Background: Sorafenib and irinotecan combination (NEXIRI) showed promising efficacy with a 65% disease control rate (DCR) in pretreated mutated (mt) KRAS mCRC. In this single arm study, CCND1 rs9344 A/A polymorphism had a predictive value (Samalin et al. 2014).This multicentre randomized phase II trial aimed to determine the 2-month progression-free survival rate (2-PFS) of NEXIRI vsIri or Soraf monotherapies in these patients (pts) after failure of all approved active drugs at the time of the study. Methods: Pts PS≤1 with progressive non-resectable mtKRAS (then RAS) mCRC pretreated with irinotecan, oxaliplatin, fluoropyrimidines and bevacizumab (none with regorafenib), were randomized in 3 arms: NEXIRI (biweekly Iri IV 120, 150, 180mg/m² at C3 combined with a fixed dose of Soraf 400mg twice daily) vs Iri (180mg/m²) alone vs Soraf alone, until progression or toxicity, with cross-over to NEXIRI at progression. Primary endpoint was the 2-PFS (RECIST v1.1). Pharmacokinetic, pharmacogenetics and pathologic translational studies were undertaken.Results: We included 173 pts (age 62 [31-82]; PS 0/1: 38/61%) between 2012 and 2014 in 17 French centres. Main results were (median follow-up 17.5 months): See table. Conclusions: We confirmed the NEXIRI regimen efficacy in a randomized study for refractory mtRAS mCRC pts. CCND1 rs9344 may identify patients who benefit from this combination. These results justify comparing NEXIRI to Regorafenib or TAS 102 monotherapies in CCND1 rs9344 A/A pts subgroup. Other results from ancillary studies will be presented at the meeting. Clinical trial information: NCT01715441

*170 pts ^$18 (6/4/8) non-evaluable pts