Cetuximab plus 5-FU/FA/oxaliplatin (FOLFOX-4) in the first-line treatment of metastatic colorectal cancer: a large-scale Phase II study (OPUS)

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1 Cetuximab plus 5-FU/FA/oxaliplatin (FOLFOX-4) in the first-line treatment of metastatic colorectal cancer: a large-scale Phase II study (OPUS) C Bokemeyer, E Staroslawska, A Makhson, I Bondarenko, JT Hartmann, Y Shelygin, O Kolesnik, C Volovat, A Zubel, P Koralewski

2 Cetuximab: mechanism of action Epidermal growth factor receptor (EGFR) is expressed by most CRCs Cetuximab is an IgG1 monoclonal antibody that: Specifically targets EGFR with high affinity Inhibits endogenous ligand binding thereby blocking dimerization, TK phosphorylation, and receptor-dependent downstream signaling Induces antibody-dependent cell-mediated cytotoxicity (ADCC)

3 Efficacy summary: cetuximab + oxaliplatin first-line in mcrc Cetuximab + FOLFOX-4 1 Cetuximab + FUFOX 2 Cetuximab oxaliplatin + capecitabine 3 No. of patients 42 49* 29 Response rate (CR+PR) 72% 57% 66% Stable disease (SD) 23% 20% 28% Disease control (CR+PR+SD) 95% 78% 93% Median PFS (months) NR Median survival (months) 30** 30.6 NR NR=not reported; PFS=progression-free survival; * n=4 not evaluable; **follow-up of 30.5 months 1 Andre et al. ASCO GI 2007:Abstract 334; 2 Dittrich et al. WCGIC 2006: Abstract O-019 ; 3 Heinemann et al. ASCO GI: Abstract 278.

4 OPUS trial: study design Patients with EGFR-expressing mcrc Stratification factor ECOG PS R A N D O M I Z E R Cetuximab + FOLFOX-4 Cetuximab IV 400 mg/m 2 IV on day 1) then 250 mg/m 2 weekly + oxaliplatin 85 mg/m 2 + FA (200 mg/m 2 days 1 and 2) + 5-FU (400 mg/m 2 bolus mg/m 2 as 22-hr infusion, days 1 and 2) every 2 weeks FOLFOX-4 Oxaliplatin 85 mg/m 2 + FA (200 mg/m 2 days 1 and 2) + 5-FU (400 mg/m 2 bolus mg/m 2 as 22-hr infusion,, days 1 and 2) every 2 weeks Treatment was continued until progression, symptomatic deterioration, or unacceptable toxicity

5 OPUS trial: study objectives Primary Best overall confirmed RR (assessed by independent review) Secondary Rate of curative surgery for metastases Duration of response Disease control rate Progression-free survival time Overall survival time Safety

6 Main inclusion criteria 18 years old with histologically confirmed colorectal adenocarcinoma First occurrence of metastatic disease, not resectable with curative intent Immunohistochemical evidence of EGFR expression in tumor 1 bi-dimensionally measurable lesion not in irradiated area ECOG PS 2 at study entry Adequate renal, hepatic and bone marrow function Life expectancy 12 weeks

7 Main exclusion criteria Known or suspected brain metastasis and/or leptomeningeal disease Previous exposure to EGFR-targeting therapy Previous oxaliplatin-based chemotherapy Previous chemotherapy for CRC except adjuvant treatment with PD documented >6 months after the end of adjuvant treatment Radiotherapy, surgery (excluding prior diagnostic biopsy) or any investigational drug in the 30 days before randomization

8 OPUS trial: statistical considerations The intent-to-treat population was used for efficacy analysis Sample size: Approximately 146 patients per group were needed to detect an odds ratio of 2.33 at level α=0.05 with a power of 90% (corresponding to a difference of 20% in RR between arms) Potential prognostic factors were further explored by logistic regression models ECOG PS, Eastern Co-operative Group performance status

9 OPUS trial: recruitment by region (79 centers) Cetuximab + FOLFOX-4: n=45 FOLFOX-4: n=49 Cetuximab + FOLFOX-4: n=97 FOLFOX-4: n=93 Cetuximab + FOLFOX-4: n=27 FOLFOX-4: n=25 Western Europe: Austria, Belgium, France, Germany Eastern Europe: Poland, Romania, Russian Federation, Ukraine Southern Europe: Greece, Italy, Portugal, Spain Rest of the world: Israel (not shown). Screened 7, Cet+FOL 0, FOL 1 Numbers refer to randomized patients

10 Study population Patients screened for EGFR expression EGFR expression in tumor Randomized ITT Safety population* Number of sites (70.6%) *1 subject was erroneously randomized in the IVRS system, and was excluded from the ITT population

11 OPUS trial: baseline patient characteristics Male/female Median age, years [range] 65 years of age ECOG PS a Patients with prior adjuvant chemotherapy FOLFOX-4 (n=168) 55/45% 60 [30 82] 35% 91% 9% 22% Cetuximab + FOLFOX-4 (n=169) 53/47% 62 [24 82] 43% 91% 9% 12% a Categories at randomization ITT population

12 OPUS trial: baseline disease characteristics Tumor site a Colon Rectum Colon and rectum Involved organs Liver Lung Bone Lymph node Other FOLFOX-4 (n=168) 53% 47% 0 87% 39% 2% 27% 16% Cetuximab + FOLFOX-4 (n=169) 54% 44% 1% 88% 38% 5% 24% 15% a Percentages may not total 100 due to rounding

