Slide 1: VELOUR: IV Aflibercept plus FOLFIRI in Second-line mCRC, Phase III Results
VELOUR Intravenous (IV) Aflibercept Versus Placebo in Combination With Irinotecan/5-FU (FOLFIRI) For Second-line Treatment of Metastatic Colorectal Cancer (mCRC): Results Of A Multinational Phase III Trial (EFC10262-VELOUR). Eric Van Cutsem’, J. Tabernero, R. Lakomy, J. Prausova, P. Ruff, G. Van Haz
Slide 2: Soluble fusion protein
Soluble fusion protein Consists of portion of extracellular domains of human VEGF receptors 1 and
Slide 3: Background and Study Rationale
Background and Study Rationale «In the preclinical setting, aflibercept exhibited improved activity when combined with irinotecan and with 5-FU ¢ Objective tumor responses were observed in patients with mCRC who received aflibercept in combination with irinotecan and 5-FU/FA in the phase | TCD 6118
Slide 4: Background: Benefit of Angiogenesis Inhibitors in mCRC
Background: Benefit of Angiogenesis Inhibitors in mCRC 1st Line 2rd Line IFL +/- bevacizumab ORR, PFS, OS (1) 2? FOLFOX/XELOX +/- FOLFOX +/- bevacizumab bevacizumab ORR, PFS, OS 2) PFS «3 (1) Hurwitz H et al. N Engl J Med 2004 (350) 2335-2342 (2) Giantonio BJ et al. ECOG E3200. J Clin Oncol 2007(25)
Slide 5: Study Design
Study Design Aflibercept 4 mg/kg IV, day 1 + FOLFIRI q2 weeks a Disease Progression Hm Death Metastatic Colorectal Cancer Stratification factors: -ECOG PS (0vs 1 vs 2) - Prior bevacizumab (Y/N) Placebo IV, day 1 + FOLFIRI q2 weeks R A N D fe} M 1 Zz E DMC review every 6 months
Slide 6: Primary Endpoint: Overall Survival
Primary Endpoint: Overall Survival Demonstrate a HR of 0.8 with 90% power and a 2-sided type | error of 0.05 Analysis with log-rank comparison and Kaplan Meier method, stratified by — ECOG PS 0 vs1vs2 — Prior treatment with bevacizumab Yes vs No Final analysis of OS~863 death events using a 2-sided
Slide 7: Secondary Endpoints
Secondary Endpoints ¢ Progression free survival and response rate: — RECIST 1.0 criteria, independent third party review — Imaging every 6 weeks — Analysis using a 2-sided nominal significance level of 0.0001 + Safety (NCI CTC v.3.0) ¢ PK and immunogenicity
Slide 8: Patient Population
Patient Population Histologically proven metastatic colorectal cancer One prior treatment with an oxaliplatin based regimen No prior irinotecan Prior bevacizumab permitted Age 2 18 years old ECOG PS: 0, 1,2 Adequate organ functions Measurable or non-measurable disease Written informed consent
Slide 9: Patient Disposition - Analysis Populations
Patient Disposition - Analysis Populations Placebo/ Aflibercept/ FOLFIRI FOLFIRI ITT population 614 (100) 612 (100) Randomized not treated 5 (0.8) 5 (0.8) Evaluable population* 530 (86.3) 531 (86.8) N (%) Safety population 605 611 * Response rate analysis excluded patients with only non target lesio
Slide 10: Main Demographic Characteristics
Main Demographic Characteristics ITT Population Placebo Aflibercept N=614 N = 612 Age, yrs Median (Range) _—_61.0 (19:86) 61.0 (21:82) Age >65 38.8 33.5 Gender, % Male 57.5 59.6 ECOG PS*, % 57.0 57.0 40.7 40.8 2.3 2.1 *as reported per IVRS
Slide 11: Prior Chemotherapy
Prior Chemotherapy ITT Population Placebo Aflibercept % N=614 N =612 Chemotherapy 100 Adjuvant only (relapse <6 mos end adjuvant) 10.4 Adjuvant + metastatic 176 Metastatic only Last Chemotherapy P! Oxaliplatin based Oxaliplatin single agent Oxaliplatin + fluoropyrimidine only Oxaliplatin + fluoropyr
Slide 12: Main Disease Characteristics
Main Disease Characteristics ITT Population % Primary site Colon Rectosigmoid Rectum Other Placebo N=614 49.2 22.1 28.3 0.3 Aflibercept N=612 47.2 20.1 32.2 0.5 > 1 metastatic sites Main metastatic organs involved Liver (overall) Liver only Lung Peritoneum 54.9 70.2 23.8 45.1 14.3 57.8 75.0 25.0 44.
