Mechanisms of osimertinib resistance and emerging treatment options. (September 2020)

• Record Type: Journal Article
• Authors: Schmid, Sabine; Li, Janice J.N.; Leighl, Natasha B.
• Is Part Of: Lung cancer. Volume 147(2020)
• Page Start: 123
• Page End: 129
• Publication Date: 2020-09
• Subjects: EGFR epidermal growth factor receptor -- ICI immune checkpoint inhibitors -- NSCLC non-small-cell lung cancer -- ORR overall response rate -- OS overall survival -- PFS progression-free survival -- RR response rate -- SCLC small cell lung cancer -- TKI tyrosine kinase inhibitor -- TMB tumor mutational burden -- VEGF vascular endothelial growth factor; Osimertinib -- Mechanisms of resistance -- MET-mediated resistance -- Tissue and plasma based molecular testing; Lungs -- Cancer -- Periodicals; Lung Neoplasms -- Abstracts; Lung Neoplasms -- Periodicals; Poumons -- Cancer -- Périodiques; Lungs -- Cancer; Periodicals; Electronic journals; Electronic journals; 616.99424
• DOI: 10.1016/j.lungcan.2020.07.014
• Languages: English
• ISSNs: 0169-5002

Abstract

Highlights: EGFR -dependent and independent resistance mechanisms to osimertinib are described. Chemotherapy remains the standard of care after osimertinib failure outside trials. Early trials show promising results for targeting specific resistance mechanisms. Abstract: Osimertinib is an irreversible EGFR-tyrosine kinase inhibitor initially approved for treatment of EGFR -positive patients exhibiting a T790 M resistance mutation in the second line setting and now emerging as the new standard of care for all EGFR positive patients as first-line treatment. Despite its efficacy, resistance to osimertinib inevitably develops and mechanisms of resistance can be grouped broadly in two categories: on-target EGFR -dependent and off-target EGFR -independent mechanisms. EGFR -dependent resistance typically is associated with additional EGFR -mutations disrupting the osimertinib binding through changes in the binding site by allosteric/ conformational transitions; EGFR -independent mechanisms are related mostly to alternate pathway activation or aberrant downstream signalling but also to lineage plasticity leading to small cell transformation. MET amplification is the most frequent off-target mechanisms of resistance to osimertinib treatment and recently published early trials show promising results for combination of MET -inhibitors with osimertinib upon development of resistance. This review will summarize mechanisms of resistance overall and in different treatment settings and will focus on potential new treatment options targeting specific acquired alterations after osimertinib failure.