1. LANCET 2011; 378: 2005–12 R3 Kim Dong Hyun / Prof. Chin Sang Ouk Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study

2. INTRODUCTION Neuroendocrine tumours, known as carcinoids.  Survival varies by  Differentiated state (well > poor)  Presence of metastasis (locoregional > distant metastasis)  Primary site (jejunum, ileum, and cecum > lung and colon)  Somatostatin analogues ( octreotide and lanreotide)  Improvement of the hormone-related symptoms  Antitumour activity, prolonging time to disease progression

3. INTRODUCTION mTOR (The mammalian target of rapamycin)  Autocrine activation of the mTOR signalling pathway  Mediated through insulin-like growth factor I  Associated with neuroendocrine tumour cell proliferation  Everolimus, an oral inhibitor of mTOR  Antitumour activity in patients with advanced pancreatic neuroendocrine tumours

4. INTRODUCTION Goal  To assess the combination of everolimus plus octreotide long-acting repeatable (LAR) in patients with low-grade or intermediate-grade neuroendocrine tumours (carcinoid).

5. METHODS Participants  Between Jan 10, 2007, and April 2, 2010, multicenter, double- blind, phase 3 study in multiple countries.  Inclusion criteria  Aged 18 years or older  Low or intermediate-grade advanced neuroendocrine tumours,  Disease progression established by radiological assessment within the past 12 months.  History of secretory symptoms (diarrhea or flushing) attributable to carcinoid syndrome.

6. Procedures  Randomisation was done by interactive voice response systems  Randomly assigned participants (1:1)  10 mg oral everolimus once daily or matching placebo.  In conjunction with IM 30 mg octreotide LAR every 28 days.  Treatment continued until disease progression or withdrawal from treatment because of adverse events. METHODS

7. Procedures - continued  Primary endpoints  Progression-free survival  Secondary endpoints  Objective response rate  Overall survival  Changes from baseline in 5-hydroxyindoleacetic acid and chromogranin A concentrations  Safety METHODS

8. RESULTS

11. Central radiology review Local investigator reivew

14. 24 h urinary 5-hydroxyindoleacetic acid concentrations Serum chromogranin A p treatment=0.0041 p treatment <0.0001

16. Conclusion Everolimus plus octreotide LAR, compared with placebo plus octreotide LAR, improved progression free survival in patients with advanced neuroendocrine tumours associated with carcinoid syndrome.