MABEL – a large multinational study of cetuximab plus irinotecan in metastatic colorectal cancer progressing on irinotecan H Wilke, R Glynne-Jones, J Thaler, A Adenis, P Preusser, E Aranda Aguilar, MS Aapro, N van den Berg, SP Eggleton, S Siena

Background Globally, CRC is the fourth most common cancer in men and the third in women The 5-year survival for patients with metastatic CRC is 5-30% The epidermal growth factor receptor (EGFR) is expressed in 75-89% of CRCs and is associated with decreased survival Cetuximab is an IgG1 monoclonal antibody targeting the EGFR The BOND study demonstrated the efficacy of cetuximab in mCRC progressing on irinotecan

MABEL study MABEL is a multicenter, open, uncontrolled study investigating cetuximab + irinotecan in patients with EGFR-detectable mCRC whose last treatment regimen contained irinotecan Patients from 8 European countries MABEL is to date the largest cetuximab study published in this setting This presentation reports pre-final data of the MABEL study

Study objectives Primary objectives – To determine the PFS rate at 12 weeks after initiation of cetuximab treatment Secondary objectives: – To determine PFS at 24 weeks after initiation of cetuximab treatment and every 12 weeks thereafter – To determine the median overall survival time and the survival rate at 6 months after the initiation of cetuximab treatment and every 6 months thereafter – Safety and toxicity

Treatment scheme

Patients and methods Main inclusion criteria Histologically confirmed metastatic CRC ≥ 1 bidimensionally measurable lesion IHC evidence of EGFR expression in the primary tumor or a metastasis Previous treatment with one of 4 pre-defined irinotecan regimens as the most recent chemotherapy treatment Imaging-based progressive disease (PD) Karnofsky PS ≥ 80%

Patients and methods Main exclusion criteria Documented or symptomatic brain metastases Radiotherapy or major surgery within 4 weeks prior to study entry Previous exposure to EGFR-targeted therapy

Assessments Imaging of chest, pelvis and abdomen was performed at baseline and every 12 weeks during treatment Assessment of PD was based on WHO criteria Any death without previous progression occurring within 120 days after last tumor assessment and symptomatic deterioration leading to discontinuation of study treatment (unless CT- or MRI-scan confirmed absence of PD) was regarded as progression Best response was based on investigator subjective assessment

Results – Treatment patterns 1147 patients were included in the intent-to-treat evaluation of safety and efficacy – 93 received irinotecan 125 mg/m 2 /w – 670 received irinotecan 180 mg/m 2 q2w – 356 received irinotecan 350 mg/m 2 q3w – 28 received irinotecan regimens other than those specified in the protocol The median time between the end of the last cycle of pre-study irinotecan treatment and progression was 10 days

Pre-study and on-study treatment regimens

Patient baseline characteristics

Safety Treatment was generally well tolerated Diarrhea and rash were the most common side effects – Grade 3 / 4 diarrhea (20%) – Grade 3 / 4 skin and subcutaneous tissue disorders (including acne-like rash) (19%)

Relevant grade 3 / 4 adverse events

Overall survival n=1147 *

Overall survival by irinotecan regimen

Progression-free survival n=1147 *

Progression-free survival by irinotecan regimen

Best response Best response (clinical global impression) – 3 complete responses – 228 partial responses – 287 stable disease Response rate: 20% (95% CI 18-23%) Disease control rate: 45% (42-48%) Best response was considered not to be evaluable in 9% of patients

Conclusions (I) The PFS rates for cetuximab + irinotecan exceeded the expected rate of 50% ± 3% For all irinotecan regimens, similar PFS and overall survival times were seen at all time points analyzed Treatment was well tolerated – The most common side effects were skin and subcutaneous tissue disorders Known side effects of irinotecan were not increased compared with historical controls The estimated median overall survival of 9.2 months is in line with that reported for cetuximab + irinotecan in the BOND study

Conclusions (II) The results of this large study (n=1147) indicate that the benefits of combining cetuximab with irinotecan noted previously in clinical studies are achievable in routine clinical practice in a wider community setting