Vebreltinib plus PLB1004 in EGFR-mutated NSCLC with acquired MET amplification or overexpression after failure on EGFR-TKI treatment: A phase Ib/II study.

8632 Background: MET amplification (METamp) or overexpression (METov) is the most common “off-target” mechanism that drives resistance to EGFR-TKIs. Vebreltinib is a potent and selective c-Met inhibitor, while PLB1004 is an oral, potent, irreversible, and selective EGFR-TKI with potent blood-brain barrier penetration and broad tyrosine kinase activity. Methods: This open-label, multicenter phase Ib/II study evaluated vebreltinib and PLB1004 in Chinese patients (pts) with EGFR-mutated NSCLC with METamp or METov after EGFR-TKI failure. Patients were eligible if they were METamp positive by NGS or FISH, or METov by IHC (3+). Phase Ib part established vebreltinib 150 mg BID and PLB1004 80 mg QD as the RP2D. Phase II further investigated the efficacy and safety of RP2D in four cohorts, stratified by MET gene status and previous EGFR-TKIs: 1: Progression after 1st-/2nd-generation EGFR-TKIs, T790M (-), with METamp (GCN ≥ 5 and/or MET/CEP7 ≥ 2 by FISH). 2: Progression after 3rd-generation EGFR-TKIs with METamp (GCN ≥ 5 and/or MET/CEP7 ≥ 2 by FISH). 3: Progression after EGFR-TKIs, T790M (-) for 1st-/2nd-generation TKIs, with METamp (GCN < 5 and MET/CEP7 < 2 by FISH, but positive by NGS). 4: Progression after EGFR-TKIs (1st-/2nd-/3rd-generation), T790M (-) for 1st-/2nd-generation TKIs, with METov (IHC 3+), and without METamp (GCN < 5 and MET/CEP7 < 2 by FISH, and negative by NGS). Results: There were 56 pts enrolled, with 13 in phase Ib and 43 in phase II (2/35/1/5 in four cohorts). The mean age was 58.8 ± 8.9 years, and 53.6% were male with the majority of patients having stage IV disease (98.2%). Prior EGFR-TKIs included 1st- (7.1%), 2nd- (5.4%), and 3rd-generation (87.5%) TKIs. Confirmed overall response rate (ORR) was 50.0%, and all cases (n=28) were partial response (PR). Disease control rate (DCR) was 89.3% (50/56). The median progression-free survival (mPFS) was 9.9 months. In 19 pts with brain metastases, ORR was 42.1% and mPFS was 9.5 months. There were 47 METamp-positive pts as detected by NGS (regardless of FISH), and these pts had an ORR of 53.2% and mPFS of 9.6 months. All pts (100%) reported treatment-related adverse events (TRAEs), with grade ≥ 3 TRAEs in 11 pts (19.6%). Serious adverse events were observed in 5 pts (8.9%), all of which were treatment-related. None discontinued treatment or died due to TRAE. The most common TRAEs were rash (64.3%), oedema peripheral (60.7%) and paronychia (48.2%). Conclusions: Vebreltinib and PLB1004 at RP2D demonstrates notable efficacy and manageable safety in EGFR-mutated NSCLC with METamp or METov after EGFR-TKIs failure. Findings from our phase Ib+II data suggest that NGS reported METamp+ could be utilized to identify target patients to receive combination of PLB1004 + Vebreltinib. Further studies are warranted to confirm these findings. Clinical trial information: NCT06343064 .