Impact on Quality of Life of Adding Cetuximab to Irinotecan in Patients Who Have Failed Prior Oxaliplatin-Based Therapy: Results From the EPIC Trial Cathy Eng 1, J. Maurel 2, W. Scheithauer 3, L. Wong 4, M. Lutz 5, G. Middleton 6, R. Stoller 7, A. Zubel 8, H. Lu 9, A. F. Sobrero 10 1 Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX, 2 Hospital Clinic I Provincial, Barcelona, SPAIN, 3 Universitatesklinik, Wien, AUSTRIA, 4 Scott &White Hospital, Temple, TX, 5 Caritasklinik St. Theresia, Saarbrücken, GERMANY, 6 St Luke's Cancer Centre, Guildford, UNITED KINGDOM, 7 University of Pittsburgh Cancer Center, Pittsburgh, PA, 8 Gastrointestinal Medical Oncology, Merck KGaA, Darmstadt, GERMANY, 9 Bristol-Myers-Squibb, Wallingford, CT, 10 Ospedale San Martino, Genova, ITALY

Quality of Life As An Endpoint in mCRC Similar QoL Reported in Control and Experimental Arms Irinotecan After 5FU Failure As single agent (vs BSC, except for worse diarrhea scores) As single agent (vs BSC, except for worse diarrhea scores) Added to 5FU Added to 5FU (Cunningham 1998, Rougier 1998) Irinotecan Added to FU (Delayed Deterioration of QoL) (Saltz 2000, Douillard 2000) Oxaliplatin Added to FU (De Gramont 2000) Bevacizumab Added to FU or IFL (Chawla 2005) First-line mCRC Pre-Treated mCRC

Rationale for EPIC Study Design Focus on mCRC patients after oxaliplatin failure  Irinotecan is the approved standard of care Phase II data indicated that irinotecan +cetuximab is an effective combination  Saltz 2001, Cunningham 2004 Inclusion of quality of life as endpoint in mCRC  Survival time has increased from 10 to 20 months in last 10 years  Long-term survival = increased importance in QoL

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 QoL Assessment Baseline, Week 4, Week 10 then every other cycle (Q 6 weeks)

All Randomized Patients Cetuximab + Irinotecan Cetuximab + Irinotecan N = 648 (%) N = 648 (%)Irinotecan N = 650 (%) N = 650 (%) GENDER Male / Female 405 ( 62.5) / 243 ( 37.5) 411 ( 63.2) / 239 ( 36.8) AGE (years) Median Minimum-Maximum 23.0 – – 90.0  ≥ 65 years 255 (39.4) 275 (42.3) ECOG Performance Status (53.7) 316 (48.6) (40.1) 295 (45.4) 2 35 (5.4) Not Reported Not Reported 5 (0.8) 4 (0.6) Demographic Characteristics* * EGFR detectable (by IHC) * Failed an oxaliplatin based regimen - Failure = progression of disease or intolerance; ≤ 6 months of last dose of any agent - Failure = progression of disease or intolerance; ≤ 6 months of last dose of any agent

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) p-value = <0.0001

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

CETUXIMAB + IRINOTECAN N = 648 PROPORTION ALIVE MONTHS HR = (95.03% CI = – 1.114) STRATIFIED LOGRANK P-VALUE = Overall Survival Overall Survival Median OS mo 9.99 mo Post-Study Therapy Any57%65% Cetuximab11%47% Bevacizumab16%14% IRINOTECAN N = 650

Grade 3 / 4 Adverse Events 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%) 9 (1.4%) 5 (0.8%) * Composite term ** Percentages are calculated relative to the number of patients who received the given laboratory test

QoL Assessments: EORTC QLQ – C30 (v. 3.0) Global Health Status Global Health Status Functional Scales Functional Scales — Physical — Cognitive — Role — Social — Emotional Symptom Scales Symptom Scales —Fatigue — Nausea — Pain — Vomiting Single Items Single Items — Dyspnea — Constipation — Insomnia — Diarrhea — Appetite Loss — Financial Problems

Statistical Considerations The primary comparison of QoL changes used a Wei- Lachin nonparametric test  The robustness of the test was evaluated by longitudinal modeling Descriptive statistics were calculated for baseline and change from baseline QoL scores at each time point

QoL Compliance Irinotecan + Cetuximab Irinotecan Baseline 543/648 (83.8) 563/650 (86.6) 3 Weeks 399/638 (62.5) 356/629 (56.6) 9 Weeks 356/608 (58.6) 313/593 (52.8) 15 Weeks 295/524 (56.3) 267/476 (56.1) 21 Weeks 188/382 (49.2) 144/282 (51.1) 27 Weeks 134/283 (47.3) 82/172 (47.7) 33 Weeks 100/195 (51.3) 49/103 (47.6) * Information was collected until patients’ first follow-up evaluation for toxicity. For time points beyond 33 weeks, compliance was comparable between the arms. beyond 33 weeks, compliance was comparable between the arms. N (%) of Patients with QoL Data*

Baseline QoL Scores Comparison Most baseline QoL scores were balanced between treatment arms Exceptions in favor of irinotecan + cetuximab include:  Functional Scale: Social functioning  Symptoms: Fatigue  Single Items: Dyspnea, Appetite loss

On Treatment Comparison of QoL Changes from Baseline Between Treatment Arms Wei-Lachin Test Wei-Lachin Test P-value (two-sided) Comparison Global health status Functional FunctionalScalesPhysical0.002 Role0.003 Emotional0.002 Cognitive<0.001 Social0.774 No difference Favor irinotecan + cetuximab

P-value (two-sided) Symptoms Fatigue Nausea/vomiting < Pain ItemsDiarrhea Insomnia Appetite loss Constipation Dyspnea Financial problems On Treatment Comparison of QoL Changes from Baseline Between Treatment Arms Favor irinotecan + cetuximab No difference No difference Wei-Lachin Test Comparison Comparison

Overall QoL and Functional Scales Mean values and 95% CI Better Worse

Symptom Scales Mean values and 95% CI Worse Better

Conclusions The combination of cetuximab + irinotecan resulted in better QoL despite increased toxicities (diarrhea and fatigue) when compared to irinotecan alone. Although there was no difference in OS between the arms, PFS, and RR were significantly better with the addition of cetuximab. This is the first study in which the addition of a biologic agent to a cytotoxic platform in mCRC provides better QoL than the cytotoxic regimen alone.

Acknowledgements Enrolled and randomized patients and their caregivers Investigator teams across 221 sites in Europe, United States, Australia, and Hong Kong Merck KGaA  Oliver Kisker, Michael Schlichting Bristol-Myers Squibb  Justin Kopit, Bonnie Donato, Lucinda Orsini ImClone Systems Incorporated