The goal of phase Ib study was to evaluate efficacy and tolerability of the combination of vebreltinib and furmonertinib in patients with locally advanced or metastatic non-small cell lung cancer with c-met amplification after failure of EGFR-TKI treatment; to determine the maximum tolerated dose (MTD), and to evaluate the dose-limiting toxicity (DLT) and (recommended Phase 2 dose) RP2D of vebreltinib with furmonertinib.

The goal of phase II study was to evaluate efficacy [overall response rate (ORR), progression-free survival (PFS), and so on] of vebreltinib and furmonertinib in patients with locally advanced or metastatic non-small cell lung cancer with c-met amplification after failure of EGFR-TKI treatment.

Phase Ib study uses 3+3 clinical design. The Phase Ib clinical trial is designed to explore the dosing of vebreltinib, consisting of two stages: dose escalation and dose expansion. The dose escalation stage follows a 3+3 design with three escalating dose levels (100 mg BID, 150 mg BID, 200 mg BID). Each dose cohort enrolls 3 patients. If no DLTs are observed in the first 3 patients within 28 days, the dose is escalated to the next cohort. If more than 1 DLT is observed in the first 3 patients within 28 days, that dose level is deemed non-tolerable. If 1 DLT is observed in the first 3 patients within 28 days, an additional 3 patients are enrolled at that dose level. If no DLTs are observed in the additional patients, dose escalation proceeds to the next cohort. If more than 1 DLT is observed among the additional patients (i.e., a total of 2 DLTs in the cohort), the previous dose level is determined to be the MTD. After completion of DLT assessment, the investigator decided whether to continue the treatment after the end of DLT assessment based on the subject 's tolerance and the safety profile of the dose group.

The dose expansion phase, based on the safety data from the completed dose cohorts, will involve the selection of 1-2 dose cohorts by the investigators for further study. Approximately 10 additional subjects will be enrolled in each selected dose expansion cohort to determine the recommended dose for Phase II clinical trials.

In the Phase II clinical study, the recommended Phase II dose of vebreltinib, determined from the Phase Ib study, will be combined with Furmonertinib to treat locally advanced or metastatic NSCLC with c-Met amplification in patients after failure of EGFR-TKI treatment. The study aims to evaluate the efficacy and safety of this combination, with an anticipated enrollment of 20 subjects. Participants will take vebreltinib (RP2D bid) and furmonertinib (80mg qd) until disease progression or undurable toxicity.

Inclusion Criteria:

1. Fully aware this study and voluntary to sign the informed consent form, and willing and able to comply with the study procedure.
2. Aged ≥18 years, male or female.
3. Patients with histologically or cytologically confirmed unresectable and non-suitable for radical surgery, or concurrent chemoradiotherapy , locally advanced or metastatic (stage IIIB, IIIC or IV) NSCLC;
4. Documented EGFR sensitive mutations (exon 19 deletion or exon 21 L858R mutation).
5. Disease progression after prior EGFR-TKI therapy. Participants must meet both of the following 2 criteria:

(1) ≤1 prior chemotherapy regimen allowed besides EGFR-TKI. Combination with anti-angiogenic therapy or PD-1/PD-L1 inhibitors are allowed during EGFR-TKI targeted therapy or chemotherapy.

（2） Objective clinical benefit documented during previous EGFR-TKI therapy, defined by either partial or complete radiological response, or durable stable disease should be greater than 6 months after initiation of EGFR-TKI.

6. After the last line of treatment before enrollment, progression is confirmed, and blood tests confirm c-Met amplification, or re-biopsy and genetic testing confirm c-Met amplification. Any of the following criteria define c-Met amplification.

1. For tumor tissue samples, FISH detection shows GCN ≥5 and/or MET/CEP7 ≥2 (FISH results from local testing institutions/central laboratories are acceptable);
2. Tissue (wax blocks from pleural effusion centrifugation, if quality-controlled) or blood NGS testing results confirm c-Met amplification with CN ≥2.3 (NGS results from local testing institutions/central laboratories are acceptable for both tissue and blood).

7. ECOG performance status ≤1. 8. According to RECIST v1.1, the patient must have at least one target lesion as assessed by the investigator.

9. Laboratory test results must meet the following criteria:

1. Absolute neutrophil count ≥1.5×10⁹/L (without the use of growth factors within 7 days prior to the start of treatment);
2. Hemoglobin ≥90 g/L (without blood transfusion or use of growth factors within 7 days prior to the start of treatment);
3. Platelet count ≥75×10⁹/L (without blood transfusion or use of growth factors within 7 days prior to the start of treatment);
4. Serum total bilirubin ≤1.5×upper limit of normal (ULN);
5. Serum alanine aminotransferase and aspartate aminotransferase ≤3×ULN (for patients with liver metastases, both AST and ALT ≤5×ULN);
6. Creatinine clearance (Ccr) ≥60 mL/min.
7. International normalized ratio (INR) ≤1.5×ULN;
8. Asymptomatic serum amylase ≤Grade 2 (NCI-CTCAE v5.0). For patients with Grade 2 serum amylase abnormalities at the start of the study, it must be confirmed that there are no signs and/or symptoms suggestive of pancreatitis or pancreatic injury (e.g., elevated P-amylase, abnormal pancreatic imaging results);
9. Serum lipase ≤1.5×ULN. 10. Men with reproductive potential and women of childbearing potential must agree to use effective contraception from the time of signing the informed consent form until 3 months after the last dose of the study drug. Women of childbearing potential must have a negative serum pregnancy test within ≤7 days prior to the first dose of the study drug. This does not apply to female subjects who have undergone sterilization or are postmenopausal.

