Abstract 6000: Vabametkib plus lazertinib shows promising antitumor activity in advanced NSCLC with MET amplification resistant to 3rd-gen EGFR-TKIs

MET amplification (METamp) can emerge as a bypass mechanism of resistance to EGFR tyrosine kinase inhibitors (TKIs), occurring in up to 26% of patients with EGFR TKI-resistant EGFR-mutant non-small cell lung cancer (NSCLC). ABN401 (vabametkib), a highly specific MET inhibitor, is undergoing phase 2 trial (NCT04052971) and shows positive response in metastatic NSCLC patients harboring MET exon 14 skipping. Lazertinib, a 3rd Gen EGFR TKI, is effective against EGFR mutations, including common resistance mutations like T790M. To explore the potential of combination therapy of vabametkib and lazertinib in NSCLC patients, we evaluated the cytotoxic response of vabametkib in combination with various EGFR TKIs in NSCLC cell lines. To explore the feasibility of combination therapy in NSCLC patients, we assessed the drug-drug interaction (DDI) potential of vabametkib with various TKIs, focusing primarily on 3rd Gen EGFR TKI, according to ‘In vitro drug interaction studies -Cytochrome P450 enzyme- and transporter-mediated drug interactions’ (Guidance for Industry, US FDA). Additionally, the anti-tumor efficacy of vabametkib plus 3rd Gen EGFRTKI was further validated in EGFR-mutant patient-derived xenograft (PDX) models. The combination of vabametkib and 3rd Gen EGFR TKIs demonstrated strong anti-tumor efficacy (96.6% TGI) in EGFR mutants and high MET-amplified PDX model. In contrast, vabametkib alone and 3rd Gen EGFR TKI alone did not show statistical significance. In drug interaction studies using the basic static model and physiologically-based pharmacokinetic (PBPK) modeling, vabametkib did not alter the PK of the co-administered TKIs. Especially ,the potential for DDI between vabametkib and lazertinib was found to be negligible. These findings support the safe and effective use of vabametkib in combination with lazertinib and other TKIs across a broad range of therapeutic applications. These findings support potential clinical benefits of combination therapy of vabametkib and 3rd Gen EGFR TKI in patients with MET-amplified/overexpressed, EGFRm advanced NSCLC with disease progression after 1st line 3rd Gen EGFR TKIs. Consequently, a clinical trial is underway to evaluate the efficacy and safety of combining vabametkib with lazertinib. The ABN401-003 trial, a phase-2 study comprising cohort-2, is an open-label, multicenter investigation aiming to assess the efficacy and safety in patients who have experienced progression on 1st line 3rd-Gen EGFR-TKIs. Cohort-2 consists of three parts: Part 1 (safety run-in), Part 2 (a randomized dose optimization), and Part 3 (a randomized clinical trial comparing the optimal dose of vabametkib in combination therapy with standard of care). Citation Format: Nirmal Rajasekaran, Yeongmun Kim, Dawoon Jeong, Heesoo Ahn, Jeesun Kim, Yanghee Kim, Sangsuk Lee, Sunhye Im, Young Kee Shin, Jun Young Choi, Na Young Kim. Vabametkib plus lazertinib shows promising antitumor activity in advanced NSCLC with MET amplification resistant to 3rd-gen EGFR-TKIs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6000.