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 M I Z E Folfirinox Gemcitabine Oxaliplatin 85 mg/m2 over 2 h Leucovorin 400 mg/m2 over 2 h Irinotecan 180 mg/m2 in 90 mn infusion 5-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 FOLFIRINOX Gemcitabine RR (%) 31.6 9.4 PFS (mo) 6.4 3.3 OS (mo) 11.1 6.8 Gemcitabine Folfirinox

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 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

The recommended Phase II Dose Simplified LV5FU + 85 mg/m2 l-OHP + 180 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

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;23:1228-36 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

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 ?

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 1. 1997:2403-13

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 1. 1997:2403-13

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.

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

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 ?

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

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**

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 ?

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%)

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

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

The OS benefit with FOLFIRINOX is consistent across all subgroups analyzed

The OS benefit with FOLFIRINOX is consistent across all subgroups analyzed

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

Time to definitive QoL degradation

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

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