Avances en terapia sistémica en cáncer
metastásico de colon y recto (mCRC)
Mauricio Lema Medina MD
Clínica de Oncología Astorga – Clínica SOMA – Medicáncer
Medellín, Colombia
Temario (107)
 Consideraciones iniciales: Vías de transducción de señales (EGFR), y angiogénesis en mCRC (15)
 Evolución histórica del tratamiento del mCRC -1: Citostáticos convencionales (12)
 Mecanismos de acción del Bevacizumab y los MOAs anti EGFR (10)
 Evolución histórica del tratamiento del mCRC -2: Terapia molecular dirigida (39)
–
Bevacizumab en mCRC (31)
–
Cetuximab en mCRC (8)
 Evolución histórica del tratamiento del mCRC -3: Terapia individualizada (29)
–
Impacto de las alteraciones en las vías de transducción de señales del EGFR en la eficacia de Cetuximab (20)
–
(Ausencia de) Impacto de las alteraciones en las vías de trasnducción de señales del EGFR en la eficacia de
Bevacizumab (9)
 Conclusiones (2)
 Efectos adversos del Bevacizumab y de los MOAs anti EGFR (14)
Page  2
Consideraciones iniciales: Vías de transducción
de señales (EGFR), y angiogénesis en mCRC
Page  4
Page  5
EGFR es una proteina transmembrana
Dominio
Extracelular
Dominio
Transmembrana
Dominio
intracelular
Page  6
La activación del EGFR
activa múltiples procesos
Shc
Grb2
PI3-K
Sos-1
Ras
AKT
MEKK-1
Raf
MEK
mTOR
Page  7
MKK-7
ERK
La activación del EGFR activa
múltiples procesos
Shc
Grb2
PI3-K
Sos-1
Ras
AKT
MEKK-1
Raf
MEK
mTOR
Page  8
MKK-7
ERK
La activación del EGFR activa múltiples
procesos
Shc
Grb2
PI3-K
Sos-1
Ras
AKT
MEKK-1
Raf
MEK
mTOR
MKK-7
ERK
JNK
Page  9
Apoptosis
Resistance
Proliferation
Angiogenesis
Metastasis
Page  10
Page  11
Targeting the EGFR pathway:
K-Ras mutations
EGFR overexpression:
• CRC (27–77%)
• Pancreatic cancer (30–50%)
• Lung cancer (40–80%)
• NSCLC (14–91%)
TGF-α
Sos
EGFR*
K-Ras*
Grb2
B-Raf*
EGFR mutation:
• NSCLC (10%)
• Glioblastoma (20%)
MEK
MAPK
*Mutated in human cancers
NSCLC = non-small cell lung cancer
Page  12
TGF = transforming growth factor
K-Ras mutation:
• CRC (30–50%)
• Pancreatic cancer (90%)
• Papillary thyroid cancer (60%)
• NSCLC (30%)
B-Raf mutation:
• CRC (10%)
• Melanoma (70%)
• Papillary thyroid cancer (50%)
Adapted from Roberts Der. Oncogene 2007
CRC: Adenoma-Carcinoma Sequence
Normal
Colon
APC
hMSH2
hMLH1
abnormalities
(hereditary)
Hyperproliferative
Epithelium
Methylation
abnormalities
APC
hMSH2
hMLH1
inactivation
Adenoma
KRAS
mutation
18q
deletion
32% to 57%
KRAS mutant
Page  13
Carcinoma
p53
deletion
Further
accumulation
of genetic
abnormalities
Targeting the EGFR pathway
TGF-α
extracellular
R
intracellular
R
Grb2
K
K
Shc
mutation
loss
Grb2
PI3K
Sos
Ras
Akt
PTEN
mTOR
phosphorylation
Sos
FKHR
GSK–3
Raf
Bad
p27
mutation
mutation
MEK1/2
MAPK
Cyclin D1, E
Cell cycle progression
Page  14
Survival
Proliferation
Mendelsohn et al. JCO 2003
VEGF: Un Mediador Clave de Angiogenesis
Aumento de los niveles de VEGF
Genes implicados
en tumorogénesis
(p53, p73, src,
ras, vHL, bcr-abl)
Factores ambientales
(hipoxia, pH)
Factores de
crecimiento, Hormonas
(EGF, bFGF, PDGF,
IGF-1, IL-1, IL-6,
estrogen)
bFGF, basic fibroblast growth factors; EGF, epidermal growth factor; IGF, insulin-like growth factor; IL,
interleukin; PDGF, platelet-derived growth factor; VEGFR, VEGF receptor.
1. Dvorak HF. J Clin Oncol. 2002;20:4368-4380; 2. Ebos JM, et al. Mol Cancer Res. 2002;1:89-95; 3.
Page
 15 N, et al. Nat Med. 2003;9:669-676.
Ferrara
VEGF: Un Mediador Clave de Angiogenesis
Unión y activación
del VEGFR
VEGF
P
P
PLC
PKC
IP3
Surviva
l
Page  16
PI3-K
AKT
P
P
FAK
Paxillin
Ras
MAPK
Proliferation Migratio
n
ANGIOGENESIS
Activación de la
célula
endotelial
VEGF es expresado durante toda la historia natural
bFGF
bFGF
bFGF
TGFb-1 TGFb-1
VEGF VEGF VEGF VEGF
TGFb-1
PIGF
bFGF
TGFb-1
VEGF
PIGF
PIGF
PD-ECGF PD-ECGF
Pleiotrophin
Evolución tumoral
bFGF = basic fibroblast growth factor
TGFb-1 = transforming growth factor b-1
PIGF = placenta growth factor
PD-ECGF = platelet-derived endothelial cell growth factor
Page  17
www.clinicaloptions.com
Adapted from Folkman. Cancer.
Principles and practice of oncology 2005
Evolución histórica del tratamiento mCRC – 1:
Citostáticos convencionales
Evolución histórica del manejo de mCRC
¿ Hacia una enfermedad crónica ?
Terapia de
soporte
K-Ras mutado factor
pronóstico adverso, y
predictivo de no respuesta
contra terapia dirigida con
EGFR
Oxaliplatino
Capecitabina
Irinotecán
1985
1990
1998
Fluoruracilo inicia la
terapia antineoplásica
Page  19
2004
Bevacizumab
Cetuximab
2009
Nuevas molécultas
están siendo
evaluadas….
Quimioterapia en mCRC
Citostáticos convencionales
Inhibidores TS
 Fluoruracilo (IV)
Inhibidores Topo-I
 Irinotecán
 Capecitabina (PO)
 Raltitrexed (IV)
Alquilantes
 Oxaliplatino
Comentarios
4
 Modulación con
folinato
incrementa
respuesta de
Fluoruracilo.
 Oxaliplatino es
inactivo como
monoagente
TS: Timidilato sintestasa; Topo-I: Topoisomerasa I
Page  20
La combinación de 3 agentes citotóxicos incrementa la
supervivencia mediana a 17-20 meses en mCRC
Supervivencia mediana
BSC
35
30
Aproximadamente 6 meses
Meses
25
20
15
10
5
0
1980
Page  21
1985
BSC = mejor terapia de soporte
1990
1995
2000
Fluoropirimidines en mCRC
 No cambio en la supervivencia mediana con diferentes esquemas
– Supervivencia mediana: ~ 12 meses
Regimen
Respuesta, %
5-FU en bolo
7-15
5-FU en infusión
20-30
5-FU/LV
 Mayo, Roswell Park
12-35
 de Gramont (LV5-FU2)
28-33
 AIO (cada semana, 24-hour infusion)
25-44
Capecitabina
20-25
Grothey A, et al. J Clin Oncol. 2005;23:9441-9442.
Page  22
www.clinicaloptions.com
IFL vs FOLFOX vs IROX (N9741)
diseño
IFL
(n=264)
R
n=795
FOLFOX
(n=267)
IROX
(n=264)
Primary endpoint: PFS
Goldberg et al, JCO 2004
Page  23
Bolo (IFL) vs infusión
(FOLFOX)
FOLFOX4: ciclo de 14-días
5-FU 600mg/m2
iv 22 h
LV 200mg/m2
iv 2 h
d2
d1
5-FU 400mg/m2
iv bolus
LV 200mg/m2
iv 2 h
5-FU 400mg/m2
iv bolus
OX 85mg/m2
iv 2 h
5-FU 600mg/m2
iv 22 h
d3
IFL
LV 20mg/m2
iv 2 h
1
Page  24
8
5-FU 500mg/m2
iv bolus
Iri 125mg/m2
iv 1.5 h
15
22
5-FU = 5-fluorouracilo; LV = leucovorin (Folinato de calcio); OX = oxaliplatino; Iri = Irinotecán
Page  25
N9741: Sanoff HK. J Clin Oncol 26:5721-5727.
