this house believes that folfirinox is the best treatment for patients with metastatic pancreatic...

This house believes that FOLFIRINOX is

the best treatment for patients with

metastatic pancreatic adenocarcinoma

Pro Marc YCHOU Montpellier

Prodige 4 - ACCORD 11 trial design

RANDOMIZE

Folfirinox

Gemcitabine

Oxaliplatin 85 mg/m2 over 2 hLeucovorin 400 mg/m2 over 2 hIrinotecan 180 mg/m2 in 90 mn infusion5-FU 400 mg/m2 bolus 5-FU 2400 mg/m2 on 46-h infusion

1000 mg/m2 over 30 minutes weekly x 7/8 and then weekly x 3/4

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]

Gemcitabine

Folfirinox

FOLFIRINOX Gemcitabine

RR (%) 31.6 9.4

PFS (mo) 6.4 3.3

OS (mo) 11.1 6.8

ACCORD 11: QUESTIONS ABOUT THIS TRIAL

Did we have a coherent rationale to test FOLFIRINOX in a phase III trial ?

Gemcitabine : a relevant control arm ?

FOLFIRINOX: efficacious but too toxic ?

Study population: too selected ?

Did FOLFIRINOX regimen degrade Quality of Life ?

A Phase I trial to assess the triple combination

Fixed dose level of simplified LV5FU28 dose levels planned for CPT-11 and L-OHP at day 1

Level CPT-11 (mg/m²) L-OHP (mg/m²)

1 90 602 120 603 120 85 4 150 855 180 856 200 857 220 858 240 85

Ychou M et al. Annals Oncol 2003;14(3):481-9

The recommended Phase II Dose

Simplified LV5FU + 85 mg/m2 l-OHP + 180 mg/m2 CPT-11

1 h 30

2 h

2 h 46 h

Oxaliplatin85 mg/m2

Irinotecan180 mg/m2

Leucovorin400 mg/m2

Continuous 5-FU 2.400 mg/m2

Bolus 5-FU 400 mg/m2

Background

A randomized phase II-III study comparing Folfirinox regimen to gemcitabine alone was launched

Results of the phase II portion (n=88) presented at the ASCO 2007 (objective: RR ≥ 24% in the Folfirinox arm)

31.8% RR in the Folfirinox arm vs 11.4% in the gemcitabine arm

Ychou M et al. J Clin Oncol 2007;25:18S:201s

Conroy T et al. J Clin Oncol 2005;23:1228-36

Folfirinox regimen assessed in a phase II study (n=35) Promising regimen in M1 patients with good PS Median survival of 9.5 months

Due to encouraging interim results, the trial continued as a phase III study

126 locally advanced or symptomatic pancreas ADKKanorfsky between 50% and 80%Primary endpoint: clinical benefit (pain. PS. body weight)

Burris et al. : Gemcitabine vs 5FU

Gemcitabine 1000 mg/m² 30' weekly (n = 63)

5FU 600 mg/m². 30' weekly (n = 63)

RSingle blind

Burris et al. JCO Jun 1. 1997:2403-13

Burris et al. : Efficacy

Burris et al. JCO Jun 1. 1997:2403-13

5-FU Gemcitabine

Clinical benefit 4.8% (3 pts) 23.8% (15 pts)

Objective response 0% 5.4%

Median survival 4.4 months 5.65 months

1-year survival rate 2% 18%

Gemcitabine is more effective than 5-FU in alleviation of some disease-related symptomsGemcitabine confers a modest survival advantage

Prognosis of patients with metastatic pancreatic cancer is poor

5-year survival rates is 6%

Although gemcitabine became the reference treatment almost 15 years ago, attempts to improve outcomes since then have been disappointing

Ref N Agents RR, % OS, mo

1 126 Gem. vs 5-FU 5.4 vs 0.0 5.7* vs 4.4

2 322 Gem. vs Gem.+ 5-FU 5.6 vs 6.9 5.4 vs 6.7

3 313 Gem. vs Gem. + oxaliplatin 17.3 vs 26.8* 7.1 vs 9.0

4 195 Gem. vs Gem. + cisplatin 8.2 vs 10.2 6.0 vs 7.5

5 569 Gem. vs Gem. + erlotinib 8.0 vs 8.6 5.9 vs 6.2*

6 824 Gem. vs FDR Gem. vs Gem.+ oxaliplatin 6.0 vs 10.0 vs 9.0 4.9 vs 6.2 vs 5.7

7 533 Gem. vs Gem. + capecitabine 19.1 vs 12.4 6.2 vs 7.1

8 533 Gem. vs Gem. + capecitabine 12.4 vs 19.1* 6.2 vs 7.1

9 602 Gem. vs Gem. + bevacizumab 10.0 vs 11.0 6.1 vs 5.8

10 607Gem. + erlotinib vs Gem. + erlotinib +

bevacizumab8.6 vs 13.6 6.0 vs 7.1

11 735 Gem. vs Gem. + cetuximab 14.0 vs 12.0 5.9 vs 6.4

*statistically significant (p<0.05)

1. Burris et al. J Clin Oncol 1997; 2. Berlin et al. J Clin Oncol 2002; 3. Louvet et al. J Clin Oncol 2005; 4. Heinemann et al. J Clin Oncol 2006; 5. Moore et al. J Clin Oncol 2007; 6. Poplin et al. J Clin Oncol 2009; 7. Cunningham et al. J Clin Oncol 2008; 8. Cunningham et al. J Clin

Oncol 2009; 9. Kindler et al. ASCO 2007; 10. Van Cutsem et al. J Clin Oncol 2009; 11. Philip et al. ASCO 2007.

