FOLFIRI plus CETUXIMAB VS FOLFIRI plus BEVACIZUMAB CCR 1ST LINE KRAS MUTATED Pr Jean-Philippe SPANO...
Transcript of FOLFIRI plus CETUXIMAB VS FOLFIRI plus BEVACIZUMAB CCR 1ST LINE KRAS MUTATED Pr Jean-Philippe SPANO...
FOLFIRI plus CETUXIMAB VS
FOLFIRI plus BEVACIZUMABCCR 1ST LINE KRAS MUTATED
FOLFIRI plus CETUXIMAB VS
FOLFIRI plus BEVACIZUMABCCR 1ST LINE KRAS MUTATED
Pr Jean-Philippe SPANO
Hôpital Pitié-Salpêtrière, Paris
Pr Jean-Philippe SPANO
Hôpital Pitié-Salpêtrière, Paris
Copyright ©2008 AlphaMed Press
Kohne, C.-H. et al. Oncologist 2008;13:390-402
Median survival rates reporteD with colorectal cancer treated with irinotecan-based regimens
(with focus in elderly)
3
Traitements cliniques Anti-EGFTraitements cliniques Anti-EGF
Inhibiteurs de la Tyrosine kinase (Gefitinib, Erlotinib, CI-1033, EKB-569, AEE788, Lapatinib,
PKI-166)
Anticorps
monoclonaux
(Cetuximab, Panitumumab, Matuzumab, Nimotuzumab,
MDX447)
Transduction du signal
R R
K K
Ligands
Mode d’action des anticorps anti-REGF
Action directe: inhibition du REGF
panitumumab
cetuximab
Action indirecte:
Antibody Dependent Cell Mediated Cytotoxicity (ADCC)
1.00
0.75
0.50
0.25
0.00
0 20 40 60 80 100Semaine
p = 0.0001
Survie sans progression
n=88 pts
M NM
Mois
p=0.026
Survie globale
n=88 pts
M NM
1.00
0.75
0.50
0.25
0.00
0 10 20 30
Su
rviv
al p
rob
abil
ity
Su
rviv
al p
rob
abil
ity
Statut KRAS Médiane SSP (95% CI) Médiane SG (95% CI)
KRAS mutéKRAS non muté
10,1 semaines (8-16)31,4 semaines (19-36)
10,1 mois (5.1-13)14,3 mois (9.4-20)
Lièvre et coll. J Clin Oncol 2008
Mutations KRAS et réponse au cétuximab
KRAS status: Relevance confirmed in CRYSTAL and OPUS studies
Res
pon
se r
ate
(%)
0
10
20
30
40
50
60
70
CRYSTALKRAS wt
OPUSKRAS wt
FOLFIRI(n=176)
FOLFOX(n=73)
ERBITUX
+ FOLFIRI(n=172)
ERBITUX + FOLFOX
(n=61)
59
3743
61
ERBITUX + chemotherapy
Chemotherapy alone
43% risk reduction for progression
32% risk reduction for progression
CRYSTAL study (KRAS wild-type)
OPUS study (KRAS wild-type)
0.0
0.2
0.4
0.6
0.8
1.0
0 2 4 6 8 10 12 14 16 18Time (months)
PF
S
HR=0.68
HR=0.57
0.0
0.2
0.4
0.6
0.8
1.0
0 2 4 6 8 10 12 14 16 18Time (months)
PF
S
ERBITUX + FOLFIRI
FOLFIRI
ERBITUX + FOLFOX
FOLFOX
PF
S e
stim
ate
PF
S e
stim
ate
rhuMAb VEGF (Recombinant HumanizedrhuMAb VEGF (Recombinant HumanizedMonoclonal Antibody to VEGF)Monoclonal Antibody to VEGF)
vascular endothelial growth
Humanized to avoidimmunogenicity (93%human, 7% murine).