N9741
Resultados
n
IFL
264
FOLFOX
267
IROX
264
RR (%)
31
45
35
PFS (m)
6.9
8.7
6.5
OS (m)
15
19.5
17.4
p
Goldberg et al, JCO 2004
Page  26
0.0001
Efficacy: Sequence FOLFIRI/FOLFOX
Arm A
Arm B
Results
FOLFIRI  FOLFOX
FOLFOX  FOLFIRI
Patients, n
109
81
111
69
Confirmed RR, %
56
15
54
4
TTP, mos
8.5
4.2
8.0
2.5
Survival, mos
21.5
20.6
No statistically significant differences in first- or
second-line therapy RR or TTP and OS
Page  27
Tournigand C, et al. J Clin Oncol. 2004;22:229-237.
XELOX y FOLFOX4
XELOX: 21-day cycle
OX 130mg/m2
iv 2 h
d1
Rest
d2
OralCapecitabina (Xeloda) 1000mg/m2 bid
d15
d21
FOLFOX4 + Avastin/placebo: 14-day cycle
d1
Page  28
5-FU 600mg/m2
iv 22 h
LV 200mg/m2
iv 2 h
5-FU 400mg/m2
iv bolus
LV 200mg/m2
iv 2 h
5-FU 400mg/m2
iv bolus
OX 85mg/m2
iv 2 h
5-FU 600mg/m2
iv 22 h
d2
5-FU = 5-fluorouracil; LV = leucovorin; OX = oxaliplatin; PL = placebo
d3
CapeOx Noninferior to FOLFOX
 Median follow-up: 17.7 mos
 HR for PFS: 1.04 (97.5% CI: 0.93-1.16)
– Upper limit of 97.5% CI: < 1.23 (noninferiority margin)
PFS
Events, n
Median (ITT), mos
Page  29
CapeOx/
CapeOx + Placebo/
CapeOx + Bevacizumab
(n = 1017)
FOLFOX-4/
FOLFOX-4 + Placebo/
FOLFOX-4 + Bevacizumab
(n = 1017)
813
826
8
8.5
Cassidy J, et al. J Clin Oncol. 2008;26:2006-2012.
Plateau de la eficacia de la quimioterapia
convencional en mCRC
 La supervivencia mediana con los citostáticos convencionales
alcanza unos 17-20 meses
Combinación
Agentes activos
Supervivencia
mediana (meses)
5-FU/LV
1 droga
11-12
Irinotecan/5-FU
2 drogas
14-15
Oxaliplatino/5-FU ± irinotecan
3 drogas
17-20
Meta-analysis Group in Cancer. J Clin Oncol. 1998;16:301-308. Saltz LB, et al. N
Engl J Med 2000;343:905-914. de Gramont A, et al. J Clin Oncol. 2000;18:29382947. Goldberg RM, et al. J Clin Oncol. 2002;20:4591-4596. Tournigand C, et al. J
Clin Oncol. 2004;22:229-237.
Page  30
www.clinicaloptions.com
Quimioterapia en mCRC
La combinación de citostáticos incrementa la supervivencia
Comentarios
Inhibidores TS
Inhibidores TS
 Fluoruracilo (IV)
 Fluoruracilo (IV)
 Capecitabina (PO)
 Capecitabina (PO)
Inhibidores Topo-I
Alquilantes
 Irinotecán
TS: Timidilato sintestasa; Topo-I: Topoisomerasa I
Page  31
 Oxaliplatino
4
 La supervivencia
mediana con la
exposición a los 3
agentes es de
aproximadamente 20
meses.
 Grothey A, et al J Clin
Oncol. 2005;23:94419442.
Mecanismos de acción del
Bevacizumab y los MOAs anti EGFR
VEGF (Bevacizumab)
Bevacizumab
 Mab Recombinante
humanizedo anti VEGF
 Neutraliza todas las isoformas
de VEGF A
 T1/2 17-21 días
Page  34TM
Avastin
(bevacizumab) [package insert]. San Francisco, Calif: Genentech, Inc; 2004.
Bevacizumab (Avastin®): Mecanismo de Acción
Bevacizumab
VEGF
P
P
Page  35
P
P
Bevacizumab (Avastin®): Mecanismo de Acción
Bevacizumab
VEGF
P
P
P
P
BLOQUEO de la activación del VEGFR
Page  36
EGFR (Cetuximab, Panitumumab)
Cetuximab
 IgG1 (anticuerpo quimérico)
 Anti EGFR (y sus heterodímeros)
 Aprobado en 2004 en mCRC
Page  38
Courtesy of: Paulo Hoff
MAb Anti-EGFR
Extracelular
Intracelular
Shc
Grb2
PI3-K
AKT
Sos-1
Ras
MEKK-1
Page  39
Raf
MOAs Anti-EGFR
Extracelular
Intracelular
Shc
Grb2
PI3-K
Sos-1
mK-Ras
AKT
MEKK-1
Raf
MEK
Page  40
www.clinicaloptions.com
mTOR
MKK-7
Targeting the EGFR pathway
TGF-α
extracellular
R
intracellular
R
Grb2
K
K
Shc
mutation
loss
Grb2
PI3K
Sos
Ras
Akt
PTEN
mTOR
phosphorylation
Sos
FKHR
GSK–3
Raf
Bad
p27
mutation
mutation
MEK1/2
MAPK
Cyclin D1, E
Cell cycle progression
Page  41
Survival
Proliferation
Mendelsohn et al. JCO 2003
Evolución histórica del tratamiento mCRC – 2:
Terapia molecular dirigida
Bevacizumab en mCRC – Primera
línea
Phase III Trial With Bevacizumab
Therapy in First-Line MCRC
Untreated
MCRC
R
A
N
D
O
M
I
Z
E
Bolus IFL + placebo
(n = 412)
Bolus IFL + BV
(n = 403)
5-FU/LV + BV
(n = 110):
Closed due to lack of
efficacy
Hurwitz. NEJM, 2004
Page  44
Courtesy of: Paulo Hoff
Phase III Trial of Bevacizumab
in First-Line mCRC
IFL +
Placebo
(n=411)
IFL +
Bevacizumab
(n=402)
P Value
0.0036
ORR (%)
35
45
CR
2.2
3.7
PR
32.5
41.2
Hurwitz H et al. N Engl J Med 2004;350:2235–42
Page  45
Courtesy of: Paulo Hoff
Probability of being progression-free
Phase III Trial : PFS
Median PFS (months)
IFL + placebo: 6.2 (95% CI: 5.6–7.7)
IFL + bevacizumab: 10.6 (95% CI: 9.0–1.0)
HR=0.54 (95% CI: 0.45–0.66) p<0.001
1.0
0.8
0.6
IFL + bevacizumab
0.4
IFL + placebo
0.2
6.2
0
0
10.6
10
20
30
PFS (months)
Hurwitz H et al. N Engl J Med 2004;350:2335–42
Page  46
Courtesy of: Paulo Hoff
Phase III Trial: Survival
Median survival (months)
IFL + placebo: 15.6 (95% CI: 14.3–17.0) vs
IFL + bevacizumab: 20.3 (95% CI: 18.5–24.2)
HR=0.66 (95% CI: 0.54–0.81) p<0.001
Probability of survival
1.0
0.8
0.6
IFL + bevacizumab
IFL + placebo
0.4
0.2
15.6
0
0
10
20.3
20
Survival (months)
30
40
Hurwitz H et al. N Engl J Med 2004;350:2335–42
Page  47
Courtesy of: Paulo Hoff
Trial of Bevacizumab plus
FOLFIRI/mIFL (BICC-C): design
R
n=430
Initial design
Amended design
FOLFIRI
(n=144)
FOLFIRI+Bev.
(n=60)
mIFL
(n=141)
XELIRI
(n=145)
R
n=117
Feb 2003 – April 2004
Primary endpoint: PFS
mIFL+Bev.
