Vebreltinib Plus Furmonertinib in Patients With EGFR-mutated Advanced Non-small Cell Lung Cancer and High PD-L1 Expression

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.

Inclusion criteria

• 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)
• Central laboratory-confirmed PD-L1 Tumor Proportion Score (TPS) ≥50%
• At least one measurable target lesion according to RECIST v1.1 criteria
• Asymptomatic or locally treated stable brain metastases are allowed.
• ECOG performance status 0-1
• Expected survival ≥3 months
• Adequate organ function

Exclusion criteria

• 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)
• 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)
• Require use of strong CYP3A4 inhibitors or inducers within 1 week before first dose or during the study
• Uncontrolled systemic diseases
• Cardiac dysfunction: QTcF >470ms (average of three ECGs) at screening; NYHA functional class ≥3 or LVEF <50%
• Dysphagia, active digestive system disease, or history of major gastrointestinal surgery that may affect drug absorption
• History of acute or chronic pancreatitis or pancreatic surgery
• Other conditions deemed unsuitable for participation by the investigator