Background: Inhibition of the MEK/ERK pathway through Raf has been shown to sensitize tumor cells resistant to chemotherapy. Sorafenib (Sor) is an oral multi-tyrosine kinase inhibitor (TKI) affecting tumor proliferation and angiogenesis through inhibition of the Ras/Raf/MEK/ERK, VEGF, and PDGF pathways. Fluoropyrimidines and similar TKIs have each demonstrated efficacy as monotherapy in advanced mCRC. Documenting clinical activity and manageable toxicity of these antineoplastic class combinations is a clinical unmet need. Methods: Eligible pts had progressive mCRC after prior oxaliplatin and irinotecan, at least 1 measurable target lesion by RECIST, ECOG PS 0-1, and adequate organ function. Pts received Cape (1000mg/m² PO BID D1-14) and Sor (400mg PO BID max via dose escalation per cycle). Cycles were q21d with tumor assessments q9w until progression. Primary endpoint was PFS with secondary endpoints including objective and biochemical response rates, OS, toxicity and quality of life. Sample size was based on a 50% improved median PFS from 3 (historical) to 4.5 months (mo) using Woolson’s one-sample one-sided logrank test. Results: 42 pts were treated with median f/u of 4.6 mo. Patient demographics are shown in table. Median number of cycles was 5.6 (range 1-39). Compared to historical controls, median PFS and OS were 4.1 vs. 3mo (p < 0.039) and 8.7 vs. 6mo, respectively. Clinical benefit rate (CR+PR+SD) was 52%. 31 pts (74%) had a grade 3 AE (16/31 were HFS). There was one grade 4 (sepsis) and no g5 toxicities. Four pts (9%) discontinued due to toxicity. Conclusions: The combination of SorCape in this heavily pre-treated population significantly improved PFS with manageable, but notable toxicity. Molecular predictors of response are being analyzed. Further studies involving the combination of fluoropyrimidines with multi-targeted TKIs are indicated. Clinical trial information: NCT01471353