Slide 13: Other Baseline Characteristics
Other Baseline Characteristics ITT Population Placebo Aflibercept % N=614 N=612 Allgrades Grade3-4 Allgrades Grade 3-4 Anemia 476 0 44.2 Elevated alkaline 54.0 0.8 52.5 phosphatase Hypoalbuminemia 15.6 0.2 > ULN Elevated LDH 55.2
Slide 14: Discontinuation of Study Treatment
Discontinuation of Study Treatment ITT Population Placebo Aflibercept % N=614 N= 612 Discontinued study treatment 97.4 96.9 Disease progression 71.2 49.8 Adverse event 12.1 26.6 Patient request 7.0 12.6 Investigator decision 3.4 ete) Metastatic surgery 1.6 2.0 Other causes* 21 2.6 Study treatment on
Slide 15: Treatment Exposure
Treatment Exposure Placebo Aflibercept N=605 N=611 Total number of cycles 6127 6362 Median (range) 8.0 (1 : 67) 9.0 (1: 50) Safety Population Aflibercept or placebo infusions Total number 6035 5632 Median (range) 8 (1: 67) 7 (1:35) Relative dose intensity (%) 92 83 Patients with at least 1 dose modi
Slide 16: Overall Survival Kaplan-Meier Curve
1.0 Symbol=Censor Placebo/FOLFIRI Median = 12.06 months 0.9 = Aflibercept/FOLFIRI = -=--= Median = 13.50 months os Stratified HR=0.817 [95.34%Cl, 0.713-0.937] or Log-rank p= 0.0032 06 0.5 04 0.3 4 & 7 & s 3 = = i= 3 £ 0.2 04 0.0 0 3 12 15 18 21 24 27 Number at Risk Time (Months) Placebo 614 573 485
Slide 17: Overall Survival by Strata
STRATA (AS PER IVRS) All patients ECOG PS=0 ECOG PS=2 No prior bevacizumab Prior bevacizumab HR [95.34% Cl] FAVORS AFLIBERCEPT 0.817 (0.713 to 0.937) 0.768 (0.695 to 0.928) 0.869 (0.71 to 1.063) 0.978 (0.43 to 2.221) 0.788 (0.669 to 0.927) 0.862 (0.673 to 1.104) ECOG: Eastem Cooperative Oncology Gro
Slide 18: Progression-Free Survival Kaplan-Meier Curve
1.0 Symbol=Censor Placebo/FOLFIRI Median = 4.67 months 0.9 Aflibercept/FOLFIRI =--=-- Median = 6.90 months os Stratified HR=0.758 [99.99%Cl = 0.578-0.995] o7 Log-rank p = 0.00007 06 0.5 0.4 ¢ £ a a s 3 = rH 4 a w] 0.3 0.2 04 0.0 0 a) 6 Number at Risk Placebo 614 355171 AFLL 612420247. Cut-off date =
Slide 19: Response Rate, Independent Review Committee
Response Rate, Independent Review Committee Placebo Aflibercept Evaluable population*, % N=530 N=531 Best Overall Response Complete response 0.4 Partial response 10.8 Stable disease 64.9 Progressive disease 21.5 Not evaluable 2.5 4.0 Overall Response Rate (CR or PR) 11.4 19.8 95% Cl 8.5 to 13.8 16.4
Slide 20: Safety: Most Frequent Adverse Events
Safety — Most frequent AEs, with = 5% difference in incidence between treatment arms, excluding anti-VEGF class events Safety Population, % of patients Placebo, N= 605 Aflibercept N = 611 All All Grades _S7A0°34 Grades Diarrhea ; 78 69.2 19.3 Neutropenia™ ; 295 678 367 Complicated neutropenia 28 57
Slide 21: Safety: Anti-VEGF Associated Events
Safety — Anti-VEGF Associated Events Safety population, % of Placebo N = 605 Aflibercept N= 611 Grouped Term, PT All Grade Grade 3/4__AllGrade _Grade 3/4 Proteinuria” 407 12 62.2 79 Hypertension 107 15 aA 193 Haemorrhage 19.0 Ane 378 ia) Epistaxis 74 0 277 0.2 Gl origin 51 1.0 10.0 2.0 Dysphonia (PT
Slide 22: Number of deaths within 30d from last dose
Number of deaths within 30d from last dose Disease progression Adverse events: Infections (sepsis and neutropenic sepsis) Death/sudden death Pulmonary embolism GI hemorrhage (duodenal ulcer) Gl disorders (inflammation/obstruction) Respiratory disorders 02 Other™ 0 ~Other: dehydration (2pts), metabol
Slide 23: Conclusions
Conclusions ¢ Adding aflibercept to FOLFIRI in mCRC previously treated with an oxaliplatin based regimen provided benefits that are both statistically and clinically significant: — Improvement in overall survival (HR=0.817 [95.34%CI, 0.713- 0.937], p = 0.0032) — Improvement in PFS (HR=0.758 [99.99%C
Slide 24: Conclusions: benefit of angiogenesis inhibitors in mCRC
Conclusions: benefit of angiogenesis inhibitors in mCRC 1st Line 2"4 Line IFL +/- bevacizumab FOLFIRI +/- aflibercept ORR, PFS, OS (1) OS, PFS, RR « VELOUR FOLFOX/XELOX +/- FOLFOX +/- bevacizumab bevacizumab ORR, PFS, OS 2) PFS only ¢3) (1) Hurwitz H et al. N Engl J Med 2004 (350) 2335-2342 (2) Gian
Slide 25: Acknowledgements
Acknowledgements Thank you to all patients, their families and all the investigators who participated: Italy (contd) Romania (cont'd) : * Malloy A *curcaR *Volovat C orga P Russia
Slide 26: Acknowledgements
Acknowledgements Thank you to all patients, their families and all the investigators who participated: United States + Radford * Asin Polka J Mantel A * Gross ian T Disclosure This study (NCT00561470) was funded by sanofi. Aflibercept is being developed in oncology in a partnership between Regeneron