Gematinib Combined With Lenvatinib for the Treatment of Locally Advanced or Metastatic Non-small Cell Lung Cancer With MET Protein Overexpression: A Prospective, Multicenter, Phase II Clinical Study

• 1. Age: 18 - 80 years old; 2. Locally advanced or metastatic non-small cell lung cancer confirmed by pathological histology or cytology; 3. Previous failure of at least one standard first-line treatment; 4. Overexpression of MET protein: IHC 3+ (≥50% of tumor cells are strongly positive) or IHC 2+ (≥50% of tumor cells are moderately positive); 5. At least one measurable lesion (RECIST v1.1); 6. ECOG score 0 - 2; 7. Normal liver and kidney function: AST and ALT \< 2.5 times the upper limit of normal, total bilirubin \< 1.5 times the upper limit of normal; serum creatinine ≤ 1.5 times the upper limit of normal and creatinine clearance rate ≥ 30 mL/min; sufficient bone marrow function: neutrophils > 1.0 × 109/L, hemoglobin > 90 g/L, platelets > 100 × 109/L; 8. Expected survival time ≥ 3 months; Subjects refuse or the investigator assesses that the patient cannot tolerate chemotherapy, fully understand and voluntarily participate in this study.

Exclusion Criteria:

• 1. Positive driver genes for non-small cell lung cancer (including: EGFR mutations, ALK fusion positive, ROS1 fusion positive, BRAF V600 mutations, NTRK fusion, MET14 exon skipping mutations, RET fusion); 2. Previously treated with EGFR-TKI; 3. Present with symptomatic brain metastases; 4. Central-type lung squamous cell carcinoma; 5. Diagnosed with a malignancy other than non-small cell lung cancer within 5 years prior to the first administration (excluding cured skin basal cell carcinoma, skin squamous cell carcinoma, and/or resected carcinoma in situ); 6. Currently participating in an interventional clinical study treatment, or having received other study drugs or used study devices within 4 weeks prior to the first administration; 7. Due to gastrointestinal diseases or other diseases that may affect the absorption of the trial drug (such as inability to swallow the drug, severe ulcers, uncontrollable nausea, vomiting, diarrhea, malabsorption syndrome, ulcerative colitis, extensive gastrectomy and small intestine resection, etc.); 8. Having uncontrollable pleural effusion, pericardial effusion or ascites that require repeated drainage; 9. Having a bleeding tendency (such as active gastrointestinal ulcers) or using anticoagulants or vitamin K antagonists such as warfarin, heparin or their analogues for treatment; 10. Within 2 weeks prior to the first administration of the study drug, having active hemoptysis requiring clinical intervention; 11. Having undergone surgery within 4 weeks prior to the first administration; 12. Having clinically significant cardiovascular diseases, including:

  • NYHA III or above congestive heart failure
  • Proven history of severe uncontrolled arrhythmia in the past
  • Acute myocardial infarction, severe or unstable angina pectoris, coronary artery or peripheral artery bypass surgery within 6 months prior to the first administration
  • Left ventricular ejection fraction (LVEF) \< 50%

  • Congenital long QT syndrome or any known torsades de pointes (TdP) history or unexplained sudden death family history; 13. Imaging (CT or MRI) shows tumor invasion of major blood vessels or unclear boundaries with blood vessels; 14. Having experienced arterial or venous thromboembolic events within 6 months, cerebrovascular accidents including transient ischemic attack, deep vein thrombosis, pulmonary embolism, etc.

    15. Known HIV infection/active hepatitis B (HBsAg positive and HBV DNA ≥ 1000IU/ml or 2000copies/ml)/hepatitis C; 16. Unable to discontinue the use of or not having discontinued the use of drugs with MATE1 and MATE-K substrates (metformin, cimetidine, lamivudine, acyclovir, etc.) within 2 weeks before enrollment; 17. Urinalysis indicates urine protein ≥ ++, and confirmed 24-hour urine protein quantification > 1.0 g; 18. Pregnant and lactating patients; 19. Male and female subjects with reproductive capacity who have not taken effective contraceptive measures during the trial period and within 6 months after the end of treatment; 20. Patients with interstitial lung disease history; 21. History of alcohol abuse or drug abuse; 22. Patients with mental disorders and unable to cooperate with treatment; 23. Hypertension that cannot be controlled by medication; For patients with a history of hypertension, if antihypertensive treatment can adequately control blood pressure, they are allowed to be enrolled; 24. The investigator determines that they are not suitable for enrollment; 25. Other specified conditions.