Abstract 6500: Dependence of EGFR-mutant NSCLC on MET as demonstrated by vebreltinib, a novel and selective brain-penetrating MET kinase inhibitor

Abstract

Abstract Background: Although EGFR inhibitors (EGFRi), preferably osimertinib, have offered substantial benefit for the classical plus T790M EGFR-mutant NSCLC patients, drug resistance develops and poses a critical challenge for long-term survival. The resistance is rooted to either on-target secondary EGFR mutations or compensatory oncogenic pathways bypassing EGFRi intervention, one of which appears to be treatment-acquired MET amplification (METamp). In this study we set out to understand the conditions when the tumor cells become dependent on MET. Methods: NSCLC patient-derived tumor models (PDX) carrying classical and T790M EGFR driver mutations were selected based on EGFRi history and concurrent MET gene copy numbers or RNA expression levels: Type 1) resistant to osimertinib with METamp; Type 2) partially resistant to osimertinib with METamp; and Type 3) sensitive to osimertinib with low MET expression, no METamp. These PDX xenograft mice were treated with vebreltinib (APL-101) at clinically relevant doses as single agent or in combination with osimertinib. The pharmacodynamic effects on EGFR and MET phosphor (P)- and total proteins were analyzed from tumor samples harvested during and at the end of treatments. Results: Vebreltinib single agent inhibited tumor growth of the type-1 PDX. One such PDX was resistant to chemotherapies, BRAF inhibitor and EGFRi including osimertinib, was inhibited by vebreltinib with ED50 of 3 mg/kg (p.o/q.d.). Another such PDX tumor appeared to be eradicated by vebreltinib treatment at 10 mg/kg (p.o/q.d.) and the mice became tumor-free on Day 18 and remained so after dosing stop on day 21 with last observation at study end (Day 70). In comparison, reference METi savolitinib showed only partial tumor size reduction against the same PDX tumor, not as durable as vebreltinib, and did not eradicate tumor growth at the same dose as vebreltinib or in combo with Osimertinib. Re-grown tumor after savolitinib osimertinib combo dosing stop was inhibited completely by vebreltinib follow-on treatment. In the type-2 PDX, tumor growth was partially inhibited by vebreltinib but was completely inhibited by combo of vebreltinib and osimertinib. The anti-tumor activity of vebreltinib in type-1 and type-2 PDX was associated with pharmacodynamic inhibition of P-MET and P-EGFR and MET protein degradation. In the type-3 PDX, tumor growth appeared to be eradicated by osimertinib and not inhibited by vebreltinib. However, addition of vebreltinib suppressed tumor re-growth after osimertinib dosing stop. Conclusion: EGFR-mutant NSCLC resistance to EGFRi may be dependent on MET pathway regardless of acquired METamp, whereas METamp may dictate the degree of MET dependence. Our data supports the hypothesis that adding vebreltinib to EGFRi overcome MET dependent resistance with durable effect or preventing MET dependent resistance to maximize therapeutic benefits. Citation Format: Xiaoling Zhang, Elaine Liu, Yan Song, Peony Yu, Sanjeev Redkar, Guo-Liang Yu. Dependence of EGFR-mutant NSCLC on MET as demonstrated by vebreltinib, a novel and selective brain-penetrating MET kinase inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6500.