FOLFIRINOX : un nouveau standard dans les

adénocarcinomes pancréatiques ?

FOLFIRINOX : un nouveau standard dans les

adénocarcinomes pancréatiques ?

Christophe LouvetInstitut Mutualiste Montsouris, Paris

SFCP, Ajaccio, 10/05/2012

ADK pancréatique métastatique:Chimiothérapie ou soins de confort ?

ADK pancréatique métastatique:Chimiothérapie ou soins de confort ?

Auteur Regime n patients

Med. Surv. (mo)

Qol

Mallinson 1980

5-FU+Mtx+Vcr + cyclo + MMC BSC

21

19

10.5

2.2*

Frey 1981

5-FU + CCNU BSC

65 87

3.0 3.9

Andersen 1981

5-FU + BCNU BSC

20 20

3.2 3.4

Palmer 1994

FAM BSC

23 20

8.2 3.8*

Glimelius 1996

5-FU + LV + Etoposide BSC

29

24

6.0

2.5*

benefice dans le groupe CT

* p < 0.05

L’étude Burris (1997)L’étude Burris (1997)

Gemcitabinen=63

5-Fluorouracilen=63

Bénéfice clinique

5.65 mois ** 4.41 mois Survie médiane

** p = 0.0025

Burris H A, et al.: JCO 15: 2403, 1997

23.8% * 4.8%

* p = 0.0022

Gem ± Pemetrexed (Oettle, Ann Oncol 2006) 6.3 6.2 NSGem ± CPT-11 (Rocha-Lima, JCO 2006) 6.6 6.3 NSGem ± Exatecan (Abou-Alfa, JCO 2006) 6.2 6.7 NS

Gem ± Cisplatin (Heinemann, JCO 2006) 6.0 7.5 NSGem ± Oxaliplatine (Louvet, JCO 2005) 7.1 9.0 NSGem ± Oxaliplatine (Poplin, JCO 2009) 4.9 5.9 NSGem ± Cisplatin (Colucci, ASCO 2009) 8.3 7.2 NS

Gem Gem + X p

Gem ± 5FU bolus (Berlin, JCO 2002) 5.4 6.7 NS

Gem ± Capecitabine (Cunningham, JCO 2009) 6.2 7.1 NS

Gem ± Capecitabine (Herrmann, JCO 2007) 7.3 8.4 NSGem ± 5FU/LV (Riess, JCO 2005) 6.2 5.9 NS

Etudes de phases III dans les cancers du pancréas(chimiothérapie conventionelle)

Copyright © American Society of Clinical OncologySultana, A. et al. J Clin Oncol; 25:2607-2615 2007

Méta-analyse de survie: Gemcitabine versus Gemcitabine + autre drogue

Copyright © American Society of Clinical OncologySultana, A. et al. J Clin Oncol; 25:2607-2615 2007

Analyse par sous-groupe :Gemcitabine vs Gemcitabine + autre drogue

Résumé de la méta-analyse dans les cancersdu 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) 1108 0.76 < 0.0001Gem vs Gem + sel de platine / fluoropyrimidine (PS 2) 574 1.08 NS

Gem Gem + X p

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

Etudes de phases III dans les cancers du pancréas(thérapies ciblées)

Gem ± Marimasmat (Bramhall, BJC 2002) 5.5 5.5 NS

Gem ± Tifarbinib (Van Cutsem, JCO 2004) 6.0 6.4 NS

Anti-EGFRAnti-EGFR

Preuve du concept avec l’erlotinib (Moore, JCO 2007)

Pas de confirmation avec le cetuximab (Philip, ASCO 2008)

Pas de synergie avec le bevacizumab (Van Cutsem, JCO 2009)

Pas de marqueur moléculaire prédictif (K-ras?)

Rash prédictif de survie ? (Moore, 2007; Van Cutsem, 2009)

Preuve du concept avec l’erlotinib (Moore, JCO 2007)

Pas de confirmation avec le cetuximab (Philip, ASCO 2008)

Pas de synergie avec le bevacizumab (Van Cutsem, JCO 2009)

Pas de marqueur moléculaire prédictif (K-ras?)

Rash prédictif de survie ? (Moore, 2007; Van Cutsem, 2009)

AntiangiogéniquesAntiangiogéniques

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)

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 perfusion de 30mn ou de 10 mg/m²/mn?

R

Gemcitabine1500 mg/m²10mg/m²/min

Gemcitabine2200mg/m²

30 minN=80

Rép 16.6%PFS 3.4 moisOS 8 moisSurvie à 1 an: 23%

Rép 2.7%PFS 1.9 moisOS 5 moisSurvie 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

Stratification :

center performance status: 0 versus 1 location of the tumor: head versus other location of the primary

Metastaticpancreaticcancer

RANDOMIZE

Folfirinox

Gemcitabine

6 months of chemotherapy recommended

CT scans: obtained

every 2 months

for both arms:

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

CharacteristicFolfirinox

N=171

GemcitabineN=171

p

Median age (yrs)

[range]

61

[25-76]

61

[34-75]NS

Sex Male

Female

106 (62%)

65 (38%)

105 (61.4%)

66 (38.6%) NS

Baseline PS 0

1

2

64 (37.4%)

106 (62.0%)

1 (0.6%)

66 (38.6%)

105 (61.4%)

0 (0.0%)NS

Location of primary Head

Other

62 (36.3%)

109 (63.7%)

60 (35.1%)

111 (64.9%) NS

Disease characteristics

CharacteristicFolfirinox

N=171

GemcitabineN=171

p

Synchronous metastases

Metachronous metastases

156 (91.2%)

15 (8.8%)

