CHICAGOThe addition of dalotuzumab (MK-0646) to cetuximab and irinotecan (Ir) failed to improve progression-free survival (PFS) and overall survival (OS) in patients with chemorefractory KRAS wild-type metastatic colorectal cancer (mCRC), according to study investigators at the American Society of Clinical Oncology’s 2011 Annual Meeting. Predictive biomarker analysis is ongoing to identify subpopulations that may have benefit from dalotuzumab therapy during the trial.

David J. Watkins, MBBS, of The Royal Marsden Hospital, London, UK, and colleagues sought to determine if dalotuzumab improved PFS and OS in combination with cetuximab and irinotecan in patients with KRAS wild-type mCRC in this randomized, placebo-controlled, multicenter, international, Phase 2/3 study. Eligible patients had previously failed both irinotecan and oxaliplatin and had progressed on or within 3 months of their last therapy.

Patients were randomized to receive either dalotuzumab 10mg/kg weekly or 15mg/kg loading dose followed by 7.5mg/kg every alternative week or placebo combined with cetuximab and irinotecan at standard dose/schedule. Patients continued on treatment until disease progression with radiological response assessments every 6 weeks.

The trial was stopped at the first interim analysis with 345 patients with KRAS wild-type patients enrolled as neither dalotuzumab dosing regimen achieved proof-of-concept. Median PFS for all randomized KRAS wild-type status patients (per intent-to-treat [ITT] population) was 3.3 months in the 10mg/kg group (HR=1.41, P=0.978) and 5.4 in the 7.5mg/kg group (HR=1.22, P=0.881) vs. 5.6 in the placebo group. Median OS for KRAS wild-type patients (per ITT) was 10.8 months in the 10mg/kg group (HR=1.42, P=0.965) and 11.6 in the 7.5mg/kg group (HR=1.15, P=0.765) vs.14 in the placebo arm.

Higher rates of the following adverse events were noted in dalotuzumab-treated patients when compared with placebo: decreased weight (10mg/kg: 22.4%; placebo: 10.8%), dehydration (10mg/kg: 7.8%; placebo: 1.8%), hyperglycemia (10mg/kg: 33.6%; 7.5mg/kg: 40.2%; placebo: 20.7%), skin exfoliation (10mg/kg: 4.3%; placebo: 0%), peripheral sensory neuropathy (7.5mg/kg:9.4%; placebo: 2.7%), and stomatitis (7.5mg/kg: 51.3%; placebo: 36.9%). Specific adverse events did not appear to explain the difference in PFS or OS observed.