1. This house believes that FOLFIRINOX is the best treatment for patients with metastatic pancreatic adenocarcinoma
Pro
Marc YCHOU
Montpellier

2. Prodige 4 - ACCORD 11 trial designM I Z E
Folfirinox
Gemcitabine
Oxaliplatin mg/m2 over 2 h
Leucovorin mg/m2 over 2 h
Irinotecan mg/m2 in 90 mn infusion 5-FU mg/m2 bolus
5-FU mg/m2 on 46-h infusion
1000 mg/m2 over 30 minutes
weekly x 7/8 and then weekly x 3/4

3. Overall Survival FOLFIRINOX Gemcitabine RR (%) 31.6 9.4 PFS (mo) 6.4
3.3
OS (mo)
11.1
6.8
Gemcitabine
Folfirinox

4. 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 ?

5. A Phase I trial to assess the triple combination
Fixed dose level of simplified LV5FU2
8 dose levels planned for CPT-11 and L-OHP at day 1
Level
CPT-11 (mg/m²)
L-OHP (mg/m²) 1 90 60 2
120 3 85 4
150 5
180 6
200 7
220 8
240
Ychou M et al. Annals Oncol 2003;14(3):481-9

6. The recommended Phase II Dose
Simplified LV5FU + 85 mg/m2 l-OHP mg/m2 CPT-11
1 h 30
2 h
46 h
Oxaliplatin
85 mg/m2
Irinotecan
180 mg/m2
Leucovorin
400 mg/m2
Continuous 5-FU
2.400 mg/m2
Bolus 5-FU 400 mg/m2

7. Ychou M et al. J Clin Oncol 2007;25:18S:201s
Background
Folfirinox regimen assessed in a phase II study (n=35)
Promising regimen in M1 patients with good PS
Median survival of 9.5 months
Conroy T et al. J Clin Oncol 2005;23:
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
Due to encouraging interim results, the trial continued as a phase III study

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 ?

9. Gemcitabine 1000 mg/m² 30' weekly
Burris et al. : Gemcitabine vs 5FU
Single blind R
5FU 600 mg/m². 30' weekly
(n = 63)
Gemcitabine 1000 mg/m² 30' weekly
(n = 63)
126 locally advanced or symptomatic pancreas ADK
Kanorfsky between 50% and 80%
Primary endpoint: clinical benefit (pain. PS. body weight)
Burris et al. JCO Jun :

10. Burris et al. : Efficacy
Gemcitabine is more effective than 5-FU in alleviation of some disease-related symptoms
Gemcitabine confers a modest survival advantage
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%
Burris et al. JCO Jun :

11. 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
12.4 vs 19.1* 9
602
Gem. vs Gem. + bevacizumab
10.0 vs 11.0
6.1 vs 5.8 10
607
Gem. + erlotinib vs Gem. + erlotinib + bevacizumab
8.6 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.

12. Gemcitabine alone in locally advanced and metastatic pancreatic cancer
ACCORD 11 trial: results for gemcitabine are comparable to those observed across a variety of studies
Study N
RR %
PFS
months OS
Burris et al. 63
5.4
2.2
5.7
Berlin et al.
162
5.6
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
2.6
4.9
ACCORD 11*
171
9.4
3.3
6.8
* Only metastatic patients

13. 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 ?

14. Safety: main adverse events in ACCORD 11
One toxic death in each arm
AE % worst toxicity per patient
Folfirinox
N=167
Gemcitabine
N=169
P value
Grade 3
Grade 4
Neutropenia*
29.9
16.1
18.1
0.6
0.0001
Febrile Neutropenia*
4.2
1.2
0.0
0.009
Vomiting
13.9
4.1
0.002
Fatigue
21.2
1.8
13.6
0.036
Diarrhea
10.9
*No prophylactic use of G-CSF

15. Maximum Grade 3/4 toxicity in the METHEP trial (liver metastases from CRC)
CONTROL
(30 pts)
FOLFIRI-HD
(32 pts)
FOLFOX-7
FOLFIRINOX
Neutropenia*
33%
28%
27%
Thrombopenia 0% 3%
10%
13%
Febrile Neutrop.
3%**
Diarrhea
12% 7%
23%
Vomitis 9%
Mucites 6%
Asthenia
19%
* Prophylactic use of GCS-F except in 4 patients**

16. 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 ?

17. ACCORD 11: patient characteristics
Folfirinox
N=171
Gemcitabine
P value
Median age (yrs)
[range] 61
[25-76]
[34-75] NS
Sex
Male
Female
106 (62%)
65 (38%)
105 (61.4%)
66 (38.6%)
Baseline PS 1 2
64 (37.4%)
106 (62.0%)
1 (0.6%)
0 (0.0%)
Synchronous metastases
Metachronous metastases
156 (91.2%)
15 (8.8%)
161 (94.2%)
10 (5.8%)

18. ACCORD 11: disease characteristics
Folfirinox
N=171
Gemcitabine
P value
Location of primary
Head
Other
67 (39.2%)
104 (60.8%)
63 (36.8%)
108 (63.2%) NS
Biliary stent
27 (15.8%)
22 (12.9%)
Median no. of sites involved
2 (1-6)
CA19-9  59 ULN
68 (41.5%)
77 (46.7%)
Measurable site
Liver
Pancreas
Nodes
Lungs
Peritoneal
149 (88.2%)
89 (52.7%)
48 (28.4%)
33 (19.5%)
150 (87.7%)
91 (53.2%)
39 (22.8%)
49 (28.7%)
32 (18.7%)
0.049

19. ACCORD 11: Toxicity of Folfirinox in patients with biliary stent
AE % worst toxicity per patient
No stent
N=144
Stent
N=27
P value
All grades
Grade 3/4
Neutropenia*
81.2
47.1
73.1
38.5 NS
Febrile Neutropenia*
6.5
4.3
11.1
Anemia
91.4
9.4
85.2
7.4
Thrombopenia
Infection without neutropenia
5.8
1.4
 Similar risk of developing infections and hematologic toxicity

20. The OS benefit with FOLFIRINOX is consistent across all subgroups analyzed

21. The OS benefit with FOLFIRINOX is consistent across all subgroups analyzed

22. 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 ?

23. (A) Global health status
Change in mean QLQ-C30 score over time
(A) Global health status
(B) Diarrhea

24. Time to definitive QoL degradation

25. ACCORD 11: QUESTIONS ABOUT THIS TRIAL
A coherent rationale to test FOLFIRINOX in a phase III trial ?
Gemcitabine : a relevant control arm ?
FOLFIRINOX: too toxic ?
Study population: too selected ?
Did FOLFIRINOX regimen degrade Quality of Life ?
Yes
Yes
No, toxicity is manageable
Generalizable to a quite large population No

26. 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