Recognises all isoforms of
factor, K d = 8 x 10 -10 M
Terminal half life 17-21days
Median OS with oxaliplatin-based chemotherapy consistently >20 months
1. Saltz et al. JCO 2008; 2. Arnold et al. ASCO GI 20103. Kozloff et al. Oncologist 2009; 4. Van Cutsem et al. Ann Oncol 2009
5. Tabernero et al. ASCO 2010; 6. Prausova et al. WCGC 2009
aLarge, prospective, non-randomisedobservational studiesNote: Cross-study comparison
Ph
ase
III
clin
ical
tri
al
29.5
21.7
23.4
23.0
25.9
23.6
24.4
27.0
21.3
19.9
0 10 20 30
Ro
uti
ne
on
colo
gy
pra
ctic
ea
XELOX/FOLFOX4 alone (NO16966)1
Bevacizumab + FOLFOX (BRiTE)3
Bevacizumab + FOLFOX (BEAT)4
Bevacizumab + XELOX (BEAT)4
Bevacizumab + XELOX (BRiTE)3
Bevacizumab + oxaliplatin-based chemotherapy (German registry)2
Bevacizumab + XELOX/FOLFOX4 (NO16966)1
Bevacizumab + XELOX (both to PD) (MACRO)5
Bevacizumab + XELOX (Bev to PD) (MACRO)5
20 months
Median OS (months)
(n=701)
(n=312)
(n=1093)
(n=94)
(n=552)
(n=346)
(n=699)
(n=239)
(n=241)
Bevacizumab + FOLFOX46
(Czech registry)
(n=301)
Ph
ase
III
clin
ical
tri
alMedian OS with irinotecan-based
chemotherapy consistently >20 months
Bevacizumab + irinotecan-based chemotherapy (German registry)2
Bevacizumab + FOLFIRI (AVIRI)3
Bevacizumab + FOLFIRI (BRiTE)4
Bevacizumab + IFL (AVF2107g)1
Bevacizumab + FOLFIRI (BEAT)5
IFL alone (AVF2107g)1
aLarge, prospective, non-randomisedobservational studiesNote: Cross-study comparison
1. Hurwitz et al. NEJM 2004; 2. Arnold et al. ASCO GI 20103. Sobrero et al. Oncology 2009; 4. Kozloff et al. Oncologist 2009
5. Van Cutsem et al. Ann Oncol 2009; 6. Prausova et al. WCGC 2009
1. Hurwitz et al. NEJM 2004; 2. Arnold et al. ASCO GI 20103. Sobrero et al. Oncology 2009; 4. Kozloff et al. Oncologist 2009
5. Van Cutsem et al. Ann Oncol 2009; 6. Prausova et al. WCGC 2009
29.1
27.8
23.7
22.9
22.2
25.8
20.3
15.6
0 10 20 30
(n=1075)
(n=209)
(n=279)
(n=402)
(n=503)
(n=411)
20 months
Ro
uti
ne
on
colo
gy
pra
ctic
ea
Median OS (months)
Bevacizumab + XELIRI(Czech registry)6
Bevacizumab + FOLFIRI(Czech registry)6
(n=74)
(n=111)
AVF2107g: OS benefit independent of biomarker status
0.700.32
26.425.1
17.516.3
p53 overexpression
0.540.67
27.7NR
21.716.4
p53 mutation status
0.670.57
19.927.7
13.621.7
KRAS and BRAF mutation status
0.110.53
15.926.4
8.017.5
BRAF mutation status
0.690.58
19.927.7
13.6 17.6
KRAS mutation status
0.57 26.4 17.5All subjects (n=267)
HR
Median, months
BiomarkerPlacebo
+ IFL
0.2 0.5 1 2 5
HRBevacizumab
+ IFL
Ince et al. JNCI 2005
Positive (n=191)Negative (n=75)
Mutant (n=139)Wild type (n=66)
Mutant (n=88)Wild type (n=125)
Mutant (n=10)Wild type (n=217)
Mutant (n=78)Wild type (n=152)
Rationnel ……
• Quid de l’efficacité du bevacizumab chez des patients KRAS mutés?
• Qq données rétrospectives: influence KRAS mutation– Pas de différence en termes d’efficacité sur le
bévacizumab mais valeur pronostique négative de KRAS (Hurwitz et al, Oncologist 2009)
– AIO KRK-0604: efficacité équivalente entre CAPOX ou CAPIRI plus bévacizumab (Reinacher-Schick A, et al, ESMO 2010)
Schéma de l’étude: objectif RO ITT pour le sous-groupe kras muté
Stintzing S, Ann Oncol 2012
CARACTERISTIQUES DES PATIENTS
Stintzing S, et al, Ann Oncol 2012
REPONSE ET SURVIE
Stintzing S, Ann Oncol 2012
PFS et OS
Stintzing S, Ann Oncol 2012
SELON LES DIFFERENTES MUTATIONS
Stintzing S, Ann Oncol 2012
TOXICITE
Stintzing S, Ann Oncol 2012
DISCUSSION
• 1ère étude randomisée comparant de front FOLFIRI plus cetux à FOLFIRI plus béva
• De manière remarquable, dans le bras cetux, des taux de réponse de 44% (comparable à certaines études) et pas de différence S comparé au bras beva
• FOLFIRI plus beva: RO = 48% (Stintzing, 2012)• IFL plus beva = 43% (Hurwitz, Oncologist 2009)• CAPIRI plus beva = 57% (Reinacher-Schick, ESMO
2010)• FOLFIRI plus cetux : a control group?• Différences entre le type de mutation en termes de
réponse (mutation 13 et sensibilité au cetux?)
CONCLUSION
• Quelques données rétrospectives d’efficacité chez les patients KRAS mutés vis-à-vis du béva
• 1ère étude randomisée comparant cetux vs beva
• Valeur pronostique et prédictive des différents types de mutation nécessite d’être définies de manière
prospective et aussi pour chaque type d’AC
KRAS MUTATION: PREDICTIVE REALLY OR PRONOSTIC
VALUE BASICALLY ?