Background: Patients (pts) with KRAS wild-type (WT) mCRC treated with single agent anti-EGFR therapy (tx) have improved OS compared to BSC but only a 10-15% response rate. Prior EGFR tx may upregulate HER amplification. For pts with quadruple WT mCRC (KRAS, NRAS, BRAF, PIC3KA), data suggest that dual targeting of the MAPK pathway, specifically EGFR and HER2, may be more effective. The purpose of this study was to evaluate the activity of dual MAPK pathway inhibition based on HER2 status: amplified (amp), non-amplified (non-amp), or mutated (mt). Methods: This 2-arm phase II trial enrolled pts with quad WT mCRC with ECOG PS 0-2, adequate organ function, prior oxaliplatin- and irinotecan-based regimens, and known HER2 status. Arm 1: HER2 amp (confirmed as >2.14 copy number by Guardant 360) and prior anti-EGFR tx or HER2 mt (with qualifying mt) with or without prior anti-EGFR tx; Arm 2: HER2 non-amp or HER2 amp without prior anti-EGFR tx. Tx included T 4 mg/kg IV loading dose → 2 mg/kg/wk and N 240 mg po daily (Arm 1) or C 400 mg/m² IV loading dose → 250 mg/m²/wk and N 240 mg po daily (Arm 2). Imaging was performed every 8 wks with response per RECIST 1.1. Primary end point (EP) of each arm was 6 mo PFS (PFS₆). Secondary EPs: Response rate (ORR), clinical benefit rate (CBR), toxicity and exploratory assessments of N pharmacokinetics, genetic and molecular analyses, and evaluation of multiple drug combinations in PDX/PDXO models. We tested H₀: PFS₆<0.13 v H_A: PFS₆>0.47 (α=0.05; power=0.90 to reject H_A).Treating 15 pts in each arm, if ≥5 pts are alive and progression free (PFS₆ 0.33), the arm is worth further testing. Results: From Jul 2018 - Mar 2021, 25 pts enrolled from 9 different centers. Arm 1 closed due to poor accrual (n=4). Those pts have been excluded from further analysis. Arm 2 enrolled 21 pts. with 15 evaluable for response by imaging. Early discontinuation occurred in 6 of 21 pts: 2 withdrew consent, 3 due to toxicity, and 1 physician withdrawal. Of the 15 evaluable pts, there were 6 PR, 5 of 13 HER2 non-amp, 1 of 2 HER2 amp, (duration 120-171 days; mean 140) and 5 SD (duration 59-231 days; mean 124). The ORR (CR/PR) in all pts who received at least one dose of tx is 33% (6/20). 8 of 15 evaluable pts (53%) were progression free at cycle 6. Common grade 3+ AEs (>5%) included diarrhea (24%), rash (8%), and abdominal pain/distension (8%), without any grade 5 AEs. Conclusions: The combination of C+N was reasonably well tolerated with expected toxicities of diarrhea and rash. The ORR, CBR, and PFS compare favorably to pts previously relapsed following oxaliplatin and irinotecan and treated with single-agent anti-EGFR tx. Upon entry, biopsies for PDX implantation had an engraftment success rate of ̃80%. We anticipate using these grafts to establish PDXO models for molecular analyses and further drug testing. Support: NSABP Foundation, Puma Biotechnology. Clinical trial information: NCT03457896.