Potent Antitumor Activity of Ensartinib in Met Exon 14 Skipping-Mutated Non-Small Cell Lung Cancer

Authors

Yang Xia
Rui Jin
Miao Li
Fen Lan
Hao Zhu
Yinghui Yu
Da Miao
Qiyuan Wang
Yi Zhou
Giovanni Selvaggi
Songmin Ying
Jianjun Zhang
Huahao Shen
Xiuning Le
Wen Li

Publication Date

5-1-2023

Journal

Cancer Letters

DOI

10.1016/j.canlet.2023.216140

PMID

36948240

Abstract

Met proto-oncogene exon 14 skipping (METex14) mutations are targetable driver genes in approximately 3% of non-small-cell lung cancers (NSCLCs). Ensartinib, a type Ia MET inhibitor, is a multi-kinase inhibitor that has been approved for ALK-positive NSCLCs. Ensartinib was administered for compassionate use (cohort 1) and in a phase II clinical trial (cohort 2) to patients with METex14 mutant NSCLCs, with ORR as a primary endpoint. Molecular simulation was conducted to evaluate ensartinib c-MET interaction, and cell lines, patient-derived organoids (PDOs), and xenograft models were used to test the effectiveness of ensartinib. Among 29 evaluable patients, the ORR and DCR of ensartinib were 67% and 94% in cohort 1, and 73% and 91% in cohort 2. The median DoR was 6.8 months and median PFS was 6.1 months in the total population. Rash was the most common drug-related adverse event, and peripheral edema of any grade was reported in only 9% patients. Molecular simulations indicated favorable binding of ensartinib to c-MET. The kinase assay demonstrated an IC50 of 7.9 nM of ensartinib against METex14 protein. In vitro, Hs746T (METex14 mutation) and EBC-1 (MET amplification) cells were sensitive to ensartinib, with IC50 values of 31 and 44 nM, respectively. Ensartinib exhibited comparable inhibitory effects on cell migration as crizotinib and tepotinib in both cell types. In vivo, ensartinib suppressed the growth of Hs746T cells. Ensartinib also potently inhibited the viability of PDOs. Overall, Ensartinib exhibited substantial antitumor effects against METex14 mutant NSCLCs in preclinical and clinical trials, with relatively low peripheral edema rates.

Keywords

Humans, Carcinoma, Non-Small-Cell Lung, Crizotinib, Exons, Lung Neoplasms, Mutation, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-met, Animals, MET exon 14 skipping mutation, MET inhibitor, NSCLC

Published Open-Access

yes

Recommended Citation

Xia, Yang; Jin, Rui; Li, Miao; et al., "Potent Antitumor Activity of Ensartinib in Met Exon 14 Skipping-Mutated Non-Small Cell Lung Cancer" (2023). Faculty, Staff and Student Publications. 5220.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5220