2013 - Alger - Sunitinib et TED

Alger – Février 2013
Sunitinib et
TNE digestives
Emmanuel MITRY
Département d'oncologie médicale
Institut Curie
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
Sunitinib vs placebo
Survie globale
Raymond et al.. NEJM 2011
ASCO 2010
SU : 9 deaths
Placebo : 21 deaths
Median OS not reached
HR 0.409
p=0.02
Raymond et al.. ASCO 2011, A4008
et al.. ASCO 2012, A4118
ASCO Vinik
2011
6/2010
SU/placebo : 34/39 deaths
2 years after trial closure
SU/placebo : 10/85 deaths
Median OS
Sunitinib : 30.5 months
Median OS
Sunitinib : 33,0 months
Placebo : 24.4 months
Placebo : 26,7 months
HR 0.737
p=0.192
HR 0.71
p=0.115
S Faivre et al. ESMO 2012 #1155O
S Faivre et al. ESMO 2012 #1155O
TNE
pancréatiques
-  Everolimus (Phase III, RADIANT-3)
"everolimus > placebo (PFS)"
AMM
-  Sunitinib (Phase III)
"sunitinib > placebo (PFS)"
-  Bevacizumab (Phase II, BETTER)
"résultats très encourageants, à confirmer"
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
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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