Transcript ENCAJE CLÍNICO DE AFLIBERCEPT EN EL CONTEXTO ACTUAL DEL CCRM RUTH VERA ONCOLOGÍA MÉDICA CHN Madrid, 12 de Febrero de 2015 CÁNCER COLORRECTAL METASTÁSICO 5-FU/LV Aflibercept Capecitabine Irinotecan Oxaliplatin Bevacizumab Cetuximab Regorafenib* *Not approved by the.

ENCAJE CLÍNICO DE
AFLIBERCEPT EN EL
CONTEXTO ACTUAL
DEL CCRM
RUTH VERA
ONCOLOGÍA MÉDICA CHN
Madrid, 12 de Febrero de 2015
CÁNCER COLORRECTAL METASTÁSICO
5-FU/LV
Aflibercept
Capecitabine
Irinotecan
Oxaliplatin
Bevacizumab
Cetuximab
Regorafenib*
*Not approved by the EMA or for use in the Czech Republic
Panitumumab
Advances in the treatment of Stage IV CRC
1980
1985
1990
1995
2005
2000
2010
2015 +
BSC
5-FU
Irinotecan
Capecitabina
Oxaliplatino
Cetuximab
Bevacizumab
Survival benefit
from 6 months to 24-30 months
Panitumumab
Aflibercept
Regorafenib
Braun MS, et al. Ther Adv Med Oncol. 2011;3:43-52.
 CONCEPTOS IMPORTANTES
ESTRATEGIA
“Continnium of care”
1st line
70 %
2nd line
3rd line
CONDICIONADO
POR LAS
LÍNEAS
ANTERIORES
“GOALS”
• Prolongation of survival
• Cure
• Improving tumour-related symptoms
• Stopping tumour progression
• And/or Quality of life
“Backbone of first Chemotherapy”
• Fluoropiridin-based chemotherapy:
Oxaliplatin
Irinotecan
R
FOLFIRI → FOLFOX
FOLFOX → FOLFIRI
• Similar activity
• Both partners for biological agents
• Different toxicity profile
“Exposure to All Drugs Is Important”
• Exposure to all three active
cytotoxic drugs improves
survival1
• No clear survival advantage to
any one specific first-line
regimen1
P=.0008
Ox + iri
IFL
FU/Lv + iri
FU/Lv + Ox
• The availability of biologic
therapies has improved
survival further
1. Grothey et al, J Clin Oncol 2004; 2. Falcone et al ASCO 2013;
3. Stintzing et al ASCO 2013, 4. Takahari et al ASCO 2013
“ only trials with a combination
of citotoxics and bilogical agents
… SURVIVAL > 24 months”
1st line
70 %
2nd line
3rd line
TRATAMIENTO DE SEGUNDA LÍNEA CON TERAPIAS ANTIEGFR
CETUXIMAB en 2ª Linea
EPIC (SOBRERO)
Irinotecán vs Irinotecán + CETUXIMAB
ERBITUX +
irinotecan
(n=648)
Irinotecan
(n=650)
Hazard
ratio
p-value
16%
4%
-
<0.0001
PFS meses
4.0
2.6
0.69
≤0.0001
OS, meses
10.7
10.0
0.975
0.71
ORR
20% K-ras
13% BV previo
47% CET
TRATAMIENTO DE SEGUNDA LÍNEA CON TERAPIAS ANTIEGFR
PANITUMUMAB en 2ª Linea
PEETERS (181)
FOLFIRI vs FOLFIRI + PANITUMUMAB
FOLFIRI (Q2W) +
panitumumab 6 mg/kg
(Q2W*)
Metastatic
CRC
(n=1186)
R
1:1
FOLFIRI (Q2W*)
E
n
d
o
f
t
r
e
a
t
m
e
n
t
Stratification by:
• ECOG score: 0-1 vs. 2
• Prior oxaliplatin exposure for mCRC
• Prior bevacizumab exposure for mCRC
 Study endpoints: PFS/OS (co-1°); ORR, safety, HRQoL
Peeters M, et al. J Clin Oncol 2010; 28:4706-13.
