Transcript Document PPT – 2Mo

FOLFIRINOX : un nouveau
standard dans les
adénocarcinomes pancréatiques ?
Christophe Louvet
Institut Mutualiste Montsouris, Paris
SFCP, Ajaccio, 10/05/2012
ADK pancréatique métastatique:
Chimiothérapie ou soins de confort ?
Auteur
Regime
Mallinson
1980
5-FU+Mtx+Vcr
+ cyclo + MMC
BSC
5-FU + CCNU
BSC
5-FU + BCNU
BSC
FAM
BSC
5-FU + LV +
Etoposide
BSC
Frey
1981
Andersen
1981
Palmer
1994
Glimelius
1996
n
patients
21
Med. Surv.
(mo)
10.5
19
65
87
20
20
23
20
29
2.2*
3.0
3.9
3.2
3.4
8.2
3.8*
6.0
24
2.5*
* p < 0.05
Qol
benefice
dans le
groupe
CT
L’étude Burris (1997)
Gemcitabine
n=63
Bénéfice clinique
Survie médiane
5-Fluorouracile
n=63
23.8% *
5.65 mois **
4.8%
4.41 mois
* p = 0.0022
** p = 0.0025
Burris H A, et al.: JCO 15: 2403, 1997
Etudes de phases III dans les cancers du pancréas
(chimiothérapie conventionelle)
Gem
Gem + X
p
Gem ± Exatecan (Abou-Alfa, JCO 2006)
Gem ± CPT-11 (Rocha-Lima, JCO 2006)
Gem ± Pemetrexed (Oettle, Ann Oncol 2006)
6.2
6.6
6.3
6.7
6.3
6.2
NS
NS
NS
Gem ± 5FU bolus (Berlin, JCO 2002)
Gem ± Capecitabine (Herrmann, JCO 2007)
Gem ± 5FU/LV (Riess, JCO 2005)
Gem ± Capecitabine (Cunningham, JCO 2009)
5.4
7.3
6.2
6.2
6.7
8.4
5.9
7.1
NS
NS
NS
NS
Gem ± Cisplatin (Heinemann, JCO 2006)
Gem ± Oxaliplatine (Louvet, JCO 2005)
Gem ± Oxaliplatine (Poplin, JCO 2009)
Gem ± Cisplatin (Colucci, ASCO 2009)
6.0
7.1
4.9
8.3
7.5
9.0
5.9
7.2
NS
NS
NS
NS
Méta-analyse de survie:
Gemcitabine versus Gemcitabine + autre drogue
Copyright A.
© American
of Clinical25:2607-2615
Oncology
Sultana,
et al. J Society
Clin Oncol;
2007
Analyse par sous-groupe :
Gemcitabine vs Gemcitabine + autre drogue
Copyright ©A.
American
Clinical Oncology
Sultana,
et al. JSociety
Clin of
Oncol;
25:2607-2615 2007
Résumé de la méta-analyse dans les cancers
du pancréas avancés
N pts
HR
p
Gem vs Gem + drogue X
4465
0.91
0.004
Gem vs Gem + sel de platine
1248
0.85
0.01
Gem vs Gem + fluoropyrimidine
1813
0.90
0.03
Gem vs Gem + autre drogue
1404
0.99
NS
Gem vs Gem + sel de platine / fluoropyrimidine (PS 0-1)
Gem vs Gem + sel de platine / fluoropyrimidine (PS 2)
1108
574
0.76
1.08
< 0.0001
NS
Etudes de phases III dans les cancers du pancréas
(thérapies ciblées)
Gem
Gem + X
p
Gem ± Marimasmat (Bramhall, BJC 2002)
5.5
5.5
NS
Gem ± Tifarbinib (Van Cutsem, JCO 2004)
6.0
6.4
NS
Gem ± Erlotinib (Moore, JCO 2007)
5.9
6.4
.03
Gem ± Bevacizumab (Kindler, ASCO 2007)
6.1
5.8
NS
Gem ± Cetuximab (Philip, ASCO 2007)
5.9
6.4
NS
Gem ± GV1001 (Buanes, ASCO 2009)
7.3
5.9
NS
Gem – Erlotinib ± Beva (Van Cutsem, JCO 2009)
6.0
7.1
NS
Gem ± Axitinib (Kindler, ESMO 2009)
7.4
8.2
NS
Gem ± Aflibercept : arrêt pour futilité, « press release » 2009
Anti-EGFR
Preuve du concept avec l’erlotinib
(Moore, JCO 2007)
Pas de confirmation avec le cetuximab
Pas de synergie avec le bevacizumab
(Philip, ASCO 2008)
(Van Cutsem, JCO 2009)
Pas de marqueur moléculaire prédictif (K-ras?)