13 OPUS trial: overall response and disease control rates (ITT) Response rate (%) FOLFOX-4 (n=168) p=0.064 a 35,7 45,6 Overall response rate Cetuximab + FOLFOX-4 (n=169) ,2 Disease control rate Complete response Partial response Response rate (CR+PR) FOLFOX-4 (n=168) 0.6% 35.1% 35.7% Cetuximab + FOLFOX-4 (n=169) 1.2% 44.4% 45.6% Common odds ratio Cetuximab + FOLFOX-4 vs FOLFOX-4: OR=1.516 a Cochran-Mantel-Haenszel Test stratified by ECOG PS 0-1 vs 2

14 Response rate (%) OPUS trial: response rates by subgroup FOLFOX-4 p = , ,7 36,8 35,9 All ITT patients p = ECOG PS = 0 or 1 Cetuximab + FOLFOX-4 p = Liver metastases only 39,1 p = ,4 n=168 n=169 n=152 n=153 n=39 n=50 n=69 n=74 One metastatic site only

15 OPUS trial: response in subgroups Subgroup (number of patients in Group A vs B) Age <65 years (96 vs 109) 65 years (73 vs 59) Number of responses Group A vs B 46 vs vs 23 OR [95% CI] 1.82 [1.03, 3.21] 1.14 [0.57, 2.31] Leukocytes / mm 3 (124 vs 131) 60 vs [1.19, 3.35] Liver metastasis only One metastatic site Region Yes (50 vs 39) 27 vs 14 1 (74 vs 69) 41 vs 27 Western Europe (72 vs 75) 42 vs [0.88, 5.07] 2.00 [1.02, 3.93] 2.29 [1.18, 4.46] Eastern Europe (97 vs 93) 35 vs [0.61, 2.04] Body surface area >1.8 m 2 (69 vs 81) 31 vs 25 LDH >upper normal limit (82 vs 63) 39 vs [0.94, 3.68] 2.07 [1.03, 4.14] Alkaline phosphatase <300 U/L (128 vs 128) 61 vs [1.22, 3.42] No benefit under cetuximab Benefit under cetuximab

16 Association between skin reactions and response rate 80 Cetuximab + FOLFOX-4, n=168 (IRC data) Overall response rate (%) Grade 0 Grade 1 Grade 2 Grade 3-4* n=23 n=59 n=62 n=24 Maximum skin reactions during first 21 days of treatment *There were no grade 4 skin reactions

17 OPUS trial: secondary endpoints Objective Overall resection rate, % R0 resection rate, % Response duration, months [95%CI] Disease control rate, % [95%CI] Median PFS time, months [95%CI] FOLFOX [ ] 81.5 [ ] 7.2 [ ] Cetuximab + FOLFOX [ ] 84.6 [ ] 7.2 [ ] Hazard ratio [95%CI] Overall survival [ ] not mature

18 Treatment exposure: relative dose intensity >80% 5-FU Oxaliplatin Cetuximab Safety population FOLFOX-4 alone n=168 Cetuximab + FOLFOX-4 n=170 FOLFOX 4 alone n=168 Cetuximab + FOLFOX-4 n=170 Cetuximab + FOLFOX-4 n=170 Number of patients (SAF) %

19 Safety: patients with AEs causing discontinuation of treatment Discontinuation of: Number (%) of subjects Cetuximab + FOLFOX-4 (n=170) FOLFOX-4 (n=168) Study treatment (cetuximab or FOLFOX-4) Chemotherapy (FOLFOX-4) only Cetuximab Both cetuximab and chemotherapy (FOLFOX-4) 50 (29.4) 35 (20.6) 29 (17.1) 11 (6.5) 30 (17.9) 30 (17.9) 0 ( ) 0 ( )

20 OPUS trial: safety Incidence, n (%) Adverse event (AE) Any grade 3/4 AE occurring in 3 subjects Neutropenia Diarrhea Neurotoxicity a Leukopenia Fatigue Other grade 3/4 toxicity Skin reactions Infusion-related reactions Treatment-related deaths Cetuximab Chemotherapy FOLFOX-4 (n=168) 53 (31.5) 10 (6.0) 10 (6.0) 9 (5.4) 5 (3.0) 0 3 (1.8) 0 1 (0.6) Cetuximab + FOLFOX-4 (n=170) 47 (27.6) 12 (7.1) 6 (3.5) 12 (7.1) 6 (3.5) 24 (14.1) b 7 (4.1) 0 1 (0.6) a Includes peripheral sensory neuropathy and neuropathy b There were no grade 4 skin reactions or acne-like rash Magnesium measurements were available only from a subset of patients

21 OPUS trial: summary The addition of cetuximab to FOLFOX-4 in the first-line setting of metastatic CRC increased overall response rate by 10% (45.6% vs 35.7%). In the evaluated sample size, this difference was not statistically significant Significant improvement in response rate was seen for patients with baseline ECOG PS 0 1 (p=0.032) or patients whose disease is limited to one metastatic site The rate of curative resection of metastases was doubled by the addition of cetuximab The secondary endpoint of PFS did not show a significant difference Treatment was generally well tolerated Further analysis ongoing (including biomarkers)

22 OPUS trial: acknowledgments The authors would like to thank The patients The site investigators, co-investigators, and study teams The study team at Merck Serono