L
o
n
g
t
e
r
m
f
o
l
l
o
w
u
p
Median PFS, months
Panitumumab + FOLFIRI
(n = 303)
FOLFIRI
(n = 294)
5.9
3.9
Hazard ratio
0.73
(P = 0.004)
(P-value)
Median OS, months
14.5
Hazard ratio
0.85
(P = 0.12)
(P-value)
ORR, n (%)
(95% CI)
12.5
(35)
(10)
(30–41)
(n = 297)
(7–14)
(n = 285)
Peeters M, et al. J Clin Oncol 2010; 28:4706-13.
20050181 study RAS analysis
EXON 1
EXON 2#
12
KRAS
EXON 1
12
13
13
44.9%
EXON 2
12
NRAS
EXON 3
12 1313
2.2%
EXON 4
59
61
59 61
4.4%
EXON 3
59
117
146
117 146
7.7%
EXON 4
61
59 61
5.6%
117
117
146146
0%
Overall RAS
ascertainment rate: 85%
18% (107/597) of WT KRAS exon 2 tumours have RAS mutations
Peeters M, et al. J Clin Oncol 2014; 32 (suppl 3):LBA387 (and oral presentation).
Prevalence is defined as mutations detected in a population of
WT KRAS exon 2 patients whose tissues were deemed evaluable
for RAS testing; #The KRAS exon 2 data is from the overall population;
WT RAS, KRAS & NRAS exons 2/3/4
20050181 study RAS analysis
PFS (primary analysis)
Events
n (%)
Median (95% CI)
months
100
Panitumumab +
FOLFIRI (n = 204)
117 (57)
6.4 (5.5–7.4)
90
FOLFIRI (n = 211)
138 (65)
4.4 (3.7–5.5)
80
HR = 0.695 (95% CI, 0.536–0.903)
Log-rank p-value = 0.006
70
Proportion event-free (%)
60
50
40
30
20
10
0
0
2
4
6
8
10
12
14
16
18
Months
Peeters M, et al. J Clin Oncol 2014; 32 (suppl 3):LBA387 (and oral presentation).
20050181 study RAS analysis
OS (primary analysis)
Events
n (%)
100
90
Median (95% CI)
months
Panitumumab +
FOLFIRI (n = 204)
127 (62) 16.2 (14.5–19.7)
FOLFIRI (n = 211)
141 (67) 13.9 (11.9–16.1)
80
HR = 0.803 (95% CI, 0.629–1.024)
Log-rank p-value = 0.08
70
60
Proportion alive %
50
40
30
20
10
0
0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
30
32
34
Months
Peeters M, et al. J Clin Oncol 2014; 32 (suppl 3):LBA387 (and oral presentation).
TRATAMIENTO DE SEGUNDA LÍNEA CON TERAPIAS ANTIANGIOGENICAS
BEVACIZUMAB en 2ª Linea
ECOG 3200
Folfox4 vs Folfox4 + BEVACIZUMAB (10 mg)
TML
BEVACIZUMAB (5 mg) + Múltiples QT
Estudio ECOG E3200 (GIANTONIO)
FOLFOX4
N= 291 pac.
Pacientes con
CCRm tratados
previamente con
Fluoropirimidinas
e Irinotecán
FOLFOX4 +
BEVACIZUMAB
N= 820 pac.
N= 286 pac.
No estaba permitido el uso
previo de Oxaliplatino o
Bevacizumab.
BEVACIZUMAB
N= 243 pac.
Objetivo Primario: SG.
Objetivo Secundario: SLP, TR y Seguridad.
