Acquired resistance to osimertinib in patients with non-small-cell lung cancer: mechanisms and clinical outcomes

Yuxin Mu, Xuezhi Hao, Puyuan Xing, Xingsheng Hu, Yan Wang, Teng Li, Jinyao Zhang, Ziyi Xu, Junling Li, Yuxin Mu, Xuezhi Hao, Puyuan Xing, Xingsheng Hu, Yan Wang, Teng Li, Jinyao Zhang, Ziyi Xu, Junling Li

Abstract

Purpose: Osimertinib, 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.

Methods: We 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.

Results: Of 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).

Conclusions: The 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.

Keywords: Non-small-cell lung cancer; Osimertinib; Resistance mechanism; T790M.

Conflict of interest statement

The authors have no conflict of interest.

Figures

Fig. 1
Fig. 1
Flowchart of patient selection in the molecular analysis set. NSCLC non-small-cell lung cancer, PD progressive disease, SCLC small-cell lung cancer
Fig. 2
Fig. 2
Molecular modification after acquired resistance to osimertinib
Fig. 3
Fig. 3
PFS in patients with T790M-retain or T790M-loss after progression of osimertinib therapy (a), in patients with EGFR-dependent resistance mechanism or bypass activation after progression (b). TD in patients with T790M-retain or T790M-loss after progression of osimertinib (c), in patients with an EGFR-dependent resistance mechanism or bypass activation after progression (d). PFS progression-free survival, TD treatment duration, CI confidence interval. Tick marks indicate censored observations
Fig. 4
Fig. 4
Treatment duration in 49 patients in the molecular analysis set

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