Background: Preclinically, mTOR and EGFR inhibitors are synergistic. We hypothesized that the mTOR inhibitor E would enhance clinical efficacy when added to C. The Phase I portion determined the safety, and maximum tolerated dose (MTD), and the Phase II evaluated the response and survival rates with this combination. Preliminary results of the Phase I study (ASCO 2011, Shahda et al) determined the MTD as E 5 mg po daily (qd) combined with Iri and C. Here we report overall safety and efficacy results of the Phase I/II study. Methods: Patients (pts) were treated with Iri 125 mg/m² weekly (qw) x 2 every 3 wks, C 400 mg/m² loading, then 250 mg/m² qw, and escalating doses of E: 5 mg qod, 5 mg qd and 10 mg qd in 21-day cycles (Phase I), and 5 mg qd (Phase II). Eligibility allowed KRAS mutated (MUT) mCRC. During phase II, KRAS wild-type (WT) pts were randomized to Iri+C+E vs Iri+C, and all KRAS MUT pts received Iri+C+E. Archival tumors were analyzed for biomarkers of EGFR and mTOR pathways activation. The study was discontinued early due to funding termination by Novartis. Results: 43 pts were enrolled, median age 60 y (25-77), 24 male. 30 pts enrolled in phase I (KRAS WT n = 15, KRAS MUT n = 13, KRAS unknown n = 2), and 13 pts in phase II (KRAS WT: n = 5 Iri+C+E, n = 2 Iri+C; KRAS MUT n = 6 Iri+C+E). The most common gr 3/4 AEs were diarrhea (35%), neutropenia (23%), fatigue (21%), mucositis (21%), and rash (19%). Among KRAS WT pts (n = 22) there were 1 CR, 3 PR (RR 18%), 12 SD (54%), and among KRAS MUT pts (n = 19) there were 1 PR (5%) and 11SD (52%). Median progression-free survival (PFS) and overall survival (OS) rates were 6 and 16 mos, respectively for all KRAS WT pts treated with Iri+C+E (n = 20), and 8.3 and 21.6 mos, respectively for KRAS WT pts treated at MTD (n = 11). Median PFS and OS were 4.3 and 12.3 mos, respectively for KRAS MUT pts. Only 2 KRAS WT pts were randomized to Iri+C before study closure. PD markers will be presented. Conclusions: The combination of Iri+C+E has an expected toxicity profile, and was clinically active as second-line treatment for KRAS WT mCRC pts. Further studies should assess the CRC pts most likely to benefit from mTOR inhibitors in addition to EGFR blockade. (NCT00522665) Clinical trial information: NCT00522665