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Brief Report: Heterogeneity of Acquired Resistance Mechanisms to Osimertinib and Savolitinib

 Sun Min Lim  ;  San-Duk Yang  ;  Sangbin Lim  ;  Hyo Sup Shim  ;  Byoung Chul Cho 
 JTO Clinical and Research Reports, Vol.2(6) : 100180, 2021-06 
Journal Title
JTO Clinical and Research Reports
Issue Date
MET ; Osimertinib ; Resistance ; Savolitinib
Introduction: MET amplification is a frequently observed mechanism of resistance to osimertinib, and coinhibition strategy of MET and EGFR revealed promising results in recent clinical trials. Nevertheless, acquired resistance mechanisms to combined EGFR and MET inhibition are poorly understood. In this study, we investigated the mechanisms of acquired resistance to osimertinib and savolitinib by using pretreatment and post-treatment tissue analysis.

Methods: Whole-exome sequencing was performed in EGFR-mutant, MET-amplified patients who received osimertinib and savolitinib using tissues obtained both before and after therapy. All patients achieved partial response or durable stable disease to osimertinib and savolitinib before developing acquired resistance.

Results: After progression on osimertinib and savolitinib, whole-exome analysis revealed MET-dependent mechanisms of resistance, such as acquired MET p.D1246H mutation, MET p.Y1230C mutation, and MET copy number gain. As for MET-independent mechanisms, development of ERBB2 mutation and amplification and copy number gains in amplifications in CCNE, CCND1, CDK6, and EGFR were observed. Patient 2 harbored an acquired PIK3CA p.H1047R mutation in which resistance could be overcome with combination of PI3K inhibitor and osimertinib in the patient-derived xenograft model.

Conclusions: Our study reveals that acquired resistance to savolitinib plus osimertinib can occur from both MET-dependent and MET-independent mechanisms.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
Yonsei Authors
Shim, Hyo Sup(심효섭) ORCID logo https://orcid.org/0000-0002-5718-3624
Lim, Sun Min(임선민)
Cho, Byoung Chul(조병철) ORCID logo https://orcid.org/0000-0002-5562-270X
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