Rash prédictif de survie ?
(Moore, 2007; Van Cutsem, 2009)
Antiangiogéniques
Résultats négatifs en phase III avec mAb, TKI
et VEGF-trap
– CALBG (G + Beva) (Kindler, JCO 2008)
– AVITA (G + B + Erlo) (Van Cutsem, JCO 2009)
– AGILE (G + Axitinib) (Kindler, ESMO/ECCO 2009)
– VANILLA (G + Aflibercept) (Press release-stop pour futilité)
Pas de marqueur prédictif (polymorphisme VEGFR-1 ?)
Pas de “surrogate marker” (PA diastolique?) (Spano, Lancet 2008)
Gemcitabine perfusion de 30mn ou de 10
mg/m²/mn?
Gemcitabine
1500 mg/m²
10mg/m²/min
Rép 16.6%
PFS 3.4 mois
OS 8 mois
Survie à 1 an: 23%
R
N=80
Gemcitabine
2200mg/m²
30 min
Rép 2.7%
PFS 1.9 mois
OS 5 mois
Survie à 1 an : 0%
Tempero, JCO 2004
RANDOMIZED PHASE III TRIAL COMPARING FOLFIRINOX (5FU/leucovorin,
irinotecan and oxaliplatin)
VS GEMCITABINE AS FIRST-LINE TREATMENT
FOR METASTATIC PANCREATIC ADENOCARCINOMA
Prodige 4 - ACCORD 11/0402 trial: final results
T. Conroy, F. Desseigne, M. Ychou, M. Ducreux, O. Bouché,
R. Guimbaud, Y. Bécouarn, C. Montoto-Grillot, S. Gourgou-Bourgade,
A. Adenis, FNCLCC-FFCD Prodige group
Centre Alexis Vautrin, Nancy; Centre Léon Bérard, Lyon; Centre Val d'Aurelle, Montpellier;
Institut Gustave Roussy, Villejuif; Centre Hospitalier R. Debré, Reims;
Institut Claudius Regaud, Toulouse; Institut Bergonié, Bordeaux;
Fédération Nationale des Centres de Lutte Contre le Cancer - BECT, Paris;
Centre Oscar Lambret, Lille; FRANCE
FOLFIRINOX versus Gemcitabine for
Metastatic Pancreatic Cancer
Thierry Conroy, M.D., Françoise Desseigne, M.D., Marc Ychou, M.D., Ph.D., Olivier
Bouché, M.D., Ph.D., Rosine Guimbaud, M.D., Ph.D.,
Yves Bécouarn, M.D., Antoine Adenis, M.D., Ph.D., Jean-Luc Raoul, M.D., Ph.D.,
Sophie Gourgou-Bourgade, M.Sc., Christelle de la Fouchardière, M.D.,
Jaafar Bennouna, M.D., Ph.D., Jean-Baptiste Bachet, M.D.,
Faiza Khemissa-Akouz, M.D., Denis Péré-Vergé, M.D., Catherine Delbaldo, M.D.,
Eric Assenat, M.D., Ph.D., Bruno Chauffert, M.D., Ph.D., Pierre Michel, M.D., Ph.D.,
Christine Montoto-Grillot, M.Chem., and Michel Ducreux, M.D., Ph.D.,
for the Groupe Tumeurs Digestives of Unicancer and the PRODIGE Intergroup*
N Engl J Med 2011;364:1817-25.
