→5mg eod)

6. Efficacy and safety assessments Primary end point : progression-free survival The time from randomization to the first documentation of PD or death from any cause Not PD or dided  the time of the last adequate tumor assessment (overall lesion response) Secondary end points : confirmed objective response rate, the duration of response, overall survival and safety Efficacy (intention-to-treat analysis) Tumor measurements : baseline, every 12 weeks, local & central investigators Safety Monitoring and recording of all adverse events, regular monitoring of laboratory evaluations, vital signs, P/Ex every 4 weeks

7. RESULTS Median follow-up : 17 mo. Median duration of Tx : Everolimus, 8.79 mo. Placebo, 3.74 mo.

10. Figure 1.

13. Grade 1~2 adverse events : m/c Death 12 (6%), everolimus 4 (2%), placebo  8case (7/1)was related to the study drug Discontinuation 13%, everolimus 2%, placebo Adverse events necessitating dose adjustment - stomatitis, pneumonitis, thrombocytopenia, diarrhea, anemia

14. CONCLUSIONS Everolimus, as compared with placebo, improves progression-free survival in patients with advanced pancreatic neuroendocrine tumors. Adverse events : grade 1 and 2 events  allowing for long- term daily administration.