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

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)


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.

Original languageEnglish
Article number100180
JournalJTO Clinical and Research Reports
Issue number6
Publication statusPublished - 2021 Jun

Bibliographical note

Publisher Copyright:
© 2021 The Authors

All Science Journal Classification (ASJC) codes

  • Oncology
  • Pulmonary and Respiratory Medicine


Dive into the research topics of 'Brief Report: Heterogeneity of Acquired Resistance Mechanisms to Osimertinib and Savolitinib'. Together they form a unique fingerprint.

Cite this