1. Cetuximab plus 5-FU/FA/oxaliplatin (FOLFOX-4) in the first-line treatment of mCRC: OPUS, a phase II study *Carsten Bokemeyer, Elzbieta Staroslawska, Marek Nowacki, Irina Mitashok, Elena Kuznetsova, Paolo Cortes, Carlos Garcia Girón, Oksana Tarasova, Angela Zubel, Yaroslav Shparyk *University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany

2. OPUS OPUS study design Cetuximab + FOLFOX-4 400 mg/m 2 initial IV infusion (day 1) then 250 mg/m 2 weekly + oxaliplatin 85 mg/m 2 + 5-FU/FA every 2 weeks FOLFOX-4 oxaliplatin 85 mg/m 2 + 5-FU/FA every 2 weeks EGFR-expressing metastatic CRC Stratification factors: ECOG PS 0-1, 2 R Treatment until progression, symptomatic deterioration or unacceptable toxicity

3. OPUS Best overall confirmed responses (IRC) FOLFOX-4 (n=168) Cetuximab + FOLFOX-4 (n=169) CR0.6%1.2% PR35.1%44.4% * Cochran-Mantel-Haenszel (CMH) test Odds ratio = 1.516, p=0.064* FOLFOX-4 Cetuximab + FOLFOX-4

4. OPUS Efficacy: response rate all patients and ECOG 0-1 stratum Response rate, %Cetuximab + FOLFOX-4 FOLFOX-4 All45.6 (n=169) 35.7 (n=168) ECOG 0-1*49.0 (n=153) 36.8 (n=152) * p=0.032**, Odds ratio: 1.648 [95% CI:1.043, 2.604] **Cochran-Mantel-Haenszel (CMH) test

5. OPUS OR [95% CI] Favors FOLFOX Favors Cetuximab + FOLFOX Subgroup (number of patients) Efficacy by subgroups 2.00 [1.02, 3.93]1 (74 vs 69)One metastatic site 2.11 [0.88, 5.07] Liver metastasis only Yes (50 vs 39) ≤10 000 / mm 3 (124 vs 131) Leucocytes 2.00 [1.19, 3.35] 2.07 [1.03, 4.14]>upper normal limit (82 vs 63)LDH Alkaline phosphatase <300 U/L (128 vs 128)2.04 [1.22, 3.42] 1.82 [1.03, 3.21] 1.14 [0.57, 2.31] <65 years (96 vs 109) ≥65 years (73 vs 59) Age 2.29 [1.18, 4.46] 1.12 [0.61, 2.04] Western Europe (72 vs 75) Eastern Europe (97 vs 93) Region All ITT subjects (n= 169 vs 168) 0.1 1 1025 ECOG 0/1 1.648 [1.043, 2.604] 1.516 [0.97, 2.35]

6. OPUS Association between skin reactions and response rate Cetuximab + FOLFOX-4, n=168 (IRC data) n=23n=59n=62n=24 Maximum skin reactions during first 21 days of treatment *There were no grade 4 skin reactions

7. OPUS Safety in treated patients Safety population n=338 Cetuximab + FOLFOX-4 n= 170, % FOLFOX-4 n= 168, % Any grade 3/4 AE in  3 subjects Neutropenia27.631.5 Diarrhea7.16.0 Leucopenia7.15.4 Fatigue Neurotoxicity † 3.5 3.0 6.0 Cetuximab related grade 3/4 toxicity Skin reactions*14.1**0 Infusion-related reactions* Hypomagnesemia 4.1 2.0 1.8 0 Treatment-related deaths Cetuximab Chemotherapy 0 0.6 - 0.6 † Includes peripheral sensory neuropathy and neuropathy.*Special AE category **There were no grade 4 skin reactions or acne-like rash

8. OPUS Conclusions  The addition of cetuximab to FOLFOX-4 increased the RR of FOLFOX-4 by approximately 10% (45.6% vs 35.7%). There was an approximately 50% higher chance of achieving a CR or PR for those patients receiving cetuximab plus FOLFOX-4 (OR = 1.52)  Patients with baseline ECOG PS 0-1 had a statistically significant higher (65%; OR = 1.65) chance for response (49.0% vs 36.8%)  Analysis of prognostic factors for response uniformly showed an increased chance of a response by 50 to >100% in most subgroups under cetuximab plus FOLFOX-4 compared to FOLFOX-4 alone  Cetuximab in combination with FOLFOX - 4 was generally well- tolerated