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

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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

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Juin 2007 – Avril 2009

171 pts (arrêt des inclusions

après premiers résultats)

42 centres – 11 pays

7

Toxicité

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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

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PFS (objectif principal)

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Sunitinib Placebo

HR = 0,42, P<0,001

11,4 m 5,5 m

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PFS (objectif principal)

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10

Réponse tumorale (objectif secondaire)

11

Survie globale (objectif secondaire)

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HR = 0,41; p = 0,02

9 pts DCD bras sunitinib (10%) 21 pts DCD bras placebo (25%)

Sunitinib après progression ?

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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