1. 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

2. 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

3. CETUXIMAB : Clinical Development Program 3 3 rd line and beyond BOND, NCIC C0.17 2 nd line EPIC 1 st line CRYSTAL Adjuvant PETACC 8, NCCTG N0147

4. 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

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

6. Study StudyNTreatment Efficacy ORRPFSOS Oxaliplatin failure Tournigand 2004 69FOLFIRI42.5NR Irinotecan failure Rothenberg 2003 152FOLFOX9.94.6NR Tournigand 2004 69FOLFOX154.2NR Giantonio 2005 290289243FOLFOXFOLFOX+BBevacizumab9.221.83.04.87.22.710.812.910.8 Phase III Data in 2 nd Line mCRC

7. Rowland K, ASCO 05, 3519 Phase III Data in 3 rd Line mCRC N 94 126 RR 4% 16% PFS 2.7 months 5.0 months OS 8.7 months 10.0 months 1FU 2FOLFOX 3Irinotecan 1FU 2Irinotecan 3FOLFOX

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

9. Prewett M, et al. Proc AACR. 2001;42: Abstract 1543. Cetuximab + Irinotecan in mCRC Xenografts HT-29 0 1000 2000 3000 4000 5000 6000 05101520253035404550 Days Saline Irinotecan + Cetuximab Irinotecan Cetuximab Mean Tumor Volume (mm 3 )

10. Phase II Studies N Efficacy Efficacy ORR ORR TTP TTP Irinotecan failure Cunningham D. N Eng J Med 2004 21822.9% 4.1 mo Saltz L. Proc ASCO 2001 12117% NR NR Cetuximab + Irinotecan in Heavily Pre-Treated mCRC

11. Why OS as Primary Endpoint Relevance Relevance Time of Study (2002) Time of Study (2002) 1990 - OS advantage of 1° line FU vs BSC 1990 - OS advantage of 1° line FU vs BSC 1997 - OS advantage of 2° line IRI vs BSC 1997 - OS advantage of 2° line IRI vs BSC 2007 - OS advantage of 3° line CET vs BSC (NCIC) 2007 - OS advantage of 3° line CET vs BSC (NCIC) FDA Request FDA Request

12. 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

13. 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

14. EPIC Study Regimens Cetuximab Randomization 400 mg/m² Initial dose week 1 of cycle 1 250 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

15. 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

16. All Randomized Patients Cetuximab + Irinotecan Cetuximab + Irinotecan N = 648 (%) N = 648 (%)Irinotecan N = 650 (%) N = 650 (%) GenderMale 62.563.2 Female 37.536.8 Age (years) Median 61.062.0 ≥ 65 years 39.442.3 ECOG PS 053.748.6 140.145.4 25.45.4 Not reported Not reported0.80.6 Baseline Demographic Characteristics

17. Prior Anti-Cancer Therapy Cetuximab + Irinotecan N = 648 (%) Irinotecan Irinotecan N = 650 (%) Oxaliplatin99.599.5 Fluoropyrimidine97.897.2 Bevacizumab13.012.6 Prior Anti-Cancer Therapy

18. 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 1413.19.9 Median number of cycles* 53 Median irinotecan cumulative dose 1,395.2 mg/m 2 1,048.2 mg/m 2

19. 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

20. Reasons for Treatment Discontinuation

21. Response and Disease Control Rates Cetuximab + Irinotecan N (%) Irinotecan CR 9 (1.4) 1 ( 0.2) PR 97 (15) 26 ( 4.0) p-value = <0.0001 (CR + PR)(CR + PR + SD)

22. PROPORTION PROGRESSION FREE 0.0 0.2 0.4 0.6 0.8 1.0 0369121518 4.0 mo 2.6 mo MONTHS HR = 0.692 95% CI = 0.617 – 0.776 CETUXIMAB + IRINOTECAN; N = 648 IRINOTECAN ALONE; N = 650 STRATIFIED LOGRANK P-VALUE = < 0.0001 Progression Free Survival Progression Free Survival

23. PROPORTION ALIVE 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 MONTHS 036912151821242730333639 HR = 0.975 (95.03% CI = 0.854 – 1.114) CETUXIMAB + IRINOTECAN; N = 648 Median OS = 10.71 mo IRINOTECAN; N = 650 Median OS = 9.99 mo STRATIFIED LOGRANK P-VALUE = 0.7115 Overall Survival Overall Survival

24. 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

25. PROPORTION ALIVE 0.0 0.5 1.0 036912151821242730333639 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

26. Summary Progression Free Survival Progression Free Survival Prolonged - 4.0 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 - 10.7 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

27. 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.

28. 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.

29. 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

30. Back-Up Slides

31. Survival Probability 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Survival Time [Months] 036912151821242730 10.2 mo 6.2 mo |||| | || | | | | | || | | | | | | | | ||| | ||| | | | | ||| | | | | | | | | | || | | | ||| | | | | || | || ||||| ||||| || | | | | ||| | | ||| | | || ||| | | || || | || || |||| | | | || | || | ||||| | || | |||| || || | ||||| | ||| | | | |||| | | ||| || | | | ||| ||| || | |||||||||||||| || || | | | | | | | | | | | | | | | | | | | |||| || | | | || | | | | ||| | | || | || || || | | || | | || | | | |||||| | | | | ||| | | || | |||| |||| Post-Hoc Survival Analysis Subjects with Post-Study Cetuximab Excluded IRINOTECAN; N = 345 IRINOTECAN; N = 345 CETUXIMAB + IRINOTECAN; N = 575

32. PROPORTION ALIVE 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 MONTHS 03691215182124 SUBJECTS AT RISK CET+IRIN233135652953100 IRINO11859188211 0 226 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 )

33. 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 = 12.2 - 15.0 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 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 MONTHS 03 6 91215182124273033