Phase I/II study of everolimus (E) with irinotecan (Iri) and cetuximab (C) in 2nd line metastatic colorectal cancer (mCRC): Hoosier Cancer Research Network GI05-102

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.