This trial is a multicenter, single arm study of efficacy of amivantamab in combination with FOLFIRI in RAS/BRAF wild-type advanced colorectal cancer patients progressed prior treatment including oxaliplatin based chemotherapy. This trial will be conducted by Severance Hospital that is responsible for the project management of the trial. Patient recruitment will take at 3 institutions.

Participants will be treated for up to 24 cycles (approximately 2 years) after initiation of treatment with intravenous 1050mg(BW<80kg) or 1400mg(BW≥80kg) of amivantamab every 4 weeks in combination with FOLFIRI. FOLFIRI includes folic acid, 5-FU and irinotecan. FOLFIRI will be administered intravenously with folic acid 400 mg/m², 5-FU 2400 mg/m², and irinotecan 180 mg/m² every 2 weeks. This study will use ORR based on RECIST 1.1 criteria as the primary endpoint and the tumor assessment will be done every 8 weeks. Secondary endpoints are DCR, PFS, OS, and safeties. Exploratory biomarkers in tumor tissue and ctDNA in blood will be investigated in both pre-treatment and post-treatment periods.

Inclusion Criteria:

1. Participants must be ≥19 years of age.

2. The participant must have been previously diagnosed with histologically or cytologically confirmed unresectable or metastatic adenocarcinoma of the colon or rectum.

3. The participant must have a previously characterized tumor with wild-type KRAS, NRAS, and BRAF without evidence of ERBB2/HER2 amplification by immunohistochemistry (IHC) test. Local guidelines and SoC also require evaluation of dMMR/MSI-H status.

4. The participant must be diagnosed with CRC and should have received anti-EGFR and oxaliplatin-based systemic therapy in the metastatic setting (no more than one prior line of systemic therapy is allowed). According to local regulatory approvals and SoC guidelines, the participant must also be eligible for treatment with FOLFIRI.

5. Participants must have measurable disease according to RECIST v1.1. If only one measurable lesion exists, it may be used for the screening biopsy.

6. Participants must have ECOG PS 0 or 1.

7. Life expectancy ≥12 weeks as judged by the Investigator.

8. Participants must have adequate organ and bone marrow function as follows, without a history of red blood cell transfusion, platelet transfusion, or use of granulocyte colony-stimulating factor (G-CSF) within five days prior to the date of the laboratory test.

   A. Hemoglobin ≥ 8.0 g/dL B. Absolute neutrophil count ≥1.5ⅹ109/L C. Platelets ≥100ⅹ109/L D. ALT and aspartate aminotransferase (AST) ≤3ⅹupper limit of normal (ULN). If liver metastases are present, ≤ 5ⅹULN E. Total bilirubin ≤1.5ⅹULN (participants with Gilbert's syndrome can enroll if conjugated bilirubin is within normal limits) F. Serum creatinine ≤ 1.5ⅹULN, or calculated by Cockcroft-Gault formula (Refer to Appendix 9: Cockcroft-Graft Formula for Estimated Creatinine Clearance for formula) or directly measured creatinine clearance ≥ 50 mL/min

9. Negative serum pregnancy test within two weeks before the first study dose in all women of childbearing potential.

10. The subject and their partners must be willing to avoid pregnancy during the trial. Male subjects with female partners of childbearing potential and female subjects of childbearing potential must be willing to use adequate contraception.

11. The participant must sign an ICF (or their legally acceptable representative must sign) indicating that he or she understands the purpose and procedures required for the study and is willing to participate.

12. Participants must be willing and able to adhere to the lifestyle restrictions specified in this protocol.

Exclusion Criteria:

1. Participants who have received prior irinotecan-based chemotherapy.

2. Participants with an identified mutation in KRAS, NRAS, BRAF, or ERBB2/HER2 amplification by immunohistochemistry (IHC) test.

3. Participant has an uncontrolled illness, including but not limited to the following:

   A. Active bleeding diathesis B. Impaired oxygenation requiring continuous oxygen supplementation C. Psychiatric illness/social situation that would limit compliance with study requirements.

4. Participants have known active CNS metastases or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e., without evidence of progression for at least four weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable, and without requirement of steroid treatment for at least 14 days before the first dose of study treatment.

5. Participants with positive serology for HIV and HCV.

   A. Positive hepatitis C antibody (anti-HCV [hepatitis C virus]):

   Exception: Participants with a prior history of HCV who have completed antiviral treatment and have subsequently documented HCV RNA below the lower limit of quantification per local testing are eligible.

6. Anticancer treatment within 14 days before the start of trial treatment, e.g., cytoreductive therapy, radiotherapy (except for palliative bone-directed radiotherapy), immune therapy, or cytokine therapy.

7. Major surgery within 28 days before the start of trial treatment (excluding prior diagnostic biopsy).

8. Participants with a medical history of myocardial infarction within six months before treatment, symptomatic CHF (New York Heart Association Class II to IV), unstable angina pectoris, clinically significant cardiac arrhythmias, or a recent (< 6 months) cardiovascular event, including myocardial infarction, unstable angina pectoris, and stroke.

9. Gastrointestinal perforation, fistula, or any arterial thromboembolic event within six months, or any significant gastrointestinal bleeding or significant venous thromboembolism within three months prior to treatment (except for stable venous thromboembolism on ongoing appropriate anticoagulation treatment).

10. History of (non-infectious) ILD/pneumonitis, current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.

11. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within seven days before the first dose of the study drug.

12. Participants have a known previous or concurrent malignancy that has progressed or required active treatment within the past five years.

    Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g., breast carcinoma or cervical cancer in situ) who have undergone potentially curative therapy are not excluded.

13. Toxicities from previous anticancer therapies should have resolved to baseline levels or Grade 1 or less prior to the first dose of study treatment (except for alopecia or post-radiation skin changes [any grade], and Grade ≤2 hypothyroidism stable on hormone replacement).

14. The participant has had prior chemotherapy or targeted cancer therapy with an investigational anticancer agent within two weeks or four half-lives, whichever is longer, before the first administration of the study drug.

15. Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (e.g., compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.