(n=57)
May 2004 – Dec 2004
Protocol amended due
to approval of
bevacizumab
* Celecoxib data not shown
Fuchs et al, JCO 2008
Page  48
Courtesy of: Paulo Hoff
Proportion of Subjects
Who Survived
Overall Survival
Regimen
Median OS
(months)
1 Year
P Value
1
FOLFIRI+ BEV
28
87%
--
0.9
mIFL + BEV
19.2
61%
0.01
0.8
0.7
0.6
0.5
0.4
0.3
0.2
FOLFIRI + Bevacizumab
0.1
mIFL + Bevacizumab
0
0
Fuchs et al. JCO 2008
Page  49
10
20
30
40
Survival Time (months)
Courtesy of: Paulo Hoff
Phase III Trial of Bevacizumab With
Oxaliplatin-Based Therapy in CRC
+ Bevacizumab
(7.5 mg/kg, q3w)
XELOX
+ Placebo
Previously
untreated MCRC
Primary
end point:
TTP
+ Bevacizumab
(5 mg/kg, q2w)
FOLFOX4
+ Placebo
Saltz L, et al. JCO 2008
Page  50
Courtesy of: Paulo Hoff
Progression-free Survival
1.0
HR = 0.83 [97.5% CI 0.72–0.95] (ITT)
p = 0.0023
PFS estimate
0.8
0.6
0.4
0.2
8.0
9.4
0
0
25
5
15
20
FOLFOX+placebo/XELOX+placebo
N=701; 547 events
FOLFOX+bevacizumab/XELOX+bevacizumab N=699; 513 events
Saltz L, et al. JCO 2008
Page  51
10
Months
Courtesy of: Paulo Hoff
Efficacy
XELOX/FOLFOX
N=701
XELOX/FOLFOX + bev
49%
47%
0.99
PFS (mos)
8.0
9.4
0.0023
OS (mos)
19.9
21.3
0.076
Response rate (%)
Saltz L, et al. JCO 2008
Page  52
P-value
N=699
Courtesy of: Paulo Hoff
Patients should remain ‘on treatment’* to achieve
optimal clinical benefit with bevacizumab
6 months
1.0
FOLFOX4/XELOX + bevacizumab
Estimated probability
FOLFOX4/XELOX + placebo
0.8
0.6
On treatment: HR=0.63
(PFS 10.4 vs 7.9 months, p<0.0001)
0.4
General: HR=0.83
(PFS 9.4 vs 8.0 months, p=0.0023)
0.2
0
0
5
10
PFS (months)
15
20
*Prespecified secondary analysis
Page  53
Saltz, et al. ASCO 2007 (poster)
Phase III Trial of Bevacizumab + Panitumumab-CT
With Bev-CT in CRC (PACCE)
Bev + Pan
Ox-CT
Bev
Previously
untreated MCRC
Bev + Pan
Iri-CT
Bev
Hecht JR, et al. JCO 2008
Page  54
Primary
end point:
PFS
Phase III Trial of Bevacizumab + Panitumumab-CT
With Bev-CT in CRC (PACCE)
Bev + Pan
Ox-CT
Bev
Previously
untreated MCRC
Bev + Pan
Iri-CT
Bev
Hecht JR, et al. JCO 2008
Page  55
Primary
end point:
PFS
Phase III Trial of Bevacizumab + Panitumumab-CT
With Bev-CT in CRC (PACCE)
Hecht JR, et al. JCO 2008
Page  56
Phase III Trial of Bevacizumab + Panitumumab-CT
With Bev-CT in CRC (PACCE)
Hecht JR, et al. JCO 2008
Page  57
Phase IV BRiTE
Therapy in First-Line MCRC
Untreated
MCRC
Page  58
E
N
R
O
L
L
Bev + CT
Grothey, et al. JCO 2008
Phase IV BRiTE
Therapy in First-Line MCRC
PFS FOLFOX + Bev: 10 m (n=1092)
Untreated
MCRC
E
N
R
O
L
L
Bev + CT
PFS FOLFIRI + Bev: 10.4 m (n=280)
Page  59
Grothey, et al. JCO 2008
BRiTE:* continuation of bevacizumab post-first progression significantly
increases OS (time from initiation of first-line treatment to death)
Post-progression therapy
Estimated probability
1.0
Bevacizumab post-PD (n=642)
No bevacizumab post-PD (n=531)
No treatment (n=253)
0.8
0.6
0.4 Post-progression bevacizumab
HR=0.48 (95% CI: 0.41–0.57)
p<0.001
0.2
12.6
0
Page  60
0
5
10
*Non-randomised, observational trial
19.9
15
20
OS (months)
31.8
25
30
35
Grothey, et al. ASCO 2007 (poster)
Grothey, et al. JCO 2008
BRiTE:* continuation of bevacizumab post-first progression significantly
increases survival beyond progression, irrespective of subgroup factors
Subgroup
Age at disease progression
<65 years
≥65 years
Race
White
Black
Other
Baseline ECOG PS
0
1
≥2
Site of primary tumour
Colon
Rectum
First-line chemotherapy regimen
FOLFOX
FOLFIRI
Other
Exposed to EGFR inhibitors
No
Yes
Exposed to all three active chemotherapy
agents
No
Yes
Time to first progression
<6 months
≥ 6 months
Best first-line response
Complete response/partial response
SD/PD
All patients
Page  61
HR
95% CI
0.47
0.51
0.37–0.60
0.40–0.65
0.51
0.32
0.48
0.42–0.62
0.18–0.57
0.21–1.08
0.53
0.45
0.37
0.40–0.71
0.35–0.59
0.18–0.65
0.49
0.49
0.40–0.59
0.32–0.75
0.47
0.38
0.62
0.37–0.59
0.24–0.59
0.46–0.85
0.52
0.42
0.41–0.66
0.32–0.54
0.51
0.42
0.39–0.68
0.33–0.52
0.48
0.52
0.37–0.62
0.41–0.65
0.44
0.50
0.49
0.33–0.59
0.41–0.63
0.41–0.58
Favours bevacizumab
0
*Non-randomised, observational trial
0.5
Favours
CTx
1
Grothey, et al. JCO 2008
Phase II–IV
clinical trials
PFS benefits of bevacizumab with irinotecanbased therapy confirmed in daily practice
FOLFIRI alone1
(n=109)
Bevacizumab + FOLFIRI (BICC-C)2
(n=209)
Bevacizumab + FOLFIRI (PACCE)3
(n=115)
Bevacizumab + FOLFIRI (AVIRI)4
(n=209)
Daily
practice*
Bevacizumab + FOLFIRI (MD Anderson)5
11.2
11.7
11.1
12.5
(n=120)
Bevacizumab + FOLFIRI (BRiTE)7
(n=280)
Bevacizumab + FOLFIRI (BEAT)8
(n=503)
0
Page  62
10 months
(n=43)
Bevacizumab + XELIRI (AIO 0604)6
*Large prospective, observational trials
8.5
2
12.1
10.9
11.6
4
6
8
10
Median PFS (months)
12
14
1. Tournigand, et al. JCO 2004; 2. Fuchs, et al. JCO 2007; 3. Hecht, et al. JCO 2009
4. Ackland, et al. ASCO GI 2008; 5. Kopetz, et al. ASCO 2007; 6. Reinacher-Schick, et al.
ASCO 2008; 7. Grothey, et al. JCO 2008; 8. Van Cutsem, et al. ESMO 2008
PFS benefits of bevacizumab with oxaliplatinbased therapy confirmed in daily practice
Daily
practice‡
Phase II/III
clinical trials
XELOX/FOLFOX4 alone (NO16966)1
(n=699)
Bevacizumab + XELOX/FOLFOX4
(NO16966)1
Bevacizumab + XELOX/FOLFOX4
‘on treatment’* (NO16966)1
(n=699)
(n=410)
Bevacizumab + XELOX (AIO 0604)3
(n=127)
Bevacizumab + FOLFOX (BRiTE)4
10.4
11.1
10.4
(n=1,092)
10.0
Bevacizumab + FOLFOX (BEAT)5
(n=552)
11.3
Bevacizumab + XELOX (BRiTE)4
(n=94)
11.2
Bevacizumab + XELOX (BEAT)5
(n=346)
0
*Secondary endpoint
‡Large prospective, observational trials
Page  63
9.4
(n=699)
Bevacizumab + oxaliplatin (PACCE)2
10 months
8.0
10.8
2
4
6
8
Median PFS (months)
10
12
1. Saltz, et al. JCO 2008; 2. Hecht, et al. JCO 2009
3. Reinacher-Schick, et al. ASCO 2008 (poster); 4. Grothey, et al. JCO 2008
5. Van Cutsem, et al. ESMO 2008 (poster)
MACRO: Maintenance Bev vs Continued Bev +
XELOX in Patients With mCRC
Patients with
previously
untreated mCRC
(N = 480)
Induction
Therapy
XELOX +
Bevacizumab
6 cycles
XELOX + Bevacizumab
(n = 239)
Bevacizumab
(n = 241)
Maintenance cycles administered q3w:
Oxaliplatin 130 mg/m2 IV on Day 1
Capecitabine 1000 mg/m2 BID PO on Days 1-14
Bevacizumab 7.5 mg/kg IV on Day 1
Page  64
Tabernero J, et al. ASCO 2010. Abstract 3501.
