Randomized Phase III Trial of Cetuximab Plus Irinotecan vs Irinotecan Alone for Metastatic Colorectal Cancer (mCRC) after Failing Prior Oxaliplatin-based Therapy: The EPIC Trial Alberto F. Sobrero 1, Louis Fehrenbacher 2, Fernando Rivera 3, Ernst-Ulrich Steinhauer 4, Jana Prausova 5, Christophe Borg 6, Yousif Abubakr 7, Angela Zubel 8, Christiane Langer 9, Howard Burris III 10 1 Ospedale San Martino, Genova, Italy; 2 Kaiser Permanente Medical Center, Vallejo, CA; 3 Hospital Universitario Marques de Valdecilla, Santander, Spain; 4 Klinikum Kassel, Kassel, Germany; 5 Motol University Hospital, Prague, Czech Republic; 6 CHU Besancon, Besancon, France; 7 Florida Oncology Associates, Jacksonville, FL; 8 Merck KGaA, Darmstadt, Germany; 9 Bristol-Myers-Squibb, Wallingford, CT; 10 The Sarah Cannon Cancer Center, Nashville, TN

Disclosures AuthorEmployment Consultant / Advisor Stock Owner Honoraria AF Sobrero Merck KGaA*, Roche, Pfizer, Sanofi Aventis, Amgen A Zubel Merck KGaA* C Langer Bristol-Myers Squibb H Burris Bristol-Myers Squibb L Fehrenbacher No conflicts of interest to disclose F Rivera No conflicts of interest to disclose E U Steinhauer No conflicts of interest to disclose J Prausova No conflicts of interest to disclose C Borg No conflicts of interest to disclose Y Abubakr No conflicts of interest to disclose * Darmstadt, Germany

CETUXIMAB : Clinical Development Program 3 3 rd line and beyond BOND, NCIC C nd line EPIC 1 st line CRYSTAL Adjuvant PETACC 8, NCCTG N0147

Cetuximab: Multiple Mechanisms of Action IgG1 monoclonal antibody IgG1 monoclonal antibody Competitively inhibits ligand binding to EGFR Competitively inhibits ligand binding to EGFR Blocks receptor dimerization, TK phosphorylation, and signal transduction Blocks receptor dimerization, TK phosphorylation, and signal transduction IgG1-induced Antibody-Dependent Cell Cytotoxicity IgG1-induced Antibody-Dependent Cell Cytotoxicity EGFR ADCC

EPIC Study Design Cetuximab / Irinotecan Irinotecan Failure of Oxaliplatin-Based Therapy Survival WHY?

Study StudyNTreatment Efficacy ORRPFSOS Oxaliplatin failure Tournigand FOLFIRI42.5NR Irinotecan failure Rothenberg FOLFOX9.94.6NR Tournigand FOLFOX154.2NR Giantonio FOLFOXFOLFOX+BBevacizumab Phase III Data in 2 nd Line mCRC

Rowland K, ASCO 05, 3519 Phase III Data in 3 rd Line mCRC N RR 4% 16% PFS 2.7 months 5.0 months OS 8.7 months 10.0 months 1FU 2FOLFOX 3Irinotecan 1FU 2Irinotecan 3FOLFOX

EPIC Study Design Cetuximab / Irinotecan Irinotecan Failure of Oxaliplatin-Based Therapy Survival WHY?

Prewett M, et al. Proc AACR. 2001;42: Abstract Cetuximab + Irinotecan in mCRC Xenografts HT Days Saline Irinotecan + Cetuximab Irinotecan Cetuximab Mean Tumor Volume (mm 3 )

Phase II Studies N Efficacy Efficacy ORR ORR TTP TTP Irinotecan failure Cunningham D. N Eng J Med % 4.1 mo Saltz L. Proc ASCO % NR NR Cetuximab + Irinotecan in Heavily Pre-Treated mCRC

Why OS as Primary Endpoint Relevance Relevance Time of Study (2002) Time of Study (2002) OS advantage of 1° line FU vs BSC OS advantage of 1° line FU vs BSC OS advantage of 2° line IRI vs BSC OS advantage of 2° line IRI vs BSC OS advantage of 3° line CET vs BSC (NCIC) OS advantage of 3° line CET vs BSC (NCIC) FDA Request FDA Request

