Vebreltinib Plus Chemotherapy as First-line Treatment for MET-overexpressing NSCLC

A Phase II Study of Vebreltinib Combined With Platinum-Doublet Chemotherapy as First-Line Treatment for Locally Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC) With Negative Driver Genes and MET Overexpression

To explore the efficacy and safety of vebreltinib plus platinum-doublet chemotherapy as first-line therapy in patients with driver gene-negative, locally advanced or metastatic non-small cell lung cancer (NSCLC) with MET overexpression.

This is a prospective, single-center, single-arm Phase II clinical study designed to investigate the efficacy and safety of vebreltinib combined with platinum-based chemotherapy in treatment-naïve patients with driver gene-negative, locally advanced or metastatic non-small cell lung cancer (NSCLC) with MET overexpression.In this study, all eligible participants will provide written informed consent, and after meeting the inclusion and exclusion criteria during screening, will receive vebreltinib (150 mg orally Bid) plus platinum-doublet chemotherapy. Oral vebreltinib (150 mg Bid) will be continued until disease progression or unacceptable toxicity.

Inclusion Criteria:

1. Voluntarily sign a written informed consent form (ICF) to participate in the study; be willing and able to comply with study-related visits and procedures.

2. Male or female subjects aged 18 years or older.

3. Pathologically confirmed non-small cell lung cancer (NSCLC); outside hospital pathology reports are acceptable.

4. Newly diagnosed metastatic NSCLC (clinical Stage IVA or IVB) or recurrent NSCLC (staged in accordance with the AJCC Cancer Staging Manual 9th edition), not eligible for curative-intent surgery or radiotherapy.

5. Treatment-naïve advanced NSCLC not amenable to curative surgery or radiotherapy. For recurrent disease, prior adjuvant and neoadjuvant therapy (chemotherapy, radiotherapy, immunotherapy, biologic therapy, investigational agents), or definitive radiotherapy/chemoradiotherapy with or without immunotherapy, biologic therapy, or investigational agents is permitted if completed at least 12 months before disease recurrence.

6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0-2.

7. Driver gene-negative status confirmed by tumor tissue or blood sample, including but not limited to negative EGFR mutation, negative ALK rearrangement, negative ROS1 rearrangement, negative KRAS G12C mutation, and negative MET exon 14 skipping mutation. MET amplification is permitted: FISH demonstrating GCN ≥ 4 or MET/CEP7 ≥ 2, or positive result confirmed by NGS.

8. MET protein overexpression defined as ≥50% of tumor cells staining at IHC 2++ or stronger. Local laboratory IHC results are acceptable.

9. Estimated overall survival of at least 3 months.

10. Laboratory values meeting the following requirements:

    Absolute neutrophil count (ANC)≥1.5 × 10⁹/L; Hemoglobin≥90 g/L; Platelets≥75 × 10⁹/L; Serum total bilirubin≤1.5×upper limit of normal (ULN); Aspartate aminotransferase (AST) and alanine aminotransferase (ALT)≤3×ULN; for patients with liver metastases, AST and ALT≤5×ULN; Serum creatinine<1.5 × ULN. Creatinine clearance (CrCl)>50 mL/min, calculated using the Cockcroft-Gault formula

11. Males with reproductive potential and females of childbearing potential must agree to use highly effective contraception from signing informed consent until 3 months after the last dose of study drug. For females of childbearing potential, a serum pregnancy test must be negative within ≤7 days before the first dose of study drug.

Exclusion Criteria:

1. Spinal cord compression. Symptomatic or unstable brain metastases, unless the patient has completed curative treatment, is not receiving corticosteroid therapy, and has maintained a stable neurological status for at least 2 weeks after completion of curative treatment and steroid therapy. Patients with asymptomatic brain metastases may be included if the investigator determines there is no immediate indication for curative treatment.

2. Meeting any of the following prior treatment history criteria:

   Major surgery (e.g., intrathoracic, intra-abdominal, or intrapelvic surgery) within 4 weeks prior to enrollment, or failure to recover from side effects of such surgery. Thoracoscopic biopsy and mediastinoscopy are not considered major surgery, and patients may be enrolled 1 week after these procedures.

