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Sunitinib et TNE digestives
Emmanuel MITRY Département d'oncologie médicale
Institut Curie
Alger – Février 2013
Thérapies ciblées
- TNE bien différenciées, avancées et évolutives
- inhibiteur mTOR (everolimus)
- anti-angiogéniques
- sunitinib
- pazopanib
- bevacizumab
Sunitinib SUTENT®
• ITK anti-angiogénèse (PDGFR, VEGFR), c-KIT, RET, CSF1R, flt3
• Phase I (Faivre S et al. JCO 2006;24:25-36) – Carcinose péritonéale d'une TE rectale
Avant Après
Design
A618111
Essai randomisé de phase III en double aveugle contre placebo Randomisation 1/1
TE pancréatique bien différenciée Métastatique ou avancée non accessible à la chirurgie
En progression (RECIST, 12 mois) Bon EG OMS (0-1 SUN, 0-2 RAD)
Analogues SMS autorisés
Sunitinib vs placebo
5
Traitement
A618111
Traitement jusqu'à progression, décès ou toxicité inacceptable
Sunitinib 37,5 mg/j PO
Pas de cross-over systématique mais possibilité de recevoir le sunitinib dans un autre protocole
6
Inclusions
A618111
Juin 2007 – Avril 2009
171 pts (arrêt des inclusions
après premiers résultats)
42 centres – 11 pays
7
Toxicité
A618111 (sunitinib)
Tous grades Gr 3-4
Asthénie / Fatigue 66 10
Diarrhée 59 5
Nausée / Vomissement 45/34 1/0
Mucite 22 4
Rash 18 0
Céphalée 19 0
Douleur abdominale 28 5
HTA 26 10
Syndrome Pied-Main 23 6 Neutropénie / Thrombopénie 29/17 12/4
8
PFS (objectif principal)
A618111
Sunitinib Placebo
HR = 0,42, P<0,001
11,4 m 5,5 m
9
PFS (objectif principal)
A618111
10
Réponse tumorale (objectif secondaire)
11
Survie globale (objectif secondaire)
A618111
HR = 0,41; p = 0,02
9 pts DCD bras sunitinib (10%) 21 pts DCD bras placebo (25%)
Sunitinib après progression ?
12
ASCO 2010 ASCO 2011 Raymond et al.. ASCO 2011, A4008
SU : 9 deaths Placebo : 21 deaths
Median OS not reached
HR 0.409
p=0.02
Median OS Sunitinib : 30.5 months Placebo : 24.4 months
HR 0.737 p=0.192
6/2010 SU/placebo : 34/39 deaths
Sunitinib vs placebo
Survie globale Raymond et al.. NEJM 2011
Median OS Sunitinib : 33,0 months Placebo : 26,7 months
HR 0.71 p=0.115
2 years after trial closure SU/placebo : 10/85 deaths
Vinik et al.. ASCO 2012, A4118
S Faivre et al. ESMO 2012 #1155O
S Faivre et al. ESMO 2012 #1155O
TNE pancréatiques
- Everolimus (Phase III, RADIANT-3) "everolimus > placebo (PFS)"
- Sunitinib (Phase III)
"sunitinib > placebo (PFS)" - Bevacizumab (Phase II, BETTER)
"résultats très encourageants, à confirmer"
AMM
SUNLAND – SUnitinib - LANreotide in carcinoiD tumors
• Objectives • Evaluate the Efficacy of “Molecular Targeted Therapy + Somatostatin Analogs Combination”
regarding PFS in Patients suffering from Progressive Advanced / Metastatic Midgut NET
• Rationale • Carcinoid Syndrome is commonly treated with SSAs in patients with progressive advanced /
metastatic midgut carcinoid tumors with little evidence of direct antitumor effect (1) • High doses of SSA suggest an anti-proliferative effect (2,3) and an apoptotic effect (4,5). • MTT (Tyrosine Kinase Inhibitors) blocks signaling involved in tumors growth, progression and
metastases (6,7) • PFS and OS have been significantly increased with MTT in patients with progressive pancreatic NET
(8)
è MTT apoptotic effect could be additive to or boost the apoptotic effect of SSA è Combination of Sunitinib and Lanreotide • greater benefit/ risk than Lanreotide alone in patients with advanced midgut NET • an opportunity for a novel therapeutic strategy
1: Ruszniewski, Neuroendocrinology 2004; 2: Rinke, JCO, 2009; 3: MassuA, ESMO 2011; 4: Eriksson, Ann Oncol 1997; 5: Wiedenmann, Gastroenterol Clin Bio 2003 6: Mendel, Clin Cancer Res, 2003; 7: O’ Farrell, Blood, 2003; 8: Raymond, NEJM 2011
SUNLAND – SUnitinib - LANreotide in carcinoiD tumors
• Study design • European, Phase II Double-Blind Randomized Trial of Sunitinib + Lanreotide versus Placebo + Lanreotide • in Patients suffering from Progressive Advanced / Metastatic Midgut Carcinoid Tumors
• non operable / progressive in the prior 12 months
• Treatment arms (until disease progression) • Sunitinib (37.5 mg/d) + Lanreotide 120 mg/28d • Placebo + Lanreotide 120 mg/28d
• Evaluation of Progression Free Survival (PFS) at 6 months, requiring recruitment of 104 patients • Secondary endpoints: OS, RR, Safety, Quality of life
• Time scale • Actual date of approval in France : July 2012 • Planned recruitment: 2012-2015 • FPI: jan 2013
• Global Coordination: GERCOR (Groupe Coopérateur Multidisciplinaire en Oncologie) • International Coordinating Investigator : Pr Eric Raymond, Beaujon Hospital, Clichy, France • Supportive group : ENETS • Grant supports: Ipsen and Pfizer