EPIC Study Design Cetuximab / Irinotecan Irinotecan Failure of Oxaliplatin-Based Therapy Survival Stratified by:  Study site  ECOG PS (0 - 1, 2) Primary Endpoint: Survival Primary Endpoint: Survival Secondary Endpoints: PFS, RR, DCR, Safety, QoL Secondary Endpoints: PFS, RR, DCR, Safety, QoL Sample Size: 1298 patients in 221 centers Sample Size: 1298 patients in 221 centers N = 648 N = 650

Sample size and power Sample size and power  One interim analysis of survival (DSMB) based on O’Brien and Fleming alpha spending function  850 deaths required (90% power for declaring significance given a hazard ratio of 0.80)  1300 subjects planned Survival analysis Survival analysis  Two-sided log-rank test stratified by ECOG PS 0-1 vs 2  Kaplan-Meier curves Statistical Considerations

EPIC Study Regimens Cetuximab Randomization 400 mg/m² Initial dose week 1 of cycle mg/m² Weekly starting week 2 Irinotecan 350 mg/m 2 Q 3 wks* Irinotecan 350 mg/m 2 Q 3 wks* * or 300 mg/m 2 Q 3 weeks in patients > 70, prior RT, ECOG 2

Histologically documented mCRC Histologically documented mCRC Bi-dimensionally measurable disease Bi-dimensionally measurable disease EGFR detectable (by IHC) EGFR detectable (by IHC) Failed an oxaliplatin based regimen Failed an oxaliplatin based regimen  Failure = progression of disease or intolerance  ≤ 6 months after the last dose of any agent Key Eligibility Criteria

All Randomized Patients Cetuximab + Irinotecan Cetuximab + Irinotecan N = 648 (%) N = 648 (%)Irinotecan N = 650 (%) N = 650 (%) GenderMale Female Age (years) Median ≥ 65 years ECOG PS Not reported Not reported Baseline Demographic Characteristics

Prior Anti-Cancer Therapy Cetuximab + Irinotecan N = 648 (%) Irinotecan Irinotecan N = 650 (%) Oxaliplatin Fluoropyrimidine Bevacizumab Prior Anti-Cancer Therapy

Treatment Exposure Cetuximab (N = 603) Irinotecan (N = 634) Irinotecan (N = 629) Relative Dose Intensity ≥ 80% 78%80%86% * One cycle = 3 weeks Cetuximab + Irinotecan N = 638 Irinotecan N = 629 Median weeks Median number of cycles* 53 Median irinotecan cumulative dose 1,395.2 mg/m 2 1,048.2 mg/m 2

Safety in Treated Subjects Grade 3/4 Toxicity Cetuximab + Irinotecan N = 638 Irinotecan N = 629 Any AE > 5% 457 (71.6) 357 (56.8) Diarrhea 184 (28.8) 102 (16.2) Vomiting 39 (6.1) 40 (6.4) Fatigue 59 (9.2) 31 (4.9) Other Grade 3/4 Toxicity Acneform Rash* Acneform Rash* 52 (8.2%) 3 (0.5%) Infusion Reaction* Infusion Reaction* 9 (1.4%) 5 (0.8%) Hypomagnesemia** Hypomagnesemia** 9 (3.3%) 1 (0.4%) * Composite term ** Percentages are calculated relative to the number of patients who received the given laboratory test

Reasons for Treatment Discontinuation

Response and Disease Control Rates Cetuximab + Irinotecan N (%) Irinotecan CR 9 (1.4) 1 ( 0.2) PR 97 (15) 26 ( 4.0) p-value = < (CR + PR)(CR + PR + SD)

PROPORTION PROGRESSION FREE mo 2.6 mo MONTHS HR = % CI = – CETUXIMAB + IRINOTECAN; N = 648 IRINOTECAN ALONE; N = 650 STRATIFIED LOGRANK P-VALUE = < Progression Free Survival Progression Free Survival

PROPORTION ALIVE MONTHS HR = (95.03% CI = – 1.114) CETUXIMAB + IRINOTECAN; N = 648 Median OS = mo IRINOTECAN; N = 650 Median OS = 9.99 mo STRATIFIED LOGRANK P-VALUE = Overall Survival Overall Survival

Post-Study Therapy Cetuximab + Irinotecan (N = 648) Irinotecan* (N = 650) Any 3 rd Line Rx 57%65% Cetuximab*11%47% Bevacizumab16%14% * Majority of patients received irinotecan + cetuximab