Prodige 4 - ACCORD 11 trial design
Metastatic
pancreatic
cancer
R
A
N
D
O
M
I
Z
E
for both arms:
Folfirinox
Gemcitabine
CT scans:
obtained
every 2 months
6 months of
chemotherapy
recommended
Stratification :
 center
 performance status: 0 versus 1
 location of the tumor: head versus other location of the primary
Inclusion Criteria
 Histologically/cytologically confirmed pancreatic adenocarcinoma
 ECOG performance status of 0 or 1
 Measurable metastases
 No prior cytotoxic chemotherapy
 No prior abdominal radiotherapy
 Age 18-75 years
 Adequate hematopoietic, hepatic and renal function
 Bilirubin < 1.5 UNL
 No unstable angina or myocardial infarction within
12 months before entry
 Written informed consent
Flow Chart
Folfirinox
Gemcitabine
Total
Total randomized
171
171
342
Did not fulfill all
eligibility criteria
8*
7*
15 (4%)
Untreated patients
4
2
6 (2%)
ITT population
171
171
342 (100%)
Safety population
167
169
336 (98%)
*Folfirinox arm : 2 patients > 76 years; one patient PS=2;
5 patients with high bilirubin, high creatinine or low platelets
*Gemcitabine arm: 7 patients with high bilirubin, high creatinine or low platelets
Patients characteristics
Folfirinox
Gemcitabine
N=171
N=171
61
[25-76]
61
[34-75]
Male
Female
106 (62%)
65 (38%)
105 (61.4%)
66 (38.6%)
0
1
2
64 (37.4%)
106 (62.0%)
1 (0.6%)
66 (38.6%)
105 (61.4%)
0 (0.0%)
Head
Other
62 (36.3%)
109 (63.7%)
60 (35.1%)
111 (64.9%)
Characteristic
Median age (yrs)
[range]
Sex
Baseline PS
Location of primary
p
NS
NS
NS
NS
Disease characteristics
Characteristic
Synchronous metastases
Metachronous metastases
Median nr. of involved sites
CA19-9  59 ULN
Folfirinox
Gemcitabine
N=171
N=171
156 (91.2%)
15 (8.8%)
161 (94.2%)
10 (5.8%)
NS
NS
2 (1-6)
68 (41.5%)
2 (1-6)
77 (46.7%)
NS
NS
149 (88.2%)
89 (52.7%)
48 (28.4%)
33 (19.5%)
33 (19.5%)
150 (87.7%)
91 (53.2%)
39 (22.8%)
49 (28.7%)
32 (18.7%)
p
Measurable site
Liver
Pancreas
Nodes
Lungs
Peritoneal
NS
NS
NS
0.049
NS
Objective Response Rate
Folfirinox
Gemcitabine
N=171
N=171
Complete response
0.6%
0%
Partial response
31%
9.4%
CR/PR 95% CI
[24.7-39.1]
[5.9-15.4]
Stable disease
38.6%
41.5%
Disease control
CR+PR+SD
70.2%
50.9%
Progression
15.2%
34.5%
Not assessed
14.6%
14.6%
Median duration
of response
5.9 mo.
4 mo.
p
0.0001
0.0003
ns
Progression-Free Survival
Median PFS Folfirinox: 6.4 mo.
Median PFS Gemcitabine: 3.3 mo
HR=0.47 : 95%CI [0.37-0.59]
1.00
0.75
p<0.0001
0.50
0.25
0.00
0
3
6
9
12
15
18
21
24
27
30
33
36
0
1
0
0
0
0
0
0
0
0
Months
Number at risk
Gemcitabine 171 88
Folfirinox 171 121
26
85
8
42
5
17
2
7
0
4
Gemcitabine
0
1
Folfirinox
Overall Survival
HR=0.57 : 95%CI [0.45-0.73]
1.00
0.75
Stratified Log-rank test, p<0.0001
0.50
0.25
0.00
0
3
6
9
12 15 18 21 24 27 30 33 36
Months
Number at risk
Gemcitabine 171 134 89 48 28 14 7 6
Folfirinox 171 146 116 81 62 34 20 13
3
9
Gemcitabine
3
5
2
3
2
2
2
2
Folfirinox
Overall Survival
Median follow up: 26.6 months [95% CI: 20.5 – 44.9]
Folfirinox
N=171
Gemcitabine
N=171
p
HR
11.1 mo.
6.8 mo.