Disease
progression,
severe
toxicity, or
consent
withdrawal
MACRO: Duration of PFS Comparable Between Bev vs
XELOX + Bev
 No significant difference between treatment arms in any efficacy outcome
 Noninferiority of bevacizumab vs XELOX + bevacizumab cannot be confirmed
– The median PFS HR 95% CI (0.89-1.37) beyond the planned noninferiority limit of 1.32
Outcome
Bevacizumab
(n = 241)
XELOX/
Bevacizumab
(n = 239)
HR
(95% CI)
OR
(95% CI)
Median PFS,* mos
9.7
10.4
1.11
(0.89-1.37)
--
Median OS,* mos
21.7
23.4
1.04
(0.81-1.32)
--
49
46
--
0.89
(0.62-1.27)
Confirmed objective
response, %
*Median follow-up: 20.4-21.1 mos.
Page  65
Tabernero J, et al. ASCO 2010. Abstract 3501.
MACRO: Conclusions
 After bevacizumab + XELOX induction therapy for patients with mCRC,
maintenance bevacizumab comparable to continued bevacizumab +
XELOX
– No significant difference in any efficacy outcome between arms
 Single-agent bevacizumab may be a feasible option for patients receiving
bevacizumab + XELOX as induction therapy
Page  66
Tabernero J, et al. ASCO 2010. Abstract 3501.
Bevacizumab: only biological proven to extend
both PFS and OS in first- and second-line
Estimated probability
0.8
IFL + bevacizumab
IFL + placebo
0.6
0.4
0.2
6.2
0
10.6
0
0.6
0.2
15.6
0.2
4.7
10
10
20
PFS (months)
FOLFOX4 + bevacizumab
FOLFOX4
HR=0.75 (p=0.0011)
0.8
0.6
0.4
0.2
20.3
20
30
OS (months)
7.3
0
10.8
0
0
Page  67
0.4
1.0
0.4
0
FOLFOX + bevacizumab
FOLFOX
0.6
30
IFL + bevacizumab
IFL + placebo
HR=0.66 (p<0.001)
0.8
Second-line2
0.8
0
10
20
PFS (months)
1.0
Estimated probability
1.0
First-line1
Estimated probability
Estimated probability
1.0
40
0
12.9
12
24
OS (months)
36
1. Hurwitz, et al. NEJM 2004; 2. Giantonio, et al. JCO 2007
Bevacizumab + FU in 1st Line mCRC
mCRC with at
least one of:
65≤ age, or
PS 1-2,
3.5≤Albumin, or
Previous
abdominopelvic
RT
FU/LV (Weekly)
(n=105)
R
Main end point:
OS
Secondary end points
PFS
RR
QoL
Page  68
Kabbinavar FF. J Clin Oncol 23:3697-3705
FU/LV + Bevacizumab (5 mg/kg/q2w)
(n=104)
Page  69
Kabbinavar FF. J Clin Oncol 23:3697-3705
Page  70
Kabbinavar FF. J Clin Oncol 23:3697-3705
Bevacizumab improves survival without impacting on
health-related QoL
 First comparisons of QoL with the addition of bevacizumab to
chemotherapy
– study 2107
• IFL + placebo (n=411)
• IFL + bevacizumab (n=402)
– study 2192
• 5-FU/LV + placebo (n=105)
• 5-FU/LV + bevacizumab (n=104)
 Assessed CCS score, TOI-C, FACT-C
Addition of bevacizumab does not add to the
treatment burden of chemotherapy
Page  71
CCS = colorectal cancer subscale
Kabbinavar, et al. Oncologist 2008
Role of Bevacizumab in curable mCRC
 Phase II trial: XELOX + bevacizumab
– 54 patients with potentially resectable liver metastases
– 6 cycles of neoadjuvant therapy (1 week on, 1 week off)
– Clinical response: 74%
– pCR: 11%
Gruenberger B, et al. ASCO 2007. Abstract 4060.
Page  72
Bevacizumab in ‘borderline’ resectable mCRC: OS in
resected patients
100%
1.0
94.4%
Estimated probability
0.8
0.6
0.4
0.2
0
0
40
Page  73
63.6%
Response
n (%)
Complete pathological response
5 (9)
Partial response
36 (64)
Stable disease
12 (21)
20
OS (months)
Gruenberger, et al. ASCO 2008 (poster)
Chemotherapy-induced sinusoidal injury reduced with
addition of bevacizumab in mCRC
p=0.002
100
p=0.001
Incidence of
sinusoidal injury (%)
80
p=0.212
60
40
20
p=0.086
0
36/79
(46%)
1–8 cycles
22/38
(58%)
≥9 cycles
FOLFOX
Page  74
4/78
(6%)
1–8 cycles
4/24
(17%)
≥9 cycles
FOLFOX + bevacizumab
Zorzi, et al. ASCO GI 2009
Impact of bevacizumab on OS in mCRC:
a population-based study
Patients with mCRC (n=1,417): 2003–2004 (pre-bevacizumab)
versus 2006 (post-bevacizumab)
Proportion of patients receiving
Irinotecan or
oxaliplatin
and 5-FU:
no change (p=0.68)
Anti-EGFR
therapy:
no change
(p=0.63)
Bevacizumab
therapy:
increased
5.9% vs 30.6%
(p<0.001)
Addition of bevacizumab to systemic chemotherapy
significantly improved OS:
23.6 vs 18.6 months (p<0.001)
Page  75
Renouf, et al. ASCO GI 2009
Impact of bevacizumab in mCRC: significantly
improved OS
Estimated probability
1.0
0.8
Bevacizumab era (2006)
30.6% received
bevacizumab
0.6
0.4 Pre-bevacizumab (2003–2004)
p<0.001
5.9% received bevacizumab
Bevacizumab + standard chemotherapy
significantly improved OS:
23.6 vs 18.6 months (p<0.001)
0.2
0
0
Page  76
6
12
18
OS (months)
Bevacizumab era (2006), n=448
Pre-bevacizumab (2003–2004), n=969
24
30
Renouf, et al. ASCO GI 2009
Cetuximab en mCRC
Cetuximab versus BSC
Metastatic
colorectal cancer
with prior 5-FU,
irinotecan and
oxaliplatin
(572 pts)
R
A
N
D
O
M
I
Z
E
Cetuximab
+ BSC
(287)
BSC
(285)
Jonker et al. NEJM 2007; 357: 2040
Page  78
Courtesy of: Paulo Hoff
Cetuximab versus BSC
BSC
Cetuximab
P value
(285)
(287)
RR
0%
8%
P<0.001
PFS
1.8 months
1.9 months
HR = 0.68
P<0.001
OS
Page  79
4.6 months
Jonker et al NEJM 2007; 357: 2040
6.1 months
P=0.005
Courtesy of: Paulo Hoff
EPIC: Cetuximab + Irinotecan after Fluoropyrimidine +
Oxaliplatin failure
Cetuximab 400 mg/m2 initial dose
mCRC with
progression after 1st
line fluoropyirimidine
and Oxaliplatin
(n=1298)
cycle 1, wk 1, 250 mg/m2 weekly
Irinotecan 350 mg/m2
(n=648)
R
Primary endpoint:
