NOUVEAUTES THERAPEUTIQUES DANS LES TUMEURS NEUROENDOCRINES DIGESTIVES (Radiothérapie vectorisée et loco-régionale exclue) Philippe RUSZNIEWSKI

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1 NOUVEAUTES THERAPEUTIQUES DANS LES TUMEURS NEUROENDOCRINES DIGESTIVES (Radiothérapie vectorisée et loco-régionale exclue) Réunion APRAMEN, Paris, 2 février 2013 Philippe RUSZNIEWSKI Pôle des Maladies de l Appareil Digestif Gastroentérologie-Pancréatologie, Hôpital Beaujon, Université Paris7 Denis-Diderot

2 Antitumoral treatment In patients with LM, consider surgery first resection of the primary and LM 1- or 2- step procedures (OLT in very selected cases) In patients with non-operable LM, consider a «watch and wait strategy» if and and General considerations - Indications WD grade 1 (2?) liver involvement < 50 % stable disease on consecutive CT scans Careful monitoring of efficacy symptoms, markers, CT scan

3 Temozolomide in Pancreatic Neuroendocrine Tumors Retrospective Analysis n=30, 22 NF, 2 Gastrinoma, 2 Insulinoma, 2 VIPoma, 1 Glucag.,1 Gastr./Glucag. Best radiographic response (% change) Capecitabine 750 mg/m 2 x 2/day (d 1 14) Temozolomide 200 mg/m 2 x 1 (d 10 14); q 28 days G3/4 AEs (12%): Anemia, Thrombopenia, elevation of liver enzymes 70% PR (RECIST) Median PFS 18 months Strosberg et al, Cancer 2010

4 TARGETED THERAPIES

5 Somatostatin Analogs : Gastroenteropancreatic Neuroendocrine Tumors Management A compilation of the efficacy of different somatostatin analogues and different formulation. Mean (top) and median in parentheses. Modlin IM, et al. Aliment Pharmacol Ther. 2009

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7 Kaplan-Meier Analysis of Progression-Free Survival* 1.0 Estimate of median PFS: sunitinib: 11.1 months (95% CI: 7.4 NR) placebo: 5.5 months (95% CI: ) Survival probability Sunitinib Placebo Efficacy endpoint variable value (months) Hazard ratio (95% CI: ) P<0.001 Placebo, n Sunitinib, n *Preliminary results

8 Overall survival 1.0 Proportion of patients Number at risk Sunitinib Placebo Sunitinib Placebo HR=0.409 (95% CI 0.187, 0.894) P= Time (months)

9 Toxicity Adverse events in 20% of patients, n (%) Sunitinib (n=83) Placebo (n=82) Diarrhea 49 (59.0) 32 (39.0) Nausea 37 (44.6) 24 (29.3) Asthenia 28 (33.7) 22 (26.8) Vomiting 28 (33.7) 25 (30.5) Fatigue 27 (32.5) 22 (26.8) Hair color changes 24 (28.9) 1 (1.2) Neutropenia 24 (28.9) 3 (3.7) Abdominal pain 23 (27.7) 26 (31.7) Hypertension 22 (26.5) 4 (4.9) Hand foot syndrome 19 (22.9) 2 (2.4) Anorexia 18 (21.7) 17 (20.7) Stomatitis 18 (21.7) 2 (2.4) Dysgeusia 17 (20.5) 4 (4.9) Epistaxis 17 (20.5) 4 (4.9)

10 Overall survival two years after study closure Without adjustment for crossover With and without adjustment for crossover Median OS : 33 and 26.7 months, respectively Crossover in the placebo arm : 69 % Vinik A et al, ASCO 2012

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12 Progression free survival Percentage of event-free Censoring Times Everolimus (n/n = 109/207) Placebo (n/n = 165/203) Time (months) No. of patients still at risk Everolimus Placebo p-value obtained from stratified one-sided log-rank test Hazard ratio is obtained from stratified unadjusted Cox model Kaplan Meier median PFS Everolimus: months Placebo : 4.60 months HR: 0.35 (95% CI [0.27,0.45]) p-value: <

13 Toxicity Everolimus (n = 204) Placebo (n = 203) All Grades % Grade 3/4 % All Grades % Grade 3/4 % Stomatitis Rash 49 < Diarrhea Fatigue <1 Nausea Peripheral edema 20 <1 3 0 Decreased appetite Occurring in >20%

14 OPTIMISM Sunitinib and everolimus both effective at improving DFS, Even in patients in whom other treatments have failed GUARDED Everolimus : what about overall survival? Will pts have to take drugs for years? (stab, no cure) E S ; S E ; S+E? Adjuvant? Neoadjuvant? S/E + PRRT? How will side-effect profiles affect long-term adherence to treatment?

15 Progression free survival After a maximum of 24 months of follow-up per patient, median PFS was 23.7 months [95%CI: 13,1; not reached]. PFS rate at 18 months was 62%. Event (Progression or death any cause) Censored 18 (53%) 16 (47%) Median [95% CI] - Months 23.7 [13,1; -] % (SD) PFS rate at 6 months 91% (5%) PFS rate at 12 months 76% (7%) PFS rate at 18 months 62% (8%) PFS rate at 24 months 50% (9%) Ducreux et al, Asco 2012

16 Temozolamide bevacizumab in patients with digestive NETs Radiographic tumor response (RECIST) No. of patients No. among patients with No. among patients with Disease response (n=34) Pancreatic NETs (n=15) carcinoid tumors (n=19) % % % Partial response Stable disease Progressive disease Not evaluable 0 3 Kulke, JCO 2012

17 Temozolamide bevacizumab in patients with digestive NETs Kulke, JCO 2012

18 Take-home messages Tailor treatment aggressivity to the risk level «Watch and wait» SSAs for slowly evolutive lesions? STZ based combinations still a standard for pancreatic NETs (Chemo)embolization very effective, especially useful in midgut primaries (very few other possibilities) Sunitinib and everolimus now approved in pts with progressive lesions from pancreatic NETs. Studies needed to better assess their place in the therapeutic strategy Combinations of cytotoxic drugs and targeted therapies should be further studied