<0.0001
0.57
[ 9 - 13.1]
[ 5.5 - 7.6]
1-yr. survival
48.4%
20.6%
18-mo. survival
18.6%
6%
Median survival
[CI 95%]
Safety: hematological AEs
Folfirinox
Gemcitabine
N=167
N=169
AE, % per patient
p
All
Grade 3/4
All
Grade 3/4
Grade 3/4
79.9
45.7
54.8
18.7
0.0001
7.2
5.4
2.4
0.6
0.009
Anemia
90.4
7.8
94.6
5.4
NS
Thrombocytopenia
75.2
9.1
54.8
2.4
0.008
Neutropenia
Febrile Neutropenia
42.5 % of the pts received G-CSF in the F arm vs 5.3% in the G arm
One toxic death occurred in each arm
AE, adverse event
Safety: main non-hematological AEs
Folfirinox N=167
AE, % per patient
Gemcitabine N=169
p
All
Grade 3/4
All
Grade 3/4
6
1.2
7.1
1.8
NS
Peripheral neuropathy
70.5
9
0.6
0
0.0001
Vomiting
61.4
14.5
43.2
4.7
0.002
Fatigue
87.3
23.2
78.7
14.2
0.036
Diarrhea
73.3
12.7
30.8
1.2
0.0001
Alopecia (grade 2)
32.5
(11.4)
3.0
(0.6)
0.0001
ALT
64.8
7.3
83.8
18.6
0.0022
Infection without
neutropenia
Inclusion Criteria
 Histologically/cytologically confirmed pancreatic adenocarcinoma
 ECOG performance status of 0 or 1
 Measurable metastases
 No prior cytotoxic chemotherapy
 No prior abdominal radiotherapy
 Age 18-75 years
 Adequate hematopoietic, hepatic and renal function
 Bilirubin < 1.5 UNL
 No unstable angina or myocardial infarction within
12 months before entry
 Written informed consent
Gemcitabine: mécanisme d’action
Uptake intracellulaire
 hENT1
 hCNT 3
Activation
 dCK
– Nucleoside Phosphate Kinase
Inactivation
– CDA
– DCTD
– 5’-NT
Action
– Inhibition de la synthèse de l’ADN
Expérience Franco-Belge
471 patients assessed for eligibility
37 excluded
adjuvant treatment unknown (n= 10)
not analyzable (n=10 )
inclusion in retrospective study (n=17)
434 assessable
No adjuvant treatment
(n=142)
Adjuvant treatment
(n=292)
Non gemcitabine-containing (n=49)
Radiotherapy alone (n=3)
RT + 5FU (n=46)
Non Gemcitabine population
gemcitabine-based (n=243)
Gemcitabine monotherapy (n=208)
Gemox (n=35 )
Gemcitabine population
Marechal R, Bachet JB, Mackey J et al, in press
Expérience Franco-Belge
Population « gemcitabine »
Overall Survival
0.25
0.50
Survival(%)
0.50
0.25
0
6
hENT1 low/moderate
dCK low
hENT1 high
dCK moderate/high
12
18
0.00
0.00
Survival(%)
0.75
0.75
1.00
1.00
Overall Survival
24
30
36
42
48
54
60
20
34
13
29
10
27
6
22
3
18
0
6
12
18
24
36
42
48
54
60
7
48
5
38
3
34
3
26
2
20
N at risk
N at risk
hENT1 low/moderate 142
hENT1 high
92
30
Months
Months
133
89
105
78
74
69
49
59
33
50
dCK low
71
dCK moderate/high 165
68
156
50
134
39
105
26
83
17
67
Marechal R, Bachet JB, Mackey J et al, in press
Expérience Franco-Belge
Population « non gemcitabine »
Overall Survival
0.25
0.50
Survival(%)
0.50
0.25
0
6
hENT1 low/moderate
dCK low
hENT1 high
dCK moderate/high
12
18
0.00
0.00
Survival(%)
0.75
0.75
1.00
1.00
Overall Survival
24
30
36
42
48
54
60
33
23
29
17
27
10
24
10
22
10
0
6
12
18
24
36
42
48
54
60
13
44
9
37
8
29
7
27
7
25
N at risk
N at risk
hENT1 low/moderate 107
hENT1 high
72
30
Months
Months
101
68
75
57
61
43
46
37
38
30
dCK low
43
dCK moderate/high 137
40
131
29
105
23
83
21
63
16
53
Marechal R, Bachet JB, Mackey J et al, in press
Expérience Franco-Belge
Cumulative Survival
1,00
,75
,50
,25
0,00
0
6
12
18
24
30
36
42
48
54
60
66
72
Time (months)
N at risk
hENT1 low and any dCK

36
30
18
10
6
5
3
1
0
0
0
0
0
hENT1 moderate and any dCK

106
103
87
64
43
28
18
12
10
7
3
2
1
hENT1 high and dCK low

22
22
17
14
10
7
3
3
3
3
2
1
1
hENT1 high and dCK high

69
66
60
54
47
43
30
25
23
19
16
13
9
Marechal R, Bachet JB, Mackey J et al, in press
CONCLUSIONS
FOLFIRINOX = nouveau standard, oui mais ….
Chez les patients réellement PS 0 et 1
Chez les patients avec une bilirubine normale
En première ligne métastatique (localement avancé ?)
Qu’en est-il chez les patients PS 0/1, bili normale
et hENT1 high ????