This study is an open-label, randomized, controlled, multicenter Phase IIIb clinical study, aiming to evaluate the efficacy, safety, and tolerability of Vebreltinib Enteric Capsule combined with platinum-based doublet chemotherapy compared with platinum-based doublet chemotherapy in treating subjects with locally advanced or metastatic non-squamous NSCLC who have not received previous systemic treatment and MET-positive.
The target population of this study is subjects with histologically confirmed locally advanced or metastatic non-squamous NSCLC who have not received previous systemic anti-tumor treatment and MET-positive( MET Amplification or Overexpression).
This study adopts an enrichment design. The enriched population is those with MET GCN ≥ 6, and the overall population is those with MET GCN ≥ 4.
This study consists of two parts: the lead-in period (Part 1) and the randomized controlled period (Part 2). Both the lead-in period (Part 1) and the randomized controlled period (Part 2) will include a screening period (from Day -28 to Day -1), a treatment period (until the termination of treatment), and a follow-up period (including safety follow-up and survival follow-up).
male or female subjects ≥ 18 years of age at the time of signing ICF.
histologically or cytologically confirmed diagnosis of non-radical, locally advanced (Stage IIIB and IIIC) or metastatic (Stage IV) non-squamous cell type NSCLC (refer to the American Joint Committee on Cancer [AJCC] Lung Cancer Stages, 8th edition for lung cancer staging criteria).
Part 1 (introductory stage)Subjects with MET-positive (MET amplification or MET overexpression) tumors will be enrolled. MET amplification is defined as the presence of MET amplification confirmed by second-generation sequencing (NGS) or fluorescence in situ hybridization (FISH) with a mean MET GCN ≥ 4 cells/cell or MET/CEP7 ≥ 2. MET overexpression is defined as c-Met showing strong positive (3+) staining in ≥50% of tumor cells as determined by immunohistochemistry (IHC) (central laboratory results). And subjects are required to provide sufficient tumor tissue (archived or fresh samples) for retrospective analysis in the central laboratory (see Laboratory Manual) to support the development of concomitant diagnostic reagents required for the marketing of Vebreltinib. Part 2 (Randomized Control Phase) MET amplification is defined as subjects' tumor tissue (archived or fresh samples) with an average MET GCN ≥ 4 cells/cell or MET/CEP7 ≥ 2 as confirmed by fluorescence in situ hybridization (FISH) in the central laboratory, and subjects will be required to provide sufficient tumor tissue (archived or fresh samples) for retrospective assay analysis by a central laboratory (see Laboratory Manual). Laboratory Manual) to support the development of concomitant diagnostic reagents required for the marketing of Vebreltinib.
Part 1 (Lead-in Period): Documented evidence confirms that the tumor tissue specimen tested negative for sensitive epidermal growth factor receptor (EGFR) mutations (including exon 19 deletion, exon 21 L858R or L861Q mutations, exon 18 G719X mutations, exon 20 S768I/T790M mutations, or exon 20 insertion mutations), ALK fusion-negative, ROS1 fusion-negative, and MET exon 14 skipping mutation-negative. Additionally, if the subject has already undergone testing for BRAF V600E mutation, NTRK fusion, RET fusion, or ERBB2 (HER-2) mutation, the results must be negative.
has participated in another therapeutic clinical trial within 28 days prior to the first study dose.
have undergone major surgery within 28 days prior to the first study dose or anticipate the need for major surgery during the study period. Diagnostic procedures such as thoracoscopic biopsy and mediastinoscopy may be enrolled 7 days after the procedure. No waiting period is required after implantable infusion port and catheter placement.
lung field or whole brain radiotherapy within 28 days prior to first study dose or palliative localized radiotherapy within 14 days prior to first study dose.
have received a proprietary Chinese medicine with an antitumor indication within 1 week prior to the first study dose. Has received local antitumor drug therapy (e.g., thoracic or abdominal perfusion, etc.) within 14 days or 5 half-lives, whichever is shorter, prior to the first study dose.
Parallel
Vebreltinib combined with platinum-based doublet chemotherapy.
