Background: HER2 has been shown to be a validated therapeutic target for the treatment of mCRC. Preclinical and clinical evidence supports the use of HER2-targeted agents in each of these mCRC cohorts. In HERACLES, treatment–refractory, KRAS exon 2 (codons 12 and 13) WT, HER2 amp mCRC pts were treated with T and lapatinib (L). Objective response rate (CR or PR) was 8/27 and disease control rate (CR, PR, and SD > 16 wks) was 16/27. Duration of response ranged from 24-94+ wks. Anecdotal reports have shown activity of N in HER2 mts from several cancer types. In mCRC PDX models with qualifying HER2 mts, T plus N is more active than either drug alone. In quad WT, HER2 non-amp PDX models, C plus TKI resulted in major tumor regressions not seen with C monotherapy. In NSABP FC-7, a trial of C + N in cetuximab refractory pts, HER2 amp was observed in 2/23 primary tissue samples; after C exposure, HER2 amp was seen in 5/17 samples, presumably signal upregulation under selective pressure of C. HER2 amp was concordant in tissue (CISH) and blood using cfDNA. Methods: This multi-center 3-cohort phase II trial is currently enrolling pts (total planned N = 35). Pts with quad WT, HER2 amp (n = 15) with prior anti-EGFR therapy and/or HER2 mt mCRC (n = 5) will receive T 4 mg/kg iv loading dose followed by 2 mg/kg/wk and N 240 mg po daily (Arm 1). Pts with quad WT, HER2 non-amp (n = 15) with no prior anti-EGFR therapy will receive C 400 mg/m2 iv loading dose followed by 250 mg/m2/wk, and N 240 mg (Arm 2). Specific pt eligibility for quad WT and HER2 status are defined below: Arm 1: HER2 amp confirmed in blood by Guardant360 assay, and prior treatment with C or panitumumab (P). HER2 mt (with qualifying mt) with or without prior treatment with C or P. Arm 2: HER2 non-amp or HER2 amp and no prior therapy with C or P. The primary aim is 6-mos progression-free survival for each cohort. Secondary aims: response rates and toxicity. Exploratory aims: genetic and molecular analyses. Specific drug combinations will be evaluated in PDX models. NCT03457896. Support: Puma Biotechnology, Inc.; NSABP Foundation, Inc. Clinical trial information: NCT03457896