Overall survival
Page  80
Sobrero AF. J Clin Oncol. 26: 2311-2319, 2008
Irinotecan
(n=650)
Cetuximab + Irinotecan vs Irinotecan in 2nd line - EPIC
Page  81
Cet + Iri
Iri
(n=648)
(n=650)
RR
16.4%
4.2%
P<0.05
PFS
4 months
2.6 months
P<0.005
OS
10.7 m
10 m
P=0.71
Sobrero AF. J Clin Oncol. 26: 2311-2319, 2008
P value
CRYSTAL: Cetuximab in First Line mCRC
Cetuximab 400 mg/m2 initial dose
cycle 1, wk 1, 250 mg/m2 weekly
Irinotecan 180 mg/m2
5-FU mg/m2 bolus +2400 mg/m2 CI
LV every 2 weeks
EGFR-expressing
mCRC
R
Irinotecan 180 mg/m2
5-FU mg/m2 bolus + 2400 mg/m2 40-h
CI
LV every 2 weeks
Stratification:
• Regions
• ECOG PS
Randomized patients: 1217
Page  82
Van Cutsem E, et al. NEJM 2009
Courtesy of: Paulo Hoff
CRYSTAL Trial: Primary Endpoint PFS
1.0
Cetuximab + FOLFIRI, n=599
0.9
FOLFIRI, n=599
0.8
HR = 0.851; 95% CI = [0.726-0.998]
PFS estimate
0.7
Stratified log-rank p-value = 0.0479
0.6
8.9 mo
0.5
1-year PFS rate
23% vs 34%
8.0 mo
0.4
0.3
0.2
0.1
0.0
0
2
4
6
8
10
12
14
16
18
20
Progression-free survival time (months)
Page  83
Van Cutsem E, et al. NEJM 2009
Courtesy of: Paulo Hoff
Correlation of Skin Toxicity and Efficacy with
Cetuximab in the CRYSTAL Study (1st Line)
CRYSTAL combination arm: Cetuximab + FOLFIRI (n=599)
1.00
Skin reaction grade 3*, n=112 (18.7%)
Skin reaction grade 2, n=243 (41%)
Skin reaction grade 0 or 1, n=244 (41%)
PFS estimate
0.75
*There were no grade 4 skin reactions
11.3 mo
9.4 mo
5.4 mo
0.50
0.25
0.00
0.0
*PFS
Page
 84=
2.5
progression-free survival
Van Cutsem et al. Proc ASCO 2007
5.0
7.5
10.0
Time (months)
12.5
15.0
17.5
20.0
Courtesy of: J Tabernero
Evolución histórica del tratamiento mCRC – 3:
Terapia individualizada
Impacto de las alteraciones en las vías de
trasnducción de señales del EGFR en la eficacia
de Cetuximab
OPUS: FOLFOX4 + Erbitux
Cetuximab 400 mg/m2 initial dose
cycle 1, wk 1, 250 mg/m2 weekly
Oxaliplatin 85 mg/m2
5-FU/FA every 2 weeks
EGFR-detectable
mCRC
R
Skin rash 0/1
FOLFOX4
Oxaliplatin 85 mg/m2
5-FU/FA every 2 weeks
Primary endpoint:
Overall response rate
Stratification:
• ECOG PS 0/1, 2
Randomized patients: 337
Page  87
Bokemeyer, et al. ASCO 2008
Courtesy of: Paulo Hoff
Relating KRAS Status to Efficacy
PFS & Response – KRAS Wild-type
KRAS wild-type: HR=0.57; p=0.016
mPFS Cetuximab + FOLFOX: 7.7 months
mPFS FOLFOX: 7.2 months
70
Cetuximab + FOLFOX
FOLFOX
60
0.9
0.8
Response rate (%)
Progression-free survival
1.0
p=0.011
Odds ratio=2.544
(95% CI: 1.238–5.227)
0.7
0.6
0.5
0.4
0.3
61
50
40
30
37
20
0.2
10
0.1
0.0
0
Page  88
2
4
6
Months
Bokemeyer C, et al. J Clin Oncol 2008
8
10
12
0
FOLFOX
Cetuximab +
FOLFOX
Courtesy of: Paulo Hoff
MOAs Anti-EGFR
Extracelular
Intracelular
Shc
Grb2
PI3-K
Sos-1
mK-Ras
AKT
MEKK-1
Raf
MEK
Page  89
www.clinicaloptions.com
mTOR
MKK-7
CRYSTAL: Summary of Efficacy Data in KRAS wt
Pre-2009 ESMO
Post-2009 ESMO
KRAS wt
KRAS wt
FOLFIRI
43
p-value
mPFS (Months)
FOLFIRI
540 (45%)
KRAS Analysis (%)
ORR (%)
Cetuximab
+FOLFIRI
1063 (89%)
59
39.7
0.0025
8.7
Cetuximab
+FOLFIRI
57.3
< 0.0001
9.9
8.4
9.9
HR
0.68
0.70
p-value
0.017
0.0012
OS (Months)
P-value
Page  90
21.0
24.9
0.22
20.0
23.5
0.0094
Courtesy of: Paulo Hoff
NCIC CTG C0.17: Overall Survival in
K-ras Wild-Type Patients
1
Proportion Alive
0.8
Study arm
MS (months)
95% CI
Cetuximab + BSC
9.5
7.7 – 10.3
BSC alone
4.8
4.2 – 5.5
0.6
HR 0.55 95% CI (0.41,0.74)
Log rank p-value: <0.0001
0.4
0.2
Cetuximab
BSC
0
0
Cetuximab 117
113
BSC
Page  91
2
108
92
4
95
69
6
8
10
12
14
Time from Randomization (Months)
81
36
Karapetis C et al, New Engl J Med 2008
52
24
34
17
20
12
9
5
16
18
6
3
2
3
Courtesy of: Paulo Hoff
Phase III MRC COIN
Untreated
MCRC
Page  92
R
A
N
D
O
M
I
Z
E
XELOX/OxMdG
(n = 815)
XELOX/OxMdG +
Cetuximab
(n = 815)
XELOX/OxMdG +
Cetuximab
(n = 815)
Intermitent
ESMO, 2009
COIN: K-ras WT OS
Survival probability
Arm A (XELOX/FOLFOX)
Arm B (XELOX/FOLFOX + cetuximab)
1.00
0.75
Arm A
Arm B
Diff.
Median OS,
months
17.9
17.0
–0.92
2-year
survival, %
36.1
34.4
-1.66
0.50
HR point estimate = 1.038
95% CI 0.90–1.20
p=0.68
0.25
0
0
No. at risk
Arm A
367
362
Arm B
6
12
18
24
30
Time (months)
36
42
316
306
250
238
154
149
19
17
1
3
83
80
44
42
Page  93
ITT analysis
Maughan, et al. ECCO-ESMO 2009 (abstract No. 6LBA)
COIN: K-ras WT PFS
Arm A (XELOX/FOLFOX)
Arm B (XELOX/FOLFOX + cetuximab)
Survival probability
1.00
0.75
Median PFS,
months
0.50
Arm A
Arm B
Diff.
8.6
8.6
+0.07
HR point estimate = 0.959
95% CI 0.84–1.09
p=0.60
0.25
0
No. at risk
Arm A
Arm B
0
6
12
18
24
30
36
367
361
245
249
92
103
41
42
18
22
11
9
6
6
42
1
0
Page  94
ITT analysis
Maughan, et al. ECCO-ESMO 2009 (abstract No. 6LBA)
COIN: No Significant Difference in OS, PFS
Between Treatment Arms, Pt Subsets
Survival Outcome,
Mos
Cetuximab +
Chemotherapy
Chemotherapy
HR (95% CI)
P Value
 Median OS
17.0
17.9
1.038 (0.90-1.20)
.68
 Median PFS
8.6
8.6
0.959 (0.84-1.09)
.60
 Median OS
19.9
20.1
1.019 (0.86-1.20)
.86
 Median PFS
9.2
8.8
0.922 (0.80-1.07)
.36
 Median OS
12.7
14.4
1.004 (0.87-1.15)
.96
 Median PFS
6.3
6.6
1.079 (0.95-1.23)
.33
Wild-type KRAS
All wild-type patients
Patients with mutated
KRAS, NRAS, or BRAF
Page  95
Maughan TS, et al. ASCO 2010. Abstract 3502.
