135 Background: Amivantamab (ami), an EGFR-MET bispecific antibody with immune cell-directing activity, has shown preclinical activity in colorectal cancer (CRC) models. MET amplification is implicated in driving resistance to anti-EGFR therapies in metastatic CRC (mCRC). We hypothesize that dual, co-inhibition of EGFR and MET with ami could improve outcomes in relapsed/refractory mCRC. Methods: OrigAMI-1 (NCT05379595) is assessing the safety and efficacy of ami as monotherapy in patients (pts) with refractory mCRC in 3 separate cohorts (Table). Eligible pts were wild-type for KRAS, NRAS, BRAF, and EGFR ectodomain by ctDNA testing, without ERBB2/ HER2 amplification. Cohorts A and B included pts with left-sided mCRC without/with prior exposure to anti-EGFR monoclonal antibodies, respectively, and cohort C included pts with right-sided mCRC. Safety population included all pts receiving the recommended phase 2 dose (RP2D; 1050 mg [1400 mg, ≥80kg]). Investigator-assessed response per RECIST v1.1 is reported for evaluable pts with post-baseline disease assessment(s) or who discontinued for any reason. Ami plus FOLFOX or FOLFIRI is being explored in additional cohorts. Results: As of September 4, 2023, 93 pts were treated at RP2D; 89 were response evaluable (median follow-up: 4.4 mo). Median age was 60 years, 66% were male, and median prior lines of therapy were 2, with 94% receiving prior bevacizumab and 69% prior anti-EGFR therapy. Best timepoint responses were: Cohort A: 7/17, 41.2%; Cohort B: 13/54, 24.1%; Cohort C: 1/18, 5.6%. Disease control rates (DCR) were 88.2%, 72.2%, and 77.8% for Cohorts A, B, and C, respectively. Median duration of response (mDoR) for confirmed responders was 7.5 and 7.4 mo for Cohorts A and B, respectively. Treatment is ongoing for the responder in Cohort C. 10/13 responders (77%) remain on treatment. Preliminary biomarker data suggest ami may be active in alterations associated with anti-EGFR antibody resistance (eg, EML4-ALK fusion, PTEN). The most frequent treatment-emergent adverse events were rash (84%) and infusion-related reactions (53%). No new safety signals were observed. Updated results will be presented at the meeting. Conclusions: Ami monotherapy demonstrated promising, durable antitumor activity in refractory mCRC, including pts treated with prior anti-EGFR therapy and pts with right-sided disease. The safety profile of ami in mCRC is manageable and consistent with prior NSCLC experience. Clinical trial information: NCT05379595 . [Table: see text]