161 (94.2%)

10 (5.8%)

NS

NS

Median nr. of involved sites

CA19-9 59 ULN

2 (1-6)

68 (41.5%)

2 (1-6)

77 (46.7%)

NS

NS

Measurable site

Liver

Pancreas

Nodes

Lungs

Peritoneal

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%)

NS

NS

NS

0.049

NS

Objective Response Rate

FolfirinoxN=171

GemcitabineN=171

p

Complete response 0.6% 0%

Partial response 31% 9.4% 0.0001

CR/PR 95% CI [24.7-39.1] [5.9-15.4]

Stable disease 38.6% 41.5%

Disease control

CR+PR+SD70.2% 50.9% 0.0003

Progression 15.2% 34.5%

Not assessed 14.6% 14.6%

Median durationof response

5.9 mo. 4 mo. ns

Progression-Free Survival

0.00

0.25

0.50

0.75

1.00

Pro

babili

ty

171 121 85 42 17 7 4 1 1 0 0 0 0Folfirinox171 88 26 8 5 2 0 0 0 0 0 0 0Gemcitabine

Number at risk

0 3 6 9 12 15 18 21 24 27 30 33 36Months

Gemcitabine Folfirinox

p<0.0001

HR=0.47 : 95%CI [0.37-0.59]

Median PFS Folfirinox: 6.4 mo. Median PFS Gemcitabine: 3.3 mo

Overall Survival

0.00

0.25

0.50

0.75

1.00

Pro

babili

ty

171146116 81 62 34 20 13 9 5 3 2 2Folfirinox171134 89 48 28 14 7 6 3 3 2 2 2Gemcitabine

Number at risk

0 3 6 9 12 15 18 21 24 27 30 33 36Months

Gemcitabine Folfirinox

Stratified Log-rank test, p<0.0001

HR=0.57 : 95%CI [0.45-0.73]

Overall Survival

Folfirinox

N=171

Gemcitabine

N=171 p HR

Median survival[CI 95%]

11.1 mo.[ 9 - 13.1]

6.8 mo.[ 5.5 - 7.6]

<0.0001 0.57

1-yr. survival 48.4% 20.6%

18-mo. survival 18.6% 6%

Median follow up: 26.6 months [95% CI: 20.5 – 44.9]

Safety: hematological AEs

AE, % per patient

FolfirinoxN=167

GemcitabineN=169

p

All Grade 3/4 All Grade 3/4 Grade 3/4

Neutropenia 79.9 45.7 54.8 18.7 0.0001

Febrile Neutropenia 7.2 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

5.4

42.5 % of the pts received G-CSF in the F arm vs 5.3% in the G armOne toxic death occurred in each armAE, adverse event

Safety: main non-hematological AEs

AE, % per patientFolfirinox N=167 Gemcitabine N=169

pAll Grade 3/4 All Grade 3/4

Infection without neutropenia

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 0.002218.618.6

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’actionGemcitabine: 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

Uptake intracellulaire hENT1 hCNT 3

Activation dCK

– Nucleoside Phosphate Kinase

Inactivation– CDA

– DCTD

– 5’-NT

Action– Inhibition de la synthèse de l’ADN

471 patients assessed for eligibility

434 assessable

37 excluded adjuvant treatment unknown (n= 10)

not analyzable (n=10 ) inclusion in retrospective study (n=17)

Adjuvant treatment(n=292)

Non gemcitabine-containing (n=49)Radiotherapy alone (n=3) RT + 5FU (n=46)

No adjuvant treatment (n=142)

gemcitabine-based (n=243)Gemcitabine monotherapy (n=208)Gemox (n=35 )

Non Gemcitabine population Gemcitabine population

Expérience Franco-Belge

Marechal R, Bachet JB, Mackey J et al, in press

Expérience Franco-Belge

Marechal R, Bachet JB, Mackey J et al, in press

0.0

00.2

50.5

00.7

51.0

0S

urv

ival(

%)

92 89 78 69 59 50 34 29 27 22 18hENT1 high142 133 105 74 49 33 20 13 10 6 3hENT1 low/moderate

N at risk

0 6 12 18 24 30 36 42 48 54 60Months

hENT1 low/moderate

hENT1 high

Overall Survival

0.0

00.2

50.5

00.7

51.0

0S

urv

ival(

%)

165 156 134 105 83 67 48 38 34 26 20dCK moderate/high71 68 50 39 26 17 7 5 3 3 2dCK low

N at risk

0 6 12 18 24 30 36 42 48 54 60Months

dCK low

dCK moderate/high

Overall Survival

Population « gemcitabine »

Expérience Franco-Belge

Marechal R, Bachet JB, Mackey J et al, in press

0.0

00.2

50.5

00.7

51.0

0S

urv

ival(

%)

72 68 57 43 37 30 23 17 10 10 10hENT1 high107 101 75 61 46 38 33 29 27 24 22hENT1 low/moderate

N at risk

0 6 12 18 24 30 36 42 48 54 60Months

hENT1 low/moderate

hENT1 high

Overall Survival

0.0

00.2

50.5

00.7

51.0

0S

urv

ival(

%)

137 131 105 83 63 53 44 37 29 27 25dCK moderate/high43 40 29 23 21 16 13 9 8 7 7dCK low

N at risk

0 6 12 18 24 30 36 42 48 54 60Months

dCK low

dCK moderate/high

Overall Survival

Population « non gemcitabine »

Expérience Franco-Belge

Marechal R, Bachet JB, Mackey J et al, in press

Time (months)

726660544842363024181260

Cum

ulat

ive

Sur

viva

l

1,00

,75

,50

,25

0,00

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

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 ????