   Treatment with traditional Chinese medicine (TCM) or Chinese patent medicine with anti-tumor indications within 1 week prior to the first dose of study drug.

   Treatment with strong CYP3A4 inducers and/or strong inhibitors, and inability to discontinue such agents for at least 1 week prior to initiation of study treatment and during the study period.

   Prior systemic anti-tumor therapy for advanced NSCLC, including chemotherapy, biologic therapy, immunotherapy, or any investigational agent, administered as non-curative surgery or radiotherapy. For recurrent disease, prior adjuvant and neoadjuvant therapy (chemotherapy, radiotherapy, immunotherapy, biologic therapy, investigational agents), or definitive radiotherapy/chemoradiotherapy with or without immunotherapy, biologic therapy, or investigational agents is permitted only if completed at least 12 months before disease recurrence.

   Radiation therapy to more than 30% of bone marrow, or large-field radiation therapy within 4 weeks prior to the first dose of vebreltinib.

   Patients with intracranial lesions requiring urgent local treatment for symptom relief are recommended for exclusion, at the discretion of the investigator.

   Any severe or uncontrolled systemic disease, including but not limited to other severe medical or psychiatric disorders or laboratory abnormalities that, in the investigator's judgment, render the study drug inappropriate for the patient or impair compliance with the protocol.

3. Meeting any of the following cardiac function or disease criteria:

   Mean corrected QT interval (QTc) > 470 ms based on three routine ECG assessments performed at least 5 minutes apart (preferably completed within 1 hour) during the screening period at rest. Calculation shall be performed using the Fridericia formula (see Appendix 5 for details), with mean QTcF > 470 ms.

   Any significant cardiac arrhythmia, such as complete left bundle branch block, second- or third-degree heart block, ventricular arrhythmia, drug-uncontrolled supraventricular or nodal arrhythmia, or other drug-uncontrolled cardiac arrhythmias.

   Any risk factors for prolonged QTc interval, including chronic hypokalemia uncorrected by supplementation, congenital long QT syndrome, and concomitant use of QTc-prolonging medications.

   Congestive heart failure of New York Heart Association (NYHA) Class ≥3. Unstable or uncontrolled diseases or conditions related to or affecting cardiac function (e.g., unstable angina pectoris, inadequately controlled hypertension defined as diastolic blood pressure > 100 mmHg and/or systolic blood pressure > 160 mmHg regardless of antihypertensive use; initiation or adjustment of antihypertensive agents prior to screening is permitted).

4. Diagnosis of another active malignancy requiring treatment within the past 3 years, other than NSCLC. Excluded are completely resected basal cell and squamous cell skin cancer, and completely resected carcinoma in situ of any type.

5. Presence of active infection, including but not limited to:

   Chronic hepatitis B (hepatitis B surface antigen [HBsAg] positive with hepatitis B virus [HBV] DNA ≥ 500 IU/ml), hepatitis C (positive anti-hepatitis C virus [HCV] antibody and positive HCV-RNA), human immunodeficiency virus (HIV) infection (positive HIV antibody), or syphilis infection.

   Active tuberculosis. Active infection requiring systemic anti-infective therapy (e.g., pneumonia) within 2 weeks prior to the first dose of study drug.

   History of interstitial lung disease (ILD), drug-induced ILD, or radiation pneumonitis requiring corticosteroid therapy; or current active interstitial lung abnormalities requiring medical therapy or other clinical intervention.

   Active gastrointestinal disorders (e.g., ulcerative lesions, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome) or other conditions (e.g., inability to swallow study medication, prior major gastrointestinal surgery) that may significantly affect absorption, distribution, metabolism, or excretion of oral study drug.

6. Known hypersensitivity to drugs of the same class as the study drug or to any of its excipients.

7. Any concurrent medical condition that may increase the risk of toxicity.

8. Pregnant or lactating females.

9. Current participation in another clinical trial, or receipt of investigational product within 2 weeks prior to the first dose of study drug.

10. Any other circumstances deemed by the investigator to render the patient ineligible for study participation, including evidence of severe or uncontrolled systemic disease such as active primary immunodeficiency disorders and allogeneic organ transplantation, which would make the patient unsuitable for enrollment or interfere with compliance with the study protocol.