Giantonio et al. J Clin Oncol 2007; 25(12):1539-44
HR=0.61
HR=0.75
Giantonio et al. J Clin Oncol 2007; 25(12):1539-44
BEV + QT
QT
(n=407) %
43%
(n=407) %
42%
FOLFIRI
(64) 16%
(57) 14%
LV5FU2 + CPT11 (Douillard regimen1)
(27) 7%
(30) 7%
XELIRI
(49) 12%
(49) 12%
Other regimens
(27) 7%
(41) 10%
57%
58%
FOLFOX4
(37) 9%
(35) 9%
mFOLFOX4
(38) 9%
(35) 9%
FOLFOX6
(64) 16%
(53) 13%
FUFOX
(23) 6%
(37) 9%
XELOX
(58) 14%
(46) 11%
Other regimens
(37) 9%
(37) 9%
Régimen QT 2ª Linea
QT basada en Irinotecan
QT basada en Oxaliplatino
SG
SLP
J. Bennouna. Lancet Oncology 2013; 14: 29-37
TRATAMIENTO DE SEGUNDA LÍNEA CON TERAPIAS ANTIANGIOGENICAS
AFLIBERCEPT en 2ª Linea
VELOUR
FOLFIRI vs FOLFIRI+ AFLIBERCEPT
Estudio VELOUR
FOLFIRI
N= 614 pac.
Pacientes con
CCRm tras fallo
a un régimen
previo basado
en oxaliplatino.
N= 1.226 pac.
R 1:1
FOLFIRI + Aflibercept
N= 612 pac.
Estratificación:
 ECOG: 0 vs. 1 vs. 2
 Bevacizumab previo s/n
Objetivo Primario: SG.
Objetivo Secundario: SLP, TR, Seguridad y FC
Van Cutsem et al, JCO 2012 Vol 30 (28): 3499-3506.
OS
 HAY CONSENSO EN EL
MANEJO DEL CCRm ?
ESMO
NCCN
NICE
ESMO guidelines: Treatment goals and strategies
determined by patient and tumor characteristics
Treatment goal
Treatment
intensity
Clearly R0-resectable liver and/or
lung metastases
Cure, decrease
risk of relapse
Nothing or
moderate (FOLFOX)
GROUP 1
Not R0-resectable liver and/or
lung metastases only, may become
resectable after induction CT
Maximum
tumor shrinkage
Upfront most active
combination
GROUP 2
Multiple metastases/sites,
with rapid progression and/or
tumor-related symptoms
Clinically relevant
tumor shrinkage
as soon as possible,
control PD
Upfront active
combination: at
least doublet
GROUP 3
Multiple metastases/sites with no
option for resection and/or initially
asymptomatic with limited risk for rapid
deterioration
Prevent further
progression, low
toxicity
Watchful waiting or
sequential approach
(triplet regimens
only in selected
patients)
Group
Clinical presentation
GROUP 0
• CT, chemotherapy
• PD, progressive disease
Schmoll H-J, et al. Ann Oncol 2012;23:2479–2516
QT+
Biológico
• Ningún estudio de secuencia …
1ª Línea
5-FU/LV
Capecitabine
Progresión
FOLFIRI
FOLFOX
Oxaliplatin
Anti-EGFR
Regorafenib*
Anti-VEGF
2ª Línea
Irinotecan
Bevacizumab
Cetuximab
RAS
wt
Aflibercept
Panitumumab
AFLIBERCEPT
Conclusiones
•
Importancia de la segunda línea en la estrategia de tratamiento (70% 2ª
Línea)
•
La elección de la 2ª línea va ligada directamente a la 1ª línea
•
Aflibercept + FOLFIRI aumentan de forma significativa la
Supervivencia Global, la Supervivencia libre de progresión y la
Respuesta en pacientes con CCRm tratados previamente con un régimen
basado en oxaliplatino (Nivel 1 de evidencia)
•
Incluido en las Guías de NCCN, ESMO en base a su evidencia
•
Hoy desconocemos la secuencia óptima de tratamiento