Non-Small-Cell Lung Cancer
Conditions
Keywords
EGFR mutation, PD-L1 high expression, Vebreltinib, Furmonertinib, Non-Small-Cell Lung Cancer
Brief summary
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.
Detailed description
Patients with advanced NSCLC harboring EGFR mutations and high PD-L1 expression (TPS ≥50%) have primary resistance to third-generation EGFR-TKI monotherapy, with a median PFS of only 3.8-5.0 months, representing an unmet clinical need. Basic research has shown that PD-L1 can inhibit protein tyrosine phosphatase through a non-immune pathway, leading to sustained MET phosphorylation and induction of MET amplification, which mediates EGFR-TKI resistance. This study aims to overcome primary resistance by simultaneously blocking the EGFR and MET pathways through the combination of the MET inhibitor Vebreltinib and the third-generation EGFR-TKI furmonertinib. The study is divided into two phases: the phase Ib dose-escalation phase adopts a parallel cohort design, enrolling two dose groups simultaneously. Each group initially enrolls 3 patients for a 28-day DLT observation period. If DLT ≤1 case, the cohort will be expanded to at least 6 evaluable patients; if DLT ≥2 cases, the cohort will be terminated. The RP2D will be determined comprehensively based on DLT incidence, incidence of grade ≥2 AEs, dose adjustment rate, and 8-week ORR. The phase II efficacy-expansion phase will use the RP2D, with the primary endpoint being median PFS. It is expected that combination therapy will prolong the median PFS from 4 months in historical data to 8.5 months. Patients will receive treatment until disease progression, death, withdrawal of informed consent, or intolerable toxicity. Imaging assessments will be performed every 8 weeks, with an additional tumor assessment on day 28 of cycle 1 for phase Ib patients. Safety assessments include adverse events, laboratory tests, electrocardiograms, and echocardiograms, graded according to NCI-CTCAE v5.0.
Interventions
DRUGVebreltinib
Administered 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
DRUGFurmonertinib 80mg
Administered orally on an empty stomach, 80mg once daily, taken concurrently with Vebreltinib.
Sponsors
Second Affiliated Hospital of Nanchang University
Beijing Pearl Biotechnology Limited Liability Company
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Voluntarily agree to participate in this study and sign a written informed consent form 2. Age ≥18 years and ≤75 years, regardless of gender 3. 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 4. 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) 5. Central laboratory-confirmed PD-L1 Tumor Proportion Score (TPS) ≥50% 6. At least one measurable target lesion according to RECIST v1.1 criteria 7. Asymptomatic or locally treated stable brain metastases are allowed. 8. ECOG performance status 0-1 9. Expected survival ≥3 months 10. Adequate organ function
Exclusion criteria
1. Histological type of small cell lung cancer or mixed small cell lung cancer 2. Prior treatment with any EGFR-TKI or MET-TKI 3. Presence of ALK fusion positive or ROS1 fusion positive 4. 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) 5. Major surgery within 4 weeks before first dose (except brain metastasis resection, which requires ≥2 weeks); thoracoscopic biopsy or mediastinoscopy is excluded (requires ≥1 week) 6. Require use of strong CYP3A4 inhibitors or inducers within 1 week before first dose or during the study 7. Uncontrolled systemic diseases 8. Cardiac dysfunction: QTcF \>470ms (average of three ECGs) at screening; NYHA functional class ≥3 or LVEF \<50% 9. Dysphagia, active digestive system disease, or history of major gastrointestinal surgery that may affect drug absorption 10. History of acute or chronic pancreatitis or pancreatic surgery 11. Other conditions deemed unsuitable for participation by the investigator
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase Ib: Incidence of Dose-Limiting Toxicities as assessed by protocol-defined criteria and CTCAE v5.0 | Up to 28 days from first dose | 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 | Up to 8 weeks from first dose | 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 | Up to 8 weeks from first dose | Proportion of participants requiring dose reduction, interruption, or discontinuation due to treatment-related toxicity |
| Phase II: Investigator-Assessed Progression-Free Survival (PFS) | From first dose until first documented disease progression or death from any cause, assessed up to 24 months | Time from first dose to first documented disease progression or death from any cause, assessed according to RECIST v1.1 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase Ib: Objective Response Rate (ORR) | Up to 8 weeks from first dose | 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) | From first dose until first documented disease progression or death from any cause, assessed up to 24 months | Proportion of participants achieving complete response (CR) or partial response (PR) per RECIST v1.1 |
| Phase II: Disease Control Rate (DCR) | From first dose until first documented disease progression or death from any cause, assessed up to 24 months | Proportion of participants achieving complete response (CR), partial response (PR), or stable disease (SD) per RECIST v1.1 |
| Phase II: Overall Survival (OS) | From first dose until death from any cause, assessed up to 36 months | Time from first dose to death from any cause |
Countries
China
Contacts
CONTACTJing Cai, MD, PhD
CONTACTLiangqian Lv, MD
STUDY_CHAIRAnwen Liu, PhD
Second Affiliated Hospital of Nanchang University
Outcome results
None listed