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 ?