ITT Survival: WT K-Ras (n=729)
XELOX/OxMdG
OS
17,9
XELOX/OxMdG +
HR
Cetuximab
(p value)
17,0
1,038
(months)
2y OS (%)
36,1
34,4
PFS
8,6
8,6
(months)
Page  96
(0,68)
0,95
(0,60)
ESMO, 2009
COIN: K-RAS and Response
All patients
K-ras WT
K-ras MT
Cetuximab
Cetuximab
Cetuximab
FOLFOX/
FOLFOX/
FOLFOX/
+ FOLFOX/
+ FOLFOX/
+ FOLFOX/
XELOX
XELOX
XELOX
XELOX
XELOX
XELOX
(n=815)
(n=367)
(n=268)
(n=815)
(n=362)
(n=297)
Best overall
response
(%)
51
Odds ratio
1.08 (p=0.428)
Page  97
53
57
64
OR=1.35 (p=0.049)
46
43
OR=0.88 (p=0.449)
Maughan, et al. ECCO-ESMO 2009 (abstract No. 6LBA)
NORDIC VII: Cetuximab in First Line mCRC
Nordic FLOX (FU 500 mg/m2 + LV
60 mg/m2, d1,2 Q2W)
mCRC
R
Nordic FLOX + Cetuximab
Nordic FLOX stop & go + Cetuximab
Endpoint:
• PFS
Randomized patients: 571
Page  98
Tveit KM, ESMO 2010
NORDIC VII: Cetuximab in First Line mCRC
Nordic FLOX (FU 500 mg/m2 + LV
60 mg/m2, d1,2 Q2W)
mCRC
R
Nordic FLOX + Cetuximab
Nordic FLOX stop & go + Cetuximab
Outcome
FLOX
F+Cet
Stop&Go-Cet
PFS
7.9
8.3
7.3
RR
41%
49%
47%
OS
20.4
19.7
20.3
Endpoint:
• PFS
Randomized patients: 571
Page  99
Tveit KM, ESMO 2010
TRIALS IN mCRC 1st Line treatment
K-Ras status WT
TRIAL
CRYSTAL
OPUS
COIN
NORDIC
Page  100
PH
PFS
FOLFIRI
FOLFIRI+
CETUXIMAB
P
FOLFIRI
FOLFIRI +
CETUXIMAB
P
8.4
9.9
0.0017
20
23.5
0.0094
FOLFOX
FOLFOX +
CETUXIMAB
P
FOLFOX
FOLFOX +
CETUXIMAB
P
7.2
8.3
0.006
18.5
22.8
0.3854
XELOX/
FOLFOX
XELOX/FOLFOX
+CETUXIMAB
P
XELOX/
FOLFOX
XELOX/FOLFOX
+ CETUXIMAB
P
8.6
8.6
0.6
17.9
17
0.68
FLOX
FLOX +
CETUXIMAB
P
FLOX
FLOX +
CETUXIMAB
P
7.9
8.3
0.3
20.4
19.7
0.30
3
2
3
OS
3
NCCTG0147: Adjuvant FOLFOX +/- Cetuximab
mFOLFOX6 q2w x12
CRC stage III
R
mFOLFOX6 q2w x12 + Cetuximab
Endpoint:
• DFS@3y
Randomized patients: 2581
Page  101
FOLFOX
FOLFOX-Cet
Total
Wt KRAS
909
955
1864
Mt KRAS
374
343
717
Total
1283
1298
2581
Goldberg RM, ASCO 2010
NCCTG0147: Adjuvant FOLFOX +/- Cetuximab
mFOLFOX6 q2w x12
R
CRC stage III
Endpoint:
• DFS@3y
Randomized patients: 2581
mFOLFOX6 q2w x12 + Cetuximab
Outcome
FOLFOX –
wt-KRAS
FOLFOX+Cet
– wt-KRAS
FOLFOX –
mut-KRAS
FOLFOX+Cet
mut-KRAS
DFS@3y
76%
72%
67%
64%
OS
88%
84%
88%
80%
Page  102
Goldberg RM, ASCO 2010
Targeting the EGFR pathway
TGF-α
extracellular
R
intracellular
R
Grb2
K
K
Shc
mutation
loss
Grb2
PI3K
Sos
Ras
Akt
PTEN
mTOR
phosphorylation
Sos
FKHR
GSK–3
Raf
Bad
p27
mutation
mutation
MEK1/2
MAPK
Cyclin D1, E
Cell cycle progression
Page  103
Survival
Proliferation
Mendelsohn et al. JCO 2003
Incidence of genetic alterations in CRC
Molecular finding
K-RAS mutation
Loss of PTEN
Epiregulin
BRAF mutation
PI3K
EGFR non-amplified
Page  104
% of Incidence
30 – 50%
19%
?
3 – 10%
13%
11 – 25%
Loupakis F et al. J Clin Oncol. 2009 Jun 1;27(16):2622-9
Laurent-Puig P, et al. J Clin Oncol 2009 doi: 10.1200/ JCO.2009.22.4295
Perrone F, et al. Ann Oncol. 2009 Jan;20(1):84-90
Goldstein NS, et al. Cancer 2001;92:1331-1346
CRYSTAL: BRAF mutations and PFS
for cetuximab
PFS according to
BRAF status in
retrospective
CRYSTAL substudy
Page  105
Köhne et al. ASCO 09. Abstract 4068
BRAF mutations and response to
cetuximab in K-RAS wild type
Page  106
Laurent-Puig P, et al. J Clin Oncol 2009 doi: 10.1200/ JCO.2009.22.4295
– Patients with wild-type
KRAS have better
prognosis vs mutated
KRAS
– Patients with mutated
BRAF have the poorest
prognosis
Maughan TS, et al. ASCO 2010. Abstract 3502.
Page  107
12
Chemotherapy
Chemotherapy +
Cetuximab
6
0
18
Median OS
(Mos)
 Strong OS prognostic effect of
KRAS, NRAS, and BRAF
mutation status evident
regardless of cetuximab use
Median PFS
(Mos)
COIN: Prognostic Effect of Mutational Status
12
6
0
n=
57 268 367
340 815 289
45 297 362
366 815 292
Mutation Status
BRAF mutation
Any mutation
All patients
KRAS wild type
KRAS mutation
All wild type
Many patients will not respond to treatment with
EGFR inhibitors due to KRAS and BRAF
mutations
mCRC patients treated with panitumumab or cetuximab (n=114)
KRAS mutational status (evaluable patients n=113)
Responders
Non-responders
Mutant KRAS
34/113 (30%)
Wild-type KRAS
79/113 (70%)
2/34 (6)*
22/79 (28)*
32/34 (94)*
57/79 (72)*
BRAF mutational status on wild-type KRAS tumours (n=79)
Responders
Non-responders
Mutant BRAF
11/79 (14%)
Wild-type BRAF
68/79 (86%)
0/11 (0)‡
22/68 (32)‡
11/11 (100)‡
46/68 (68)‡
*p<0.05 (p=0.011); ‡p<0.05 (p=0.029)
Page  108
Di Nicolantionio, et al. JCO 2008
Loss of PTEN and response to cetuximab
in K-RAS wild type
Page  109
Laurent-Puig P, et al. J Clin Oncol 2009 doi: 10.1200/ JCO.2009.22.4295
Loss of PTEN and response to
cetuximab
Responders
(CR+PR+SD) (%)
Non-responders
(%)
PTEN+
(n=33)
PTEN–
(n=22)
12 (36)
1 (5)
21 (64)
21 (95)
Estimated probability
1.0
PTEN+ median PFS = 4.7 months
PTEN– median PFS = 3.3 months
0.8
Log-rank test: p=0.005
HR=0.49; 95% CI: 0.20–0.75
0.6
0.4
0.2
0
0
2.5
5.0
7.5
10.0 12.5 15.0
PFS (months)
 Fisher’s Exact Test: p=0.008
 Concordance primary tumour sample/metastasis: 27/45 (60%)
Page  110
Loupakis, et al. JCO 2009
KRAS status and EGFR monoclonal antibodies in
chemorefractory patients
Non-responder:
BRAF mutation 10%
Responds to
standard dose
22%
KRAS
wild-type
Non-responder:
loss of PTEN
or PI3K mutation
percentage
unknown
Non-responder:
reason unknown
percentage unknown
Page  111
Responds to
increased
dose ~5%
Non-responder:
KRAS mutant 40%
KRAS
mutant
Wong, Cunningham. JCO 2008
(Ausencia de) Impacto de las alteraciones en las
vías de trasnducción de señales del EGFR en la
eficacia de Bevacizumab
AVF2107: OS by K-ras Status
Group: Mutant (N=78)
Group: Wild-Type (N=152)
HR=0.69; P=0.26
HR=0.58; P=0.04
1.0
13.6
19.9
0.6
0.4
0.4
0.2
0.0
0.0
5
10
15
20
25
30
IFL + Placebo
IFL + Avastin
0.6
0.2
0
Median
OS (mo)
0.8
Proportion Surviving
IFL + Placebo
IFL + Avastin
0.8
Proportion Surviving
1.0
Median
OS (mo)
0
Duration of Survival (months)
Page  113
Ince et al. J Natl Cancer Inst. 2005;97:981.
Hurwitz et al. GI World Congress. Abstract O-035 and poster.
5
10
15
20
25
Duration of Survival (months)
30
17.6
27.7
AVF2107: PFS by K-ras Status
Group: Mutant (N=78)
Group: Wild-Type (N=152)
HR=0.41; P=0.0008
HR=0.44; P<0.0001
1.0
Median
PFS (mo)
0.8
IFL + Placebo
IFL + Avastin
5.5
9.3
0.6
0.4
0.2
Proportion progression-free
Proportion progression-free
1.0
Median
PFS (mo)
0.8
IFL + Placebo
IFL + Avastin
7.4
13.5
0.6
0.4
0.2
0.0
0.0
0
5
10
15
20
25
Duration of Survival (months)
 114
IncePage
et al.
J Natl Cancer Inst. 2005;97:981.