11. Expected survival ≥3 months.

Exclusion Criteria:

1. Patients with ALK fusion or ROS1 fusion.
2. Patients with spinal cord compression, leptomeningeal metastasis, or symptomatic brain metastasis that requires an increase in steroid dosage to control central nervous system disease. Patients with symptomatic CNS metastases that have been controlled may be eligible for this trial.
3. Presence of other malignancies (with the exception of any type of carcinoma in situ that has been completely resected, basal cell and squamous cell skin cancers, or other tumors/cancers that have been treated with curative intent and have been disease-free for at least 3 years).
4. A history of anti-tumor treatment that meets any of the following criteria:

（1）Received traditional Chinese medicine or patent medicine with anti-tumor indications within 1 week prior to the first dose of the study drug; （2）Underwent radiotherapy targeting the lung fields and whole brain within 4 weeks prior to the first dose of the study drug, or received radiotherapy targeting other areas (excluding the lung fields and whole brain) within 2 weeks prior to the first dose. Palliative radiotherapy for bone metastases to relieve pain or prevent skeletal-related events is excluded; （3）Underwent major surgery within 4 weeks, or has not recovered from the adverse effects of these surgeries. Thoracoscopic biopsy and mediastinoscopy are not considered major surgeries, and patients may be enrolled ≥1 week after the procedure 5. Has not recovered from any toxicity or complications of prior chemotherapy, surgery, radiotherapy, or other anti-tumor treatments, i.e., not reduced to ≤Grade 1 (NCI-CTCAE v5.0), with the exception of alopecia and permanent radiation-induced damage that cannot be recovered; 6. Requires the use of strong inhibitors or inducers of cytochrome P450 3A4 enzyme 1 week prior to the first dose of the study drug and during the study period.

7. Has any severe or uncontrolled systemic disease, including but not limited to:

1. Uncontrolled hypertension, with the allowance for the initiation or adjustment of antihypertensive medications prior to screening;
2. Positive for anti-HIV, or positive for both anti-HCV and HCV-RNA, or positive for HBsAg with HBV-DNA ≥500 IU/mL
3. Active keratitis or ulcerative keratitis during the disease phase;
4. Active tuberculosis;
5. Active infection requiring systemic antimicrobial therapy within 2 weeks prior to the first dose of the study drug;
6. Other severe medical conditions or psychiatric disorders, or laboratory abnormalities that, in the investigator's judgment, make the study drug unsuitable for the patient or affect protocol compliance; 8. Cardiac dysfunction and diseases that meet any of the following criteria:

（1）The average corrected QT interval calculated by the Fridericia formula from three electrocardiograms during the screening period >470 ms; （2）Any significant arrhythmias, such as ventricular arrhythmias, uncontrolled supraventricular or junctional arrhythmias, and other uncontrolled cardiac arrhythmias （3）Any risk factors for QTc prolongation, such as severe hypokalemia, hereditary long QT syndrome, or use of drugs that prolong the QT interval; d) Congestive heart failure with New York Heart Association (NYHA) classification ≥3; echocardiography indicating left ventricular ejection fraction (LVEF) <50%； 9. History of interstitial lung disease, drug-induced interstitial lung disease, or radiation pneumonitis requiring corticosteroid therapy, or is currently receiving drug therapy or other clinical interventions, or has active interstitial lung disease; 10. Has coagulation dysfunction or bleeding tendency 11. Has difficulty swallowing, or has active gastrointestinal disease, or has undergone major gastrointestinal surgery that may significantly affect the intake or absorption of the study drug 12. Has pleural effusion, pericardial effusion, or ascites that require drainage and/or are associated with dyspnea within 4 weeks prior to the first dose of the study drug; 13. Has any clinically significant systemic disease that requires treatment, as judged by the investigator, including but not limited to thyroid disease, organ transplant recipients, history of psychiatric disorders, history of drug abuse/addiction, alcoholism, or drug use; 14. History of acute or chronic pancreatitis, pancreatic surgery, or risk factors that may increase the risk of pancreatitis; 15. Patients receiving thrombolytic therapy are not eligible for inclusion, but patients receiving anticoagulant therapy may be included, provided that they have been on a stable dose of anticoagulant therapy for at least 1 week prior to the first dose; 16. Has a known hypersensitivity to the study drug or its excipients; 17. Pregnant or breastfeeding women; 18. Currently enrolled in another study device or study drug treatment, or received other study drugs or study devices within 2 weeks prior to the first dose of the study drug; 19. Cognitive impairment that may limit their understanding or execution of the informed consent form; 20. Presence of any condition that may increase the risk associated with the administration of the study drug, or may affect the interpretation of study results, or poor compliance with the study protocol, or any other situation that the investigator deems unsuitable for enrollment.