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

Overview

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.

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.