Hurwitz et al. GI World Congress. Abstract O-035 and poster.
0
5
10
15
20
25
Duration of Survival (months)
Core Slide
AVF2107g: Response according to
K-Ras status
70
IFL + Avastin
Response rate (%)
60
60
IFL + placebo
50
40
43
37
41
30
20
10
0
K-Ras wild-type
K-Ras mutant
p=0.006
p=0.8
Hurwitz HI, et al. Oncologist 2009;14:22-8
Page  115
Bevacizumab improves patient outcome independent
of KRAS or BRAF status
Biomarker
All subjects
KRAS mutation status
Mutant
Wild-type
BRAF mutation status
Mutant
Wild-type
N
267
Placebo + IFL
Median
n
(months)
120
17.45
Bev + IFL
Median
n
(months)
147
26.35
HR
0.57
(95% CI)
(0.39–0.85)
78
152
34
67
13.60
17.64
44
85
19.91
27.70
0.69
0.58
(0.37–1.31)
(0.34–0.99)
10
217
3
97
7.95
17.45
7
120
15.93
26.35
0.11
0.53
(0.01–1.06)
(0.34–0.82)
KRAS and BRAF mutation
status
Mutant
Wild-type
88
125
37
57
13.60
21.72
51
68
19.91
27.70
0.67
0.57
(0.37–1.20)
(0.34–0.82)
p53 mutation status
Mutant
Wild-type
139
66
63
31
21.72
16.36
76
35
27.70
NR
0.54
0.67
(0.30–0.95)
(0.32–1.42)
p53 overexpression
Positive
Negative
191
75
92
28
17.45
16.26
99
47
26.35
25.07
0.70
0.32
(0.45–1.10)
(0.15–0.70)
HR
0.2
0.5
1
2
5
Survival benefit also independent of p53, VEGF (plasma and tissue) and TSP-2
Page  116
Bev = bevacizumab
Jubb, et al. JCO 2006; Ince, et al. JNCI 2005
Holden, et al. ASCO 2005 (Abstract 3555); Hurwitz, et al. Oncologist 2009
Avastin in K-RAS mutant patients
IFL
IFL + Avastin
Folfiri
Folfiri + Cetuximab
Folfox
Folfox + Cetuximab
Xelox + Avastin
Folfiri + Avastin
Progression Free Survival
Page  117
Avastin in K-RAS wild-type
IFL
IFL + Avastin
Folfiri
Folfiri + Cetuximab
Folfox
Folfox + Cetuximab
Xelox + Avastin
Folfiri + Avastin
Progression Free Survival
Page  118
Incidences of bevacizumab-associated adverse events
were comparable for the two K-RAS subgroups
Page  119
Hurwitz HI, et al. Oncologist 2009;14:22-8
TRIALS IN mCRC 1st Line treatment
K-Ras status WT
TRIAL
CRYSTAL
OPUS
COIN
PRIME
AVF2107g
Page  120
PH
PFS
FOLFIRI
FOLFIRI+
CETUXIMAB
P
FOLFIRI
FOLFIRI +
CETUXIMAB
P
8.4
9.9
0.0017
20
23.5
0.0094
FOLFOX
FOLFOX +
CETUXIMAB
P
FOLFOX
FOLFOX +
CETUXIMAB
P
7.2
8.3
0.006
18.5
22.8
0.3854
XELOX/
FOLFOX
XELOX/FOLFOX
+CETUXIMAB
P
XELOX/
FOLFOX
XELOX/FOLFOX
+ CETUXIMAB
P
8.6
8.6
0.6
17.9
17
0.68
FOLFOX
FOLFOX +
PANITUMUMAB
P
FOLFOX
FOLFOX +
PANITUMUMAB
P
8
9.6
0.023
19.7
23.9
0.072
IFL
IFL +
BEVACIZUMAB
P
IFL
IFL +
BEVACIZUMAB
P
7.4
13.5
0.0001
17.6
27.7
0.04
3
2
3
OS
3
3
Conclusiones
La adición de Bevacizumab a Quimioterapia en mCRC en primera
línea mejora los desenlaces relevantes en forma CONSISTENTE
–
–
–
–
–
–
–
–
–
Quimioterapias basadas en oxaliplatino
Quimioterapias basadas en irinotecán
Quimioterapias basadas en fluoruracilo
En pacientes con mutaciones del K-RAS, y sin ellas
En pacientes con otras mutaciones de la cascada del EGFR
Se ratifican en estudios observacionales prospectivos
Se ratifican en estudios poblacionales
Se debe continuar hasta progresión
Hay evidencia no aleatorizada, pero impactante, del beneficio de continuarlo
más allá de progresión
– Exhibe buenas tasas de respuesta en pacientes marginalmente resecables
– Parece mitigar el daño sinusoidal asociado a oxaliplatino
Page  121
Conclusiones
La toxicidad adicional asociada al Bevacizumab es manejable
Los MOAs anti EGFR no son eficaces en pacientes con mutación
del KRAS, y su uso en estos pacientes debe ser excluido de la
práctica diaria.
Los MOAs anti EGFR exhiben respuestas INCONSISTENTES en
pacientes con KRAS nativo (en primera línea)
Los MOAs anti EGFR son ineficaces en una fracción no
determinable – y no despreciable - de pacientes con mCRC por
razones biológicas (Mutaciones de BRAF, PTEN, etc)
Los MOAs anti EGFR tienen un papel en pacientes en última línea
de tratamiento (con KRAS nativo)
El Bevacizumab y los MOAs anti EGFR no deben ser combinados
Page  122
Bev o Cet en 1ª Línea- mCRC
Estudio (año pub)
N9741 (2008)
Tipo Línea
Brazo (n)
F3
1ª
FOLFOX / IFL
RR (%)
45 / 31
PFS (m) OS (m)
Comentarios
8.7 / 6.9 19.5 /
FOLFOX mejor que IFL
14.5
Hurwitz (2004)
F3
1ª
Bev IFL / IFL
45 /35
10/6
20 / 16
Registro Bev en 1ª línea
Kabbinavar (2005)
RF2 1ª
Bev FULV / FULV 21/18
17 / 13
Pacientes no candidatos a I u O
Ackland (2008)
D
1ª
FOLFIRI + Bev
50
22
Giantonio (2005)
RF2 2ª
Fox / Bev + Fox
7.2 / 12.9 Registro Bev en 2ª línea
NO16966 (2007)
F3
1ª
Fox / Bev + Fox
47 / 49
8 / 9.4 19.9 /
Bev sólo durante Negativo.
21.3
PACCE (2009)
F3
1ª
Bev+Fox/PBev+Fo 48 / 46
11.4 /
24.5 /
RR KRAS nativo Bev+Fox: 56%
x
10
19.4
PACCE (2009)
F3
1ª
Bev+Fir/PBev+FIr 40 / 43
11.7/10. 20.5/20.7
1
BICC-C (2007)
F3
1ª
Bev+Fir/Bev+mIFL 58 / 56
11.2/8.3 >23/19.2
First BEAT
OCS 1ª
Bev + QT
10.2
22.7
– No US
BRiTE
OCS 1ª
Bev + QT (>Fox)
10
25
1953 pts – US
BRiTE
OCS 1ª
BBP / No-BBP
31.8/
19.9
Cochrane
MA 1ª
Bev + QT / QT
9.7/7.1 20.5/17.7 HR 0.61 para PFS, 0.81 para OS
CRYSTAL (2009)
F3
1ª
Cet + FIr / FIr
47 / 39
8.9/8
19.9/18.6 No discriminados por KRAS
CRYSTAL (2009)
AS 1ª
Cet + FIr / FIr
59 / 43
9.9/8.7 24.9/21 KRAS nativo
COIN
(2009)
F3
1ª
Cet + Fox / FOx
51/53
8.6/8.6 17/17.9 KRAS nativo no predictivo
Abreviaturas: RR: Tasa de respuestas (PR + CR); PFS: Supervivencia libre de progresión; OS: Supervivencia global; m: meses; F: Fase; RF: Fase
aleatorizado; D: Descriptivo; OCS: Estudio de observación de cohorte, prospectivo; Fox: Fluoropirimidina + Oxaliplatino; Bev: Bevacizumab; PBev:
Panitumumab – Bevacizumab; FIr: Folfiri; Cet: Cetuximab; QT: Quimioterapia; US: Estados Unidos; BBP: Bevacizumab luego de progresión –
Bevacizumab beyond progression; HR: Hazard ratio; MA: Meta-análisis; AS: Análisis de subgrupo retrospectivo.
