The Efficacy and Safety of IBI351, Cetuximab β Combined With FOLFIRI as First-line /IBI351, Cetuximab β as Second-line in the Treatment of KRAS G12C-mutated Metastatic Colorectal Cancer

Inclusion Criteria:

The following conditions must be met:

On the day of signing the informed consent form, the age should be ≥18 years old (18-75 years old, including 18 and 75 years old).

2. The patient must have histologically and/or cytologically confirmed metastaticcolorectal cancer (stage IV) 3. There is a written test report proving the presenceof KRASG12C mutation: PCR method or NGS method detection clearly indicates KRASG12Cmutation 4. Cohort A: Untreated advanced metastatic colorectal cancer; Cohort B:Advanced metastatic colorectal cancer with disease progression after first-linestandard chemotherapy (FOLFOX,FOLFIRI,XELOX, FOLFOXIRI± targeted therapy) 5. Thereare measurable lesions according to the Recist 1.1 standard 6.ECOG PS 0-1 7. Weight ≥40Kg 8. Cardiac function test: Left ventricular ejection fraction (LVEF) ≥50%(echocardiography) 9. Life expectancy >3 months 10. Have sufficient organfunctions, including:

• There is sufficient hematopoietic function, that is, the absolute neutrophil count (A NC) ≥1.5×109/L, platelet count ≥75×109/L, and hemoglobin ≥9g/d L. Bloodtransfusion or treatment with granulocyte colony-stimulating factor, thrombopoietin,erythropoietin, etc. shall not be received within 14 days before the blood routinetest.

• Have sufficient liver function, namely total bilirubin (TBIL) < 1.5× upper limit ofnormal value (ULN), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5×ULN; If one has Gilbert syndrome, the total bilirubin is less than 2×ULN.If it is liver metastasis of the tumor, the AST and ALT should be less than 5.0×ULN.If direct bilirubin (DBIL) indicates extrahepatic obstruction, TBIL < 3.0×ULN isallowed.

• Have sufficient renal function, that is, creatinine (Cr) ≤1.5×ULN, or when Cr > 1.5×ULN, the creatinine clearance rate (CrCl) calculated using the Cockcroft-Gaultformula (see Appendix 5) ≥50 mL/min. Urine protein/creatinine ratio < 1 (or urineanalysis < 1+ or 24-hour urine protein < 1g/24 h)

• It has sufficient coagulation function, that is, prothrombin time (PT) and activatedpartial thromboplastin time (APTT) < 1.5×ULN, and the international normalized ratio (INR) < 1.5 or is within the target range of anticoagulant therapy 11. The toxicreactions of previous anti-tumor treatments need to be restored to the baselinelevel (except for the residual alopecia effect) or ≤ grade 1 before enrollment (neurotoxicity is acceptable ≤ grade 2). Immune-related Adverse Events (irAE)related to endocrine caused by previous immunotherapy, such as immune-relatedhypothyroidism that is controlled stably and asymptomatic after treatment, stillrequire stable doses of hormone replacement or physiological doses ofcorticosteroids for treatment. After the researcher assesses that it does not affectthe administration of the study drug and conducts a safety assessment, they can beenrolled 12. Have the ability to take oral medication 13. Fertile female or malesubjects must agree to adopt effective contraceptive methods from the date ofsigning the informed consent form until 30 days after the last administration ofIBI351 or 60 days after the last administration of cetuximab. The blood pregnancytest results of fertile female subjects within 7 days (inclusive) beforeadministration should be negative 14. Understand and sign the informed consent formThe researchers judged that the subjects could communicate well, be followed up onschedule, and complete the study in accordance with the provisions of the protocol-

Exclusion Criteria:

If any of the following criteria is met, the study must be excluded:

1. Inability to comply with the research protocol or research procedures.

2. dMMR or MSI-H type colorectal cancer.

3. Those who have been confirmed to be allergic to IBI 351, cetuximab β injectionand/or its excipients.

4. Have obvious cardiovascular system diseases, such as:

• Within 6 months, there have been clear cardiovascular abnormal events, such asmyocardial infarction, angina pectoris, heart failure, severe arrhythmia, orangioplasty, vascular stent implantation, coronary artery bypass surgery, etc.

• Clinically significant QT/QTcF interval prolongation (QTcF > 470ms for femalesor QTcF > 450ms for males).

5. Researchers identify patients with unstable brain metastases. For patients withbrain metastases unintentionally detected during the screening process, if they donot cause clinical symptoms and do not require therapeutic intervention, they can beallowed to be enrolled. If the researchers determine that the brain metastasis isstably controlled, the hormone dose is used stably, and the prednisone dose is ≤10mg/d (if other steroid drugs are used, it is the corresponding equivalent dose),enrollment can be allowed.

6. There are significant digestive tract diseases, such as intractable hiccups, nausea,vomiting, severe digestive tract ulcers, liver cirrhosis, active gastrointestinalbleeding, or other diseases that affect the swallowing of tablets or significantlyaffect the absorption of oral medications;

7. There are major acute or chronic infections, including: Active infections that require systemic treatment;

• Positive human immunodeficiency virus antibody (HIV-Ab) at the baseline period;

• Active hepatitis B virus infection (positive for hepatitis B surface antigenHBsAg and positive for HBV-D NA); HBsAg was negative and HBcAb was positive.Further examination of HBV-DNA levels is required. If HBV-DNA is positive, thepatient will be excluded from the group.

• Active hepatitis C virus infection (positive hepatitis C antibody HCV-Ab andpositive HCV-RNA);

• Active pulmonary tuberculosis

8. Accompanied by pleural and peritoneal effusion or pericardial effusion that requiresrepeated drainage or has obvious symptoms.

9. Accompanied by other poorly controlled systemic diseases, such as hypertension (systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg) thatremains uncontrolled even with standardized treatment, diabetes, etc.

10. Within 2 years prior to entering the study, the patient had other malignant tumors,excluding appropriately treated cervical carcinoma in situ, focal cutaneous squamouscell carcinoma, basal cell carcinoma, untreated prostate cancer, ductal carcinoma insitu of the breast, and superficial non-muscular-invasive urothelial carcinoma.

11. Previously received treatment with KRAS G12C inhibitors.

12. Had received therapeutic or palliative radiotherapy within 14 days prior to theadministration of this study.

13. Have received other anti-tumor treatments such as chemotherapy, targeted therapy,endocrine therapy, immunotherapy, other investigational drugs or investigationaldevices within 28 days before administration in this study or within 5 half-lives (whichever is shorter), excluding maintenance endocrine therapy. The patientreceived treatment with traditional Chinese patent medicines with definiteanti-tumor effects within 7 days before the administration of this study.

14. Surgical operations (excluding puncture biopsy) that may affect the administrationor evaluation of this study have been performed within 28 days prior to inclusion inthis study.

15. Have received strong suppressor or strong inducer of CYP3A4 or P-gp (see Appendix 3)within 14 days before administration in this study or within 5 half-lives of thedrug (depending on the longer period), or have taken traditional Chinese medicinewithin 7 days before administration in this study. Those who received known CYP2D6, CYP3A4, P-gp and bCRP-sensitive substrates within 14 days before administration in this study or within 5 half-lives of the drug (whichever is longer), and the therapeutic window of this substrate was relativelynarrow, unless enrolled with the unanimous consent of the investigator and sponsor.

16. Pregnant or lactating women. Other circumstances where the researchers consider itunsuitable to participate in this study.