PROPORTION ALIVE MONTH S 11.7 mo 5.8 mo 15.6 mo Correlation of Rash and OS Cetuximab + Irinotecan Arm Gr 0; N = 148 Median OS = 5.8 mo 95% CI = 4.8 – 7.1 Gr 1-2; N = 448 Median OS = 11.7 mo 95% CI = 11.1 – 13.0 Gr 3-4; N = 52 Median OS = 15.6 mo 95% CI = 13.2 – 19.3

Summary Progression Free Survival Progression Free Survival Prolonged vs 2.6 months Extent of benefit Extent of benefitImpressive Absolute value Absolute valueIncremental Overall Response Rate Overall Response Rate Higher - 16% vs 4% CR CRAppealing Overall Survival Overall Survival Unchanged vs 9.9 months Impact of post-trial CET Impact of post-trial CETSubstantial Correlation with rash Correlation with rashStrong Time on Treatment Time on TreatmentProlonged Toxicity Toxicity Higher incidence of rash, diarrhea QoL QoL Pending reporting later in 2007

CONCLUSION #1 There was no difference in overall survival. There was no difference in overall survival.Implication In patients failing oxaliplatin-based first line therapy, irinotecan-based therapy remains the standard of care. In patients failing oxaliplatin-based first line therapy, irinotecan-based therapy remains the standard of care.

CONCLUSION #2 Cetuximab plus irinotecan resulted in moderately higher toxicity. Cetuximab plus irinotecan resulted in moderately higher toxicity. RR and PFS were significantly better with the addition of cetuximab. RR and PFS were significantly better with the addition of cetuximab. Extensive post trial use of cetuximab provides a plausible explanation for the lack of OS difference. Extensive post trial use of cetuximab provides a plausible explanation for the lack of OS difference. Implication These data confirm that, despite a moderate increase in toxicity, cetuximab is a key therapeutic agent for the optimal treatment of advanced colorectal cancer. These data confirm that, despite a moderate increase in toxicity, cetuximab is a key therapeutic agent for the optimal treatment of advanced colorectal cancer.

Acknowledgements Enrolled and randomized patients and their caregivers Investigator teams across 221 sites in Europe, United States, Australia, and Hong Kong Merck KGaA – – Michael Schlichting, Marie-Louice Wilberg, Oliver Kisker Bristol-Myers Squibb – – Justin Kopit, Kathleen Williams ImClone Systems Incorporated

Back-Up Slides

Survival Probability Survival Time [Months] mo 6.2 mo |||| | || | | | | | || | | | | | | | | ||| | ||| | | | | ||| | | | | | | | | | || | | | ||| | | | | || | || ||||| ||||| || | | | | ||| | | ||| | | || ||| | | || || | || || |||| | | | || | || | ||||| | || | |||| || || | ||||| | ||| | | | |||| | | ||| || | | | ||| ||| || | |||||||||||||| || || | | | | | | | | | | | | | | | | | | | |||| || | | | || | | | | ||| | | || | || || || | | || | | || | | | |||||| | | | | ||| | | || | |||| |||| Post-Hoc Survival Analysis Subjects with Post-Study Cetuximab Excluded IRINOTECAN; N = 345 IRINOTECAN; N = 345 CETUXIMAB + IRINOTECAN; N = 575

PROPORTION ALIVE MONTHS SUBJECTS AT RISK CET+IRIN IRINO Post-Hoc Survival Analysis Prior to Cetuximab Commercialization CETUXIMAB + IRINOTECAN; n = 233 Median OS = 10.5 mo 95% CI = 7.8 – 11.3 CENSORED (No. DEAD = 64) IRINOTECAN; n = 226 Median OS = 8.6 mo 95% CI = 7.0 – 10.9 CENSORED (No DEAD = 59 )

Post-Hoc Survival Analysis Irinotecan Arm Post-Study: Cetuximab vs. Therapy Without Cetuximab vs. No Therapy Subseq. Cet.; n = 305 Median OS = 13.0 mo 95% CI = CENSORED (No. Dead = 188) Subseq. Rx, No Cet.; n = 116 Median OS = 10.1 mo 95% CI = 9.0 – 13.2 CENSORED (No. Dead = 77) No Subseq. Rx; n = 229 Median OS = 3.9 mo 95% CI = 3.5 – 4.9 CENSORED (No. Dead = 164) PROPORTION ALIVE MONTHS