Page  123
Efectos adversos de Bevacizumab y
MOAs anti EGFR
Toxicidad de clase de los Anti-VEGF (Bevacizumab)
 Hipertensión arterial
 Incremento de los LFT
 Fatiga
 Dolor en el sitio del tumor
 Coágulos
 Proteinuria
 Sangrado (Epistaxis,
hemoptisis, tumoral)
 Hipotiroidismo?
 Cefalea
 Eventos neurológicos
Page  125
 Perforación intestinal
Hypertension and Bevacizumab
 Meta-analysis of 7 trials: 1850 patients
 Bevacizumab was associated with hypertension in a dose dependent
manner:
– Low doses (3-7.5 mg/Kg): RR 3.0 (95% CI 2.2-4.2)
– High doses (10-15 mg/Kg): RR 7.5 (95% CI 4.2-13.4)
 Incidence:
– Low doses: all grades 2.7%-32%; grade 3: 8.7%
– High doses: all grades 17.6-36%; grade 3: 16%
– Placebo: grade 3: 1.7%
Zhu X, et al. Am J Kidney Dis 2007; 49: 186-193
Page  126
Courtesy of: J Tabernero
ATEs and Bevacizumab:
Pooled Analysis of Five Randomized Trials
Chemotherapy
alone
(n=782)
Bevacizumab +
chemotherapy
(n=963)
13 (1.7)
37 (3.8)
419
673
3.1 (1.7–5.3)
5.5* (3.9–7.6)
ATEs, n (%)
Person-years of observation
Rate/100 person-years (95% CI)
Hazard ratio (95% CI)
1.99** (1.05–3.75)
*p=0.076; **p=0.03
CI = confidence interval
ATE = arterial thromboembolic event

Page  127 Skillings
Higher risk observed in patients with history of ATEs and
aged ≥65 years, hypertension and proteinuria
JR, et al. Proc ASCO 2005; 23: 3019
Scappaticci FA et al. J Natl Cancer Inst 2007;99:1232-9
Courtesy of: J Tabernero
ATEs Incidence with Bevacizumab
by Risk Factor and Aspirin Use
Aspirin at baseline
Risk factor
Control %
(n/N)
All patients
2.0 (1/49)
7.6 (6/79)
1.6 (12/733)
3.5 (31/884)
0 (0/11)
5 (1/20)
1 (5/479)
1.7 (10/582)
5.3 (1/19)
10.7 (3/28)
2.5 (1/40)
18 (11/61)
Age 65 years
0 (0/32)
9.1 (5/55)
2.8 (7/247)
6.7 (19/284)
Age 65 years and
history of ATEs
0 (0/13)
12.5 (3/24)
3 (1/33)
21 (9/43)
Age <65 years and
no history of ATEs
History of ATEs
Bevacizumab
(n/N)
No aspirin at baseline
%
Control %
(n/N)
Bevacizumab
(n/N)
%
N = total number; n = subgroup
 Aspirin did not increase bleeding risk of any grade
 Grade 3/4 bleeding with and without aspirin: 3.6 versus 5.6%
Page  128 Hambleton
J, et al. Proc ASCO 2005; 23: 3554
Scappaticci FA et al. J Natl Cancer Inst 2007;99:1232-9
Courtesy of: J Tabernero
Proteinuria and Bevacizumab
 Meta-analysis of 7 trials: 1850 patients
 Bevacizumab was associated with proteinuria in a dose dependent
manner:
– Low doses (3-7.5 mg/Kg): RR 1.4 (95% CI 1.1-1.7)
– High doses (10-15 mg/Kg): RR 2.2 (95% CI 1.6-2.9)
 Incidence:
– Low doses: all grades 21-41%; grade 3: 1.0%
– High doses: all grades 22-63%; grade 3: 1.8%
– Placebo: grade 3: 0.1%
– Renal cell carcinoma patients: grade 3: 7.7%
Page  129
Zhu X, et al. Am J Kidney Dis 2007; 49: 186-193
Courtesy of: J Tabernero
Gastrointestinal perforations
Bevacizumab:
 Metaanalysis: 12,294 patients, 17 RCTs
 Gastrointestinal perforation rate: 0.9% (95% CI 0.7-1.2)
 RR 2.14, p=.011, 95% CI 1.19-3.85
 Relative risks:
– Dose 5 vs 2.5 mg/Kg/week:
RR 2.67 (95% CI 1.14-6.26) vs 1.61 (95% CI 0.76-3.38)
– Tumor type:
CRC RR 3.1 (95% CI 1.26-7.63)
RCC RR 5.67 (95% CI 0.66-48.42)
 No robust data for VEGFR inhibitors and aflibercept
Page  130
Hapani et al; Lancet Oncol 2009
Toxicidad de clase de los Anti-EGFR (Cetuximab)
 Exantema acneiforme (89%)  Cefalea (26%),
 Astenia (48%)
 Diarrea (25%),
 Náuseas leves (29%)
 Constipación leve (26%)
 Cambios en las uñas y
tejidos vecinos (14%)
 Dolor abdominal leve(26%)
 Hipomagnesemia
Page  131
Skin Toxicity: Pathophysiology
 EGFR inhibitors1:
– EGFR-inhibition driven:
– Similar in all EGFR-inhibitors.
– Cutaneous effects: dose-dependent: cetuximab (EVEREST), panitumumab,
erlotinib
– Polymorphisms in EGFR gene, intron 1
– EGFR null skin mice: similar lesions
– Unique combination: itchy acneiform eruption, xerosis, paronychia, hair
changes, telangiectasia
– Mechanism unknown
Page  132
Segaert S, et al. Ann Oncol 2006
Courtesy of: J Tabernero
Cutaneous and Nail Toxicities
Associated with Cetuximab
Acne-like Rash
Intensity
Week
1
2
3
4
Only 14% of patients experience
Grade 3 Acne-like rash
5
6
7
8
9
11
Fissures
Dry skin
Grade 3
Acne-like rash
10
12
Nail bed
Images kindly provided by Prof. Segaert
THERAPY SUGGESTIONS
Topical anti-acne
creams (drying effect)
Page  133
Emollients
Hydrocolloid
dressing/’glue’
Antiseptic
soaks or
Silver nitrate
+/- tetracyclines
+/- antihistamines
Courtesy of: J Tabernero
Correlation of Skin Toxicity and Efficacy with
Cetuximab in the BOND Study (Refractory)
BOND combination arm: Cetuximab + Irinotecan (n=218)
Maximum grade of
skin reaction
Number of
patients
Response
(%)
mTTP*
(months)
mOS**
(months)
0
32 (14.7%)
6.3
1.4
3.0
1
58 (26.6%)
8.6
1.5
6.5
2
99 (45.4%)
27.3
4.2
10.3
3
29 (13.3%)
55.2
8.2
13.7
 Skin reactions appear to be predictive for efficacy
*mTTP = median time to progression ; **mOS = median overall survival
Page  134
Cunningham D et al. N Engl J Med 2004; 351(4): 337-345.
Courtesy of: J Tabernero
Correlation of Skin Toxicity and Efficacy with
Cetuximab in the CRYSTAL Study (1st Line)
CRYSTAL combination arm: Cetuximab + FOLFIRI (n=599)
1.00
Skin reaction grade 3*, n=112 (18.7%)
Skin reaction grade 2, n=243 (41%)
Skin reaction grade 0 or 1, n=244 (41%)
PFS estimate
0.75
*There were no grade 4 skin reactions
11.3 mo
9.4 mo
5.4 mo
0.50
0.25
0.00
0.0
*PFS
=
Page
 135
2.5
progression-free survival
Van Cutsem et al. Proc ASCO 2007
5.0
7.5
10.0
Time (months)
12.5
15.0
17.5
20.0
Courtesy of: J Tabernero
Hypomagnesaemia
Hypomagnesaemia
Total
Grade 3-4
Panitumumab1
36%
3%
Cetuximab2
53%
15%
 Related to duration of treatment3:
– Grade 3-4: 6% <3 m, 23% 3-6 m, 47% >6 m
 Treatment4:
– Related symptoms: asthenia, irritability
– Be cautious in case of: cardiomyopathy, renal failure, treatment with
platin
– Grade 1-2: oral or iv replacement
– Grade 3-4: discontinuation and iv replacement, stop and go?
Courtesy of: J Tabernero
Page  136 1Van
Cutsem et al. J Clin Oncol 2007;25:1658-1664 2Jonker DJ et al. N Engl J Med 2007;357:2040–8
3Fakih MG et al. Clin Colorectal Cancer 2006;6:152–6
4Izzedine H et al. Crit Rev Oncol/Hematol 2009 (Epub)