The goal of this clinical trial is to learn if adding savolitinib to cetuximab plus FOLFOX chemotherapy works as a first-line treatment for patients with RAS/BRAF wild-type metastatic colorectal cancer, and to evaluate its safety. The main questions it aims to answer are:

Does the addition of savolitinib improve the objective response rate (ORR) compared to cetuximab plus FOLFOX alone?

What medical problems (adverse events) do participants experience when taking savolitinib in combination with cetuximab and FOLFOX?

Researchers will compare savolitinib plus cetuximab and FOLFOX (experimental group) versus cetuximab and FOLFOX alone (control group) to see if the triplet regimen provides better tumor response and survival outcomes.

Participants will:

Take oral savolitinib once daily in repeated 14-day cycles (or receive control treatment), combined with weekly cetuximab and bi-weekly FOLFOX chemotherapy

Visit the clinic every 2 weeks or 4 weeks for treatment administration, safety monitoring, and laboratory tests

Undergo tumor imaging assessments every 8 weeks (4 cycles) to evaluate treatment response and disease progression

Have regular follow-up visits for 30 days after the last dose, and then every 3 months for survival follow-up

Inclusion Criteria:

1. Voluntarily sign the informed consent form after fully understanding this study;

2. Aged 18 to 75 years (inclusive), male or female;

3. Have at least one measurable lesion (RECIST 1.1);

4. Histologically confirmed unresectable locally advanced or metastatic colorectal cancer;

5. pMMR by immunohistochemistry or unknown MMR protein expression status;

6. KRAS/NRAS and BRAF all wild-type;

7. c-MET IHC intensity score 2+ or 3+ in ≥50% of tumor cells in the primary lesion; or positive by FISH; or NGS copy number ≥3;

8. No prior systemic therapy (Note: prior neoadjuvant or adjuvant chemotherapy is allowed if disease progression/recurrence occurred during or ≥6 months after completion of such therapy);

9. ECOG performance status 0-1;

10. Life expectancy ≥12 weeks;

11. Laboratory parameters (within 14 days without blood transfusion):

    • Absolute neutrophil count ≥1.5×10⁹/L, platelet count ≥100×10⁹/L, hemoglobin ≥9 g/dL;
    • Liver function: AST and ALT ≤2.5×ULN, total bilirubin ≤1.5×ULN; if liver metastases present, AST and ALT ≤5×ULN;
    • Renal function: serum creatinine ≤1.5×ULN, creatinine clearance (CCr) ≥60 mL/min;

12. Fertile male or female patients voluntarily agree to use effective contraceptive methods during the study and for 6 months after the last dose of study treatment.

Exclusion Criteria:

1. Prior treatment with anti-EGFR monoclonal antibody therapy;

2. Prior treatment with c-MET small molecule inhibitors or monoclonal antibodies targeting c-MET or HGF;

3. Received approved or investigational systemic anti-tumor therapy within 4 weeks prior to enrollment;

4. Participated in another clinical trial of a drug not yet approved or marketed in China and received the investigational drug within 4 weeks prior to enrollment;

5. Underwent any surgery or invasive treatment or procedure (except venous catheterization, puncture drainage, etc.) within 4 weeks prior to enrollment;

6. INR >1.5 or APTT >1.5×ULN;

7. Clinically significant electrolyte abnormalities as judged by the investigator;

8. Uncontrolled hypertension (systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg);

9. Poorly controlled blood glucose (FBG ≥10 mmol/L);

10. Any disease or condition affecting drug absorption, or inability to take oral savolitinib;

11. Active gastric or duodenal ulcer, ulcerative colitis, or other gastrointestinal diseases, or active bleeding from an unresected tumor, or other conditions that may cause gastrointestinal bleeding or perforation within 28 days prior to enrollment;

12. History or evidence of significant bleeding tendency within 3 months prior to enrollment (bleeding >30 mL within 3 months, hematemesis, melena, hematochezia), hemoptysis (>5 mL fresh blood within 4 weeks), or thromboembolic events within 12 months;

13. Clinically significant cardiovascular disease (e.g., acute myocardial infarction within 6 months, unstable angina, heart failure NYHA class >2, ventricular arrhythmia requiring medication, LVEF <50%);

14. Other malignancy within the past 5 years (except adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix);

15. Active or uncontrolled serious infection:

    • Known HIV infection;
    • Known clinically significant liver disease, including active HBV infection (HBV DNA >1×10⁴ copies/mL or >2000 IU/mL);
    • Known HCV infection with positive HCV RNA (>1×10³ copies/mL), or other hepatitis, liver cirrhosis;

16. Known brain metastases (except adequately treated, inactive, asymptomatic lesions with no steroid use for at least 30 days);

17. History of allergic reaction to compounds with similar chemical or biological composition to savolitinib;

18. Persistent toxicity from prior anti-tumor therapy not recovered to ≤ Grade 2 (except alopecia and lymphopenia of any grade);

19. Pregnant or breastfeeding women;

20. Received blood transfusion, blood products, or hematopoietic factors (e.g., albumin, G-CSF) within 14 days prior to enrollment;

21. Any clinical or laboratory abnormality or other condition that, in the investigator's opinion, makes the subject unsuitable for participation in this clinical study.