Vebreltinib with Platinum Chemotherapy as First-line Treatment for MET-Overexpressing NSCLC

Inclusion criteria

Patients must meet all of the following inclusion criteria:

1. Provide written informed consent before initiation of any study-specific procedure and be willing and able to comply with study procedures.
2. Be aged ≥18 years.
3. Have histologically or cytologically confirmed NSCLC. (pathology reports from outside institutions are acceptable).
4. Have newly diagnosed locally advanced or metastatic NSCLC that is not amenable to curative surgery or radiotherapy according to the AJCC 9th edition staging system.
5. Have no prior systemic anticancer therapy for advanced or metastatic disease. Prior neoadjuvant or adjuvant systemic therapy, definitive chemoradiotherapy or radiotherapy is permitted provided that treatment was completed ≥12 months before recurrence.
6. Have an ECOG performance status of 0-2.
7. Have no actionable driver oncogene alteration identified by tissue and/or blood-based molecular testing. At a minimum, testing must exclude EGFR sensitising mutations, ALK rearrangements, ROS1 rearrangements, RET fusions, NTRK fusions, KRAS G12C mutations, BRAF V600E mutations, MET exon 14 skipping alterations and other actionable alterations according to current clinical practice and locally available testing. Concurrent MET amplification is permitted provided that the tumour meets the prespecified MET protein overexpression criterion.
8. Have MET protein overexpression, defined as moderate-to-strong (2+ or 3+) MET staining in ≥50% of viable tumour cells by IHC.
9. Have a PD-L1 TPS \<50%
10. Have an estimated life expectancy of at least 3 months.
11. Have at least one measurable lesion according to RECIST version 1.1.
12. Have adequate organ function as defined by the following laboratory criteria:

1\) absolute neutrophil count ≥1.5 × 10⁹/L; 2) hemoglobin ≥90 g/L; 3) platelets ≥75 × 10⁹/L; 4) total serum bilirubin ≤1.5 × ULN; 5) AST and ALT ≤3 × ULN, or ≤5 × ULN in patients with liver metastases; 6) serum creatinine \<1.5 × ULN. 7) creatinine clearance \>50 mL/min, calculated using the Cockcroft-Gault formula.

13\. Women of childbearing potential must have a negative pregnancy test within 7 days before the first dose and all participants of reproductive potential must agree to use effective contraception from informed consent until 3 months after the last dose of study treatment.

Exclusion criteria

Participants meeting any of the following criteria will be excluded from the study:

1\. Central nervous system conditions

1. Spinal cord compression or symptomatic, unstable brain metastases requiring urgent local treatment
2. Patients with symptomatic brain metastases may be eligible if definitive local treatment has been completed, corticosteroid therapy has been discontinued, and neurological status has remained stable for at least 2 weeks after completion of definitive treatment and corticosteroid therapy.
3. Asymptomatic brain metastases may be permitted if, in the investigator's judgement, immediate local treatment is not clinically indicated.

2\. Prior treatment and medication history

1. Major surgery, including intrathoracic, intra-abdominal, or intrapelvic surgery, within 4 weeks before enrolment, or failure to recover adequately from the effects of previous surgery. Thoracoscopic biopsy and mediastinoscopy are not considered major surgery; patients may be enrolled ≥1 week after these procedures if adequately recovered.
2. Treatment with traditional Chinese medicines or Chinese patent medicines with an antitumour indication within 1 week before the first dose of study treatment.
3. Concomitant treatment with strong CYP3A4 inducers or strong CYP3A4 inhibitors that cannot be discontinued for at least 1 week before initiation of study treatment and avoided during study treatment.
4. Any prior systemic antitumour therapy for advanced or metastatic NSCLC, including chemotherapy, immunotherapy, biologic therapy, targeted therapy, or investigational agents. For patients with recurrent disease, prior neoadjuvant or adjuvant systemic therapy, or definitive radiotherapy or chemoradiotherapy, with or without immunotherapy, biologic therapy, or investigational agents, is permitted provided that treatment was completed ≥12 months before documented disease recurrence.
5. Radiotherapy involving \>30% of the bone marrow or radiotherapy with a large treatment field within 4 weeks before the first dose of vebreltinib.
6. Use of any investigational drug within 2 weeks before the first dose of study treatment or concurrent participation in another interventional clinical trial.

3\. Other malignancies Diagnosis of another malignancy requiring active treatment within the previous 3 years, except for completely resected basal cell carcinoma or squamous cell carcinoma of the skin, or completely resected carcinoma in situ without evidence of recurrence.

4\. Active infection and pulmonary or gastrointestinal conditions

1. Active infection requiring systemic anti-infective treatment within 2 weeks before the first dose of study treatment, including clinically significant pneumonia.
2. Active tuberculosis or other clinically significant uncontrolled infection.
3. Active hepatitis B, hepatitis C, human immunodeficiency virus (HIV) infection, as defined by the following:

   * hepatitis B: positive hepatitis B surface antigen (HBsAg) with HBV DNA ≥500 IU/mL;
   * hepatitis C: positive HCV antibody with detectable HCV RNA;
   * HIV infection: positive HIV antibody;
4. History of interstitial lung disease, drug-induced interstitial lung disease, or radiation pneumonitis requiring systemic corticosteroid treatment, or current active interstitial lung disease requiring treatment or clinical intervention.
5. Active gastrointestinal disease or other conditions that may significantly affect the absorption, distribution, metabolism, or excretion of oral vebreltinib, including active ulcerative gastrointestinal lesions, uncontrolled nausea, vomiting or diarrhoea, clinically significant malabsorption syndrome, in·ability to swallow oral medication, or previous major gastrointestinal surgery that may affect drug absorption.

5\. Hypersensitivity Known hypersensitivity to vebreltinib, platinum compounds, pemetrexed, gemcitabine, nab-paclitaxel, or any of their excipients, where applicable to the planned treatment regimen.

6\. Other serious medical conditions Any serious, uncontrolled, or clinically significant medical condition that, in the investigator's judgement, could increase the risk associated with study treatment, interfere with the interpretation of study results, compromise protocol compliance, or otherwise make the participant unsuitable for the study. This includes, but is not limited to, severe or uncontrolled psychiatric disorders, active primary immunodeficiency, or a history of allogeneic organ transplantation.

7\. Pregnancy and lactation Pregnant or breastfeeding women, or women of childbearing potential who are unwilling or unable to use highly effective contraception during the study treatment period and for 3 months after the last dose of study treatment.

8\. Other conditions affecting study participation Any other condition or circumstance that, in the investigator's judgement, would make the participant unsuitable for study participation or would compromise participant safety, study compliance, or the integrity of study assessments.