DrugVebreltinib: Each cycle is 3 weeks (21 days). It is administered orally twice a day (BID), and the dosage level depends on the cohort assignment. Platinum-based doublet chemotherapy: Each cycle is 3 weeks (21 days), and it is administered once on the first day (D1) of each cycle. Pemetrexed at a dose of 500 mg/m² plus a platinum agent (carboplatin with an area under the curve (AUC) of 5 or cisplatin at a dose of 75 mg/m²) is given by intravenous infusion for 4 to 6 cycles as the initial treatment. After that, it is switched to pemetrexed (500 mg/m²) given by intravenous infusion as the maintenance treatment.
platinum-based doublet chemotherapy.
DrugPlatinum-based doublet chemotherapy: Each cycle is 3 weeks (21 days), and it is administered once on the first day (D1) of each cycle. Pemetrexed at a dose of 500 mg/m² plus a platinum agent (carboplatin with an area under the curve (AUC) of 5 or cisplatin at a dose of 75 mg/m²) is given by intravenous infusion for 4 to 6 cycles as the initial treatment. After that, it is switched to pemetrexed (500 mg/m²) given by intravenous infusion as the maintenance treatment.
Introductory phase-Dose-limiting toxicity (DLT) Incidence of DLT events during the observation period
laboratory tests, vital signs, physical examination, electrocardiogram (ECG), and the Eastern United States Collaborative Oncology Group (ECOG) clinically significant abnormal values in physical status (PS).To evaluated DLT events during the observation period.
Incidence and severity of adverse events (AEs) .
laboratory tests, vital signs, physical examination, electrocardiogram (ECG), and the Eastern United States Collaborative Oncology Group (ECOG) clinically significant abnormal values in physical status (PS).
Introductory phase-Recommended dosage for MTD and/or co-administration.
Confirm Recommended dosage for MTD and/or co-administration.
Randomized control period-Progression-free survival (PFS) as assessed by the Blinded Independent Center Review Board (BICR) according to RECIST V1.1 in the MET GCN ≥6-enriched population.
Progression Free Survival is defined as the time (in months) from the first administration of trial treatment to the date of the first documentation of PD or death due to any cause.
Introductory phase-Objective Response Rate (ORR) as assessed by the investigator according to RECIST V1.1.
Objective response rate is defined as the percentage of patients who experienced either a complete response (CR) or partial response (PR) from first administration of trial treatment to first observation of progressive disease (PD).
Introductory phase-Duration of Remission (DoR) as assessed by the investigator according to RECIST V1.1.
Duration of remission is defined as the time from the first tumor assessment as CR or PR to the first assessment of PD (Progressive Disease) or death from any cause.
Introductory phase-Disease control rate (DCR) as assessed by the investigator according to RECIST V1.1.
Disease Control Rate according to RECIST 1.1 is the percentage of patients who experienced either a complete response (CR), partial response (PR) or stable disease (SD).
Introductory phase-Progression-free survival (PFS), 6-month PFS rate as assessed by the investigator according to RECIST V1.1.
Progression Free Survival is defined as the time (in months) from the first administration of trial treatment to the date of the first documentation of PD or death due to any cause.
Introductory phase-Drug resistance related mechanism.
Subject is encouraged to provide blood samples (optional) at baseline and disease progression for retrospective analysis to explore mechanisms of resistance in molecular genes to Vebreltinib. Expression of ctDNA in patient blood detected by NGS.
Randomized control period- Second progression-free survival (PFS2) as assessed by the investigators.
Progression Free Survival is defined as the time (in months) from the first administration of trial treatment to the date of the first documentation of PD or death due to any cause.
Randomized control period- Subject Health-Related Quality of Life (HRQoL) assessment: European Five Dimensional Health Scale (EQ-5D-5L).
Health status includes 5 dimensions of mobility, self-care, daily activities, pain or discomfort, anxiety or depression. The five dimensions can be represented by the numbers 1-5. And the EQ-VAS assessment, patient can indicate health status with the numbers 0-100.
Randomized control period- To compare the differences in clinical efficacy of brentinib in combination with platinum-containing two-agent chemotherapy in different MET GCN populations.
To explore the correlation between MET gene copy number (GCN) and clinical efficacy of Vebreltinib. PFS in patients with MET GCN ≥4 or ≥6.
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