4037 Background: Response to epidermal growth factor receptor (EGFR) inhibitor, cetuximab appears to correlate with the intensity of the associated skin reaction. This randomized study investigated cetuximab dose-escalation in patients (pts) with EGFR-expressing mCRC failing irinotecan-including therapy (I). Methods: Pts were randomized 22 days after starting cetuximab (400 mg/m2 initial dose then 250 mg/m2/week [w]) with I (180 mg/m2 q 2 w) if they had not experienced >grade (G) 1 skin reaction, any other >G 2 cetuximab-related adverse event and were tolerant to I. Randomization was to standard cetuximab dose (Arm A; 250 mg/m2/w) or dose-escalation (Arm B; cetuximab dose increased by 50 mg/m2 q 2 w, until >G 2 toxicity, tumor response or dose = 500 mg/m2). Pts not randomized (Arm C) continued on standard cetuximab dose. Primary endpoint was to compare in skin and tumor biopsies, taken before and during treatment, the effects of dose-escalation on EGFR and downstream signalling markers with those of the standard cetuximab regimen. Secondary endpoints were PK, efficacy, safety, tolerability, biomarker analyses on tumor biopsies and plasma samples. Results: 284 pts screened, 221 pts EGFR-expressing, 166 pts enrolled and randomized: 45 to Arm A; 44 to Arm B. 77 non-randomized pts were included in Arm C. M/F 106/60, median age 60 years [25–79], median KPS 90 [70–100]. 24 pts in Arm B reached 500 mg/m2/w. By the cut-off date of July 31st 2006 the preliminary response rate (RR) in Arm B was 30% vs. 13% in Arm A. RR in arm C was 22%. Preliminary progression-free survival in Arm A was 3,9 mo vs. 4,8 mo in Arm B and 3,9 mo in Arm C. In Arm B, 9% pts had G 3/4 skin reactions, 0% in Arm A (14% in Arm C). Dose related increases in Cmax and AUC were observed. T1/2 values were dose independent. Conclusions: Cetuximab dose- escalation up to 500 mg/m2/w improves RR in pts with no or slight skin reactions on standard dose treatment. Overall cetuximab PK behavior is in good agreement with previous experience. Treatment was generally well tolerated. PD and biomarker results will be presented at the meeting. No significant financial relationships to disclose.