Abstract
PurposeOsimertinib, a third-generation epidermal growth factor receptor tyrosine-kinase inhibitor (EGFR-TKI), has demonstrated substantial clinical benefit in patients with non-small-cell lung cancer (NSCLC) who were resistant to early-generation EGFR-TKIs and had acquired a T790M mutation. The aim of our study was to identify the mechanisms underlying resistance to osimertinib and to correlate them with clinical outcomes.MethodsWe retrospectively analyzed patients with advanced NSCLC who received osimertinib for T790M-mutated acquired resistance to prior EGFR-TKIs between March 1, 2017 and December 31, 2018. Patients with paired molecular data of pre-osimertinib and after resistance development, which were not confirmed with small-cell lung cancer (SCLC) transformation, were included in the molecular analysis set.ResultsOf 49 patients evaluated in the molecular analysis set, 24 patients maintained T790M mutation, while 25 patients exhibited T790M-loss. Molecular modifications were identified in 27 of 49 patients including EGFR acquired mutations (C797S, C796S, G796S, V802I, V834L, E758D and G724S), non-EGFR-dependent mutations (PIK3CA, ALK, BRAF, KRAS and TP53), EGFR amplification and MET amplification. At data cutoff, median progression-free survival (PFS) was 9.3 months in the T790M-retain group compared with 7.8 months in T790M-loss patients (P = 0.053). Median PFS was significantly longer in patients with EGFR-dependent resistance mechanism (13.5 months) than in those with alternative pathway activation (8.2 months; P = 0.012).ConclusionsThe study revealed heterogeneous mechanisms of resistance to osimertinib in advanced NSCLC patients and their association with clinical outcomes. Patients who maintained T790M mutation or with EGFR-dependent resistance mechanism had longer clinical outcome benefits.
Highlights
Lung cancer is the leading cause of cancer-related deaths worldwide (Siegel et al 2015)
We collected baseline molecular data from 53 patients treated with osimertinib who had acquired a T790M resistance mutation to first- or second-generation epidermal growth factor receptor (EGFR)-tyrosine-kinase inhibitors (TKIs)
We found the EGFR C797S mutation to be the most common resistance mechanism to osimertinib in our study, and all were concurrent in cis with T790M mutation
Summary
Lung cancer is the leading cause of cancer-related deaths worldwide (Siegel et al 2015). The discovery of smallmolecule anti-cancer drugs, which target specific oncogenic driver mutations, dramatically changed the clinical therapeutic modality for patients with non-small-cell lung cancers (NSCLC). The most common oncogenic driver mutation in lung cancer is epidermal growth factor receptor (EGFR) mutation, which characterizes approximately 40–55% of all NSCLC in Asian patients (Shi et al 2014). Most patients who were treated with first- or second-generation EGFR-TKIs developed acquired resistance after about 8–14 months, and approximately 50–60% of patients had a T790M acquired resistance mutation (Yu et al 2013; Lee et al 2019). Osimertinib is a potent, irreversible, third-generation EGFR-TKI, which inhibits both
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