This is a randomized, open-label, multicenter, phase III clinical study. The aim is to evaluate the efficacy of JMT101 in combination with irinotecan in the third-line and beyond treatment of Metastatic Colorectal Cancer.

This trial is conducted in patients with refractory metastatic colorectal cancer that has progressed after second-line or higher standard therapy. Eligible patients are randomized into two arms in a 1:1 ratio to receive JMT101 in combination with irinotecan or standard of care until disease progression, unacceptable toxicity or withdrawal of consent by the patient.

Inclusion Criteria:

• 1. Age ranged from 18 to 75 years old (inclusive), regardless of gender;
• 2. Pathological diagnosis as metastatic colorectal adenocarcinoma, with RAS and BRAF wild-type and non-dMMR/MSI-H;
• 3. Tumor tissue available for central laboratory testing;
• 4. Metastatic colorectal cancer with disease progression after 2nd line treatment; previously received standard chemotherapy based on fluorouracil, oxaliplatin, irinotecan; patients are allowed to previously receive EGFR and/or VEGF inhibitors, but not allowed to previously receive regorafenib, fruquintinib;
• 5. Measurable disease according to RECIST1.1;
• 6. Eastern Cooperative Oncology Group (ECOG) score 0-1 points;
• 7. Life expectancy ≥3 months
• 8. Adequate main organs and bone marrow function.
• 9. Patients must give informed consent to this study before the experiment and voluntarily sign a written informed consent form.

Exclusion Criteria:

• 1. Participants who have been systematically treated with an EGFR inhibitor (such as cetuximab) within 4 months prior to the first dose of study drug.
• 2. Central nervous system metastasis or meningeal metastasis;
• 3. Patients with high risk of bleeding due to tumor invasion of important arteries;
• 4. Uncontrolled or requiring repeated drainage of pleural effusion, pericardial effusion, or abdominal effusion;
• 5. The adverse reactions of previous anti-tumor treatments (including radiotherapy) have not yet recovered to CTCAE 5.0 evaluation ≤ level 1;
• 6. Diagnosed as a second primary malignant tumor within 5 years prior to the first administration of the study drug;
• 7. Have received anti-tumor treatments such as chemotherapy, biological therapy, targeted therapy, etc. within 21 days before the first dose of the study drug; radiotherapy within 2 weeks before the first dose of the study drug; Chinese medicine or Chinese patent medicine with anti-tumor effect within 1 week before the first dose of the study drug;
• 8. Have received a live viral vaccine or live-attenuated vaccine within 28 days before the first dose of study drug or plan to receive it during the study;
• 9. Use of immunosuppressive medications within 14 days prior to the first dose of study drug;
• 10. Those who use strong CYP3A4 inducers within 14 days before the first administration of the study drug, or those who use strong CYP3A4 inhibitors or strong UGT1A9 inhibitors within 2 week, or those who cannot suspend the use of the above drugs during the study;
• 11. Have received radiation therapy or other localized palliative treatment within 14 days before the first dose of study drug;
• 12. Have undergone major surgery (excluding needle biopsy) or suffered severe traumatic injury within 28 days before the first dose of study drug;
• 13. Have a history of serious cardiovascular disease;
• 14. Previous or current presence of interstitial pneumonia/lung disease;
• 15. History of autoimmune diseases;
• 16. A history of immunodeficiency, including HIV testing positive, or having other acquired or congenital immunodeficiency diseases, or having a history of organ transplantation;
• 17. Have infectious diseases requiring systemic anti-infective treatment;
• 18. Active hepatitis B; hepatitis C infection; syphilis infection, active tuberculosis;
• 19. Known presence of hypersensitivity or intolerance to any component of EGFR monoclonal antibody, irinotecan hydrochloride injection, regorafenib and its excipients;
• 20. Women during lactation or pregnancy; women with fertility tested positive for blood pregnancy within 7 days prior to enrollment in the trial;
• 21. Any male and female patients with fertility who refuse to use effective contraceptive methods throughout the entire trial period and within six months after the last administration;
• 22. Other conditions that, in the opinion of the investigator, may affect the safety or compliance of drug treatment in this study, including but not limited to: psychiatric disorders, any severe or uncontrollable diseases, etc.