Gemcitabine alone in locally advanced and metastatic pancreatic cancer

Study N RR % PFSmonths

OSmonths

Burris et al. 63 5.4 2.2 5.7

Berlin et al. 162 5.6 2.2 5.4

Louvet et al. 156 17.3 3.7 7.1

Heinemann et al. 97 8.2 3.1 6.0

Moore et al. 284 8.0 3.5 5.9

Poplin et al. 275 6.0 2.6 4.9

ACCORD 11* 171 9.4 3.3 6.8

* Only metastatic patients

ACCORD 11 trial: results for gemcitabine are comparable to those observed across a variety of studies

Safety: main adverse events in ACCORD 11

AE % worst toxicity per patient

Folfirinox N=167

Gemcitabine N=169

P value

Grade 3 Grade 4 Grade 3 Grade 4

Neutropenia* 29.9 16.1 18.1 0.6 0.0001

Febrile Neutropenia* 4.2 1.2 0.0 0.6 0.009

Vomiting 13.9 0.6 4.1 0.6 0.002

Fatigue 21.2 1.8 13.6 0.6 0.036

Diarrhea 10.9 1.8 1.2 0.0 0.0001

One toxic death in each arm

*No prophylactic use of G-CSF

Maximum Grade 3/4 toxicity in the METHEP trial

(liver metastases from CRC)

* Prophylactic use of GCS-F except in 4 patients**

CONTROL(30 pts)

FOLFIRI-HD(32 pts)

FOLFOX-7(30 pts)

FOLFIRINOX(30 pts)

Neutropenia* 33% 28% 27% 33%

Thrombopenia 0% 3% 10% 13%

Febrile Neutrop. 0% 3% 0% 3%**

Diarrhea 0% 12% 7% 23%

Vomitis 7% 9% 3% 3%

Mucites 0% 6% 0% 10%

Asthenia 3% 19% 3% 13%

ACCORD 11: patient characteristics

FolfirinoxN=171

GemcitabineN=171 P value

Median age (yrs)[range]

61[25-76]

61[34-75] NS

Sex MaleFemale

106 (62%) 65 (38%)

105 (61.4%) 66 (38.6%) NS

Baseline PS 012

64 (37.4%) 106 (62.0%) 1 (0.6%)

66 (38.6%)105 (61.4%) 0 (0.0%)

NS

Synchronous metastasesMetachronous metastases

156 (91.2%) 15 (8.8%)

161 (94.2%)10 (5.8%)

NSNS

ACCORD 11: disease characteristics

FolfirinoxN=171

GemcitabineN=171 P value

Location of primary

HeadOther

67 (39.2%) 104 (60.8%)

63 (36.8%)108 (63.2%)

NSNS

Biliary stent 27 (15.8%) 22 (12.9%) NS

Median no. of sites involved 2 (1-6) 2 (1-6) NS

CA19-9 59 ULN 68 (41.5%) 77 (46.7%) NS

Measurable site

LiverPancreasNodesLungsPeritoneal

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%)

NSNSNS

0.049NS

ACCORD 11: Toxicity of Folfirinox in patients with biliary stent

Similar risk of developing infections and hematologic toxicity

AE % worst toxicity per patient

No stent N=144

StentN=27

P valueAll

grades Grade 3/4 All grades Grade 3/4

Neutropenia* 81.2 47.1 73.1 38.5 NS

Febrile Neutropenia* 6.5 4.3 11.1 11.1 NS

Anemia 91.4 9.4 85.2 7.4 NS

Thrombopenia 6.5 4.3 11.1 11.1 NS

Infection without neutropenia 5.8 1.4 7.4 0 NS

The OS benefit with FOLFIRINOX is consistent across all subgroups analyzed

(A) Global health status

0102030405060708090

100

QoL

mea

n s

core

(%

)

0 1 2 4 6 8 10Months


0102030405060708090

100

QoL

mea

n s

core

(%

)

0 1 2 4 6 8 10Months


Change in mean QLQ-C30 score over time

(B) Diarrhea

Time to definitive QoL degradation

0.00

0.25

0.50

0.75

1.00

Pro

ba

bility

163 89 35 13 4 1 1Folfirinox157 53 9 1 0 0 0Gemcitabine

Number at risk

0 3 6 9 12 15 18Months


p=.001

Kaplan-Meier estimation for TUDD ofGlobal health status/QoL (MCID 10 points)


A coherent rationale to test FOLFIRINOX in a phase III trial ?


FOLFIRINOX: too toxic ?



Yes

Yes

No, toxicity is manageable

No

Generalizable to a quite large population

Conclusion

I do believe that FOLFIRINOX is the best treatment for patients with metastatic pancreatic adenocarcinoma if :

• Bilirubin <1.5 UNL • PS 0-1• Age< 75

This combination is now tested in the adjuvant setting:

ACCORD/PRODIGE 24 trial

this house believes that folfirinox is the best treatment for patients with metastatic pancreatic...

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