Purpose: Inhibition of mTOR in addition to EGFR may overcome resistance to EGFR inhibitors in metastatic colorectal cancer (mCRC). This phase Ib/II study evaluated the safety and efficacy of the combination of irinotecan, panitumumab and everolimus. Experimental Design: Patients with KRAS exon 2 WT mCRC following failure of fluoropyrimidine based therapy received IV irinotecan and panitumumab every 2 weeks, and everolimus orally throughout a 14 day cycle. The primary endpoint of the phase II study was response rate (RR). Secondary survival outcomes were calculated using Kaplan-Meier method and analysed as intention to treat. A pre-planned exploratory biomarker analysis was performed. Results: 49 patients were enrolled. Dose level 1 (irinotecan 200mg/m2, panitumumab 6mg/kg, everolimus 5mg alternate day) was declared the MTD with no dose limiting toxicities (DLT) in 6 patients. 40 patients were treated at dose level 1: median age 60 years (37-76), 65% male, 45 and 52.5% respectively ECOG 0/1. Median dose intensity was 85%. Grade 3 toxicities were diarrhoea 23%, mucositis 18%, rash 13%, fatigue 8%, dehydration 5%, neutropenia 20%, febrile neutropenia 8%, hypomagnesemia 20% and hypokalaemia 8%. Grade 4 toxicities were hypomagnesemia 5% and neutropenia 3%. RR was 48%, stable disease 43%. Median PFS was 5.6 months and median OS 10.8 months. 25 patients were RAS/RAF WT and had a RR of 60%, median PFS of 6.4 months and OS 11.8 months. Conclusions: The toxicity of the PIE regimen is as expected and manageable. The RR of 60% in all RAS/RAF WT supports further study of this combination.
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