This is a single-arm, exploratory phase Ib/II study with a seamless design to evaluate the safety and efficacy of Vebreltinib combined with furmonertinib as first-line treatment in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring EGFR-sensitive mutations (exon 19 deletion or L858R) and PD-L1 TPS ≥50%.
In the phase Ib part, 12-16 patients will be enrolled to compare the safety and early efficacy of Vebreltinib 100mg BID versus 150mg BID in combination with furmonertinib 80mg QD, and to determine the recommended phase II dose (RP2D).
In the phase II part, 37 patients (including evaluable patients from the RP2D cohort in phase Ib) will receive treatment at the RP2D. The primary endpoint is investigator-assessed median progression-free survival (PFS). Secondary endpoints include objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. Exploratory endpoints will analyze the correlation between baseline MET abnormalities and treatment efficacy.
Voluntarily agree to participate in this study and sign a written informed consent form
Age ≥18 years and ≤75 years, regardless of gender
Histologically or cytologically confirmed locally advanced (stage IIIB-IIIC), metastatic, or recurrent (stage IV) non-small cell lung cancer, not amenable to surgical resection and definitive concurrent chemoradiotherapy
No prior systemic antineoplastic therapy for advanced/metastatic disease Histologically or cytologically confirmed EGFR-sensitive mutations (exon 19 deletion or exon 21 L858R point mutation)
Histological type of small cell lung cancer or mixed small cell lung cancer
Prior treatment with any EGFR-TKI or MET-TKI
Presence of ALK fusion positive or ROS1 fusion positive
Other active malignant tumors (except completely resected carcinoma in situ, basal cell or squamous cell skin cancer, or tumors with no recurrence for ≥3 years after curative treatment)
Single group
Vebreltinib
DrugAdministered orally on an empty stomach, 100mg or 150mg twice daily, with an interval of 12±4 hours between morning and evening doses. Dose adjustments are allowed based on toxicity, down to a minimum of 100mg BID
Furmonertinib 80mg
DrugAdministered orally on an empty stomach, 80mg once daily, taken concurrently with Vebreltinib.
Phase Ib: Incidence of Dose-Limiting Toxicities as assessed by protocol-defined criteria and CTCAE v5.0
Number of participants experiencing dose-limiting toxicities during the dose-escalation phase of the study, based on CTCAE v5.0 grading and protocol-specified DLT criteria
Phase Ib: Incidence of Grade ≥2 Treatment-Emergent Adverse Events as assessed by CTCAE v5.0
Number of participants experiencing Grade 2 or higher treatment-related adverse events
Phase Ib: Rate of dose reduction, interruption, or discontinuation due to treatment-related adverse events as assessed by CTCAE v5.0
Proportion of participants requiring dose reduction, interruption, or discontinuation due to treatment-related toxicity
Phase II: Investigator-Assessed Progression-Free Survival (PFS)
Time from first dose to first documented disease progression or death from any cause, assessed according to RECIST v1.1
Phase Ib: Objective Response Rate (ORR)
Proportion of participants achieving complete response (CR) or partial response (PR) per RECIST v1.1, assessed at 8 weeks after first dose
Phase II: Objective Response Rate (ORR)
Proportion of participants achieving complete response (CR) or partial response (PR) per RECIST v1.1
Phase II: Disease Control Rate (DCR)
Proportion of participants achieving complete response (CR), partial response (PR), or stable disease (SD) per RECIST v1.1
Phase II: Overall Survival (OS)
Time from first dose to death from any cause
Exploratory: Objective response rate by baseline MET aberration status as assessed by RECIST 1.1
Proportion of participants achieving complete response (CR) or partial response (PR), stratified by presence or absence of baseline MET aberrations (MET amplification or MET overexpression)
Exploratory: Objective response rate by MET overexpression level as assessed by RECIST 1.1
Proportion of participants achieving CR or PR, stratified by MET overexpression level ( IHC 1+,2+, 3+) measured by immunohistochemistry
Exploratory: Progression-free survival by baseline MET aberration status as assessed by RECIST 1.1
Time from first dose to first documented disease progression or death from any cause, whichever occurs first, stratified by presence or absence of baseline MET aberrations (MET amplification or MET overexpression)
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Second Affiliated Hospital of Nanchang University
Lead sponsor
Beijing Pearl Biotechnology Limited Liability Company
Collaborator
