Osimertinib is a third‐generation epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitor (TKI) that has shown marked antitumor activity in patients with EGFR‐mutated non–small‐cell lung cancer (NSCLC). However, these effects are transient and most patients develop resistance. Reversible drug‐tolerant persister (DTP) cells are defined as a small subpopulation of cells with markedly reduced sensitivity and non‐genetic acquired resistance to EGFR‐TKIs. Notch is a transmembrane receptor that plays an important role in tumorigenesis. We previously reported that there is significant crosstalk between the Notch and EGFR pathways in NSCLC. Moreover, the Notch pathway is associated with resistance to previous‐generation EGFR‐TKIs. However, the role of Notch in osimertinib resistance is not fully understood. In this study, we evaluated whether Notch is involved in osimertinib resistance. We show that NOTCH1 and Notch target genes are upregulated in osimertinib DTP cells, and that the addition of a γ‐secretase inhibitor (GSI), a Notch inhibitor, impairs drug‐tolerant persistence in vitro and in vivo. Compared with osimertinib, combined GSI and osimertinib suppress phospho‐ERK partly by enhancing DUSP1 expression. Furthermore, Notch1 and HES1 were upregulated after EGFR‐TKI treatment in half of human EGFR‐mutated NSCLC tumor tissues. These results suggest that the combination of GSI and osimertinib may be a potential therapy for EGFR‐mutated NSCLC.
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Purpose
Immune‐checkpoint inhibitors (ICIs) are effective against advanced non‐small cell lung cancer (NSCLC). However, whether the efficacy and safety of ICI treatment in elderly patients are similar to those in younger patients is unclear. This study was designed to address this question.
Methods
We enrolled patients who received ICI monotherapy in Japan between December 2015 and December 2017; those ≥75 years of age comprised the elderly group. We compared the efficacy and safety of ICI monotherapy in elderly patients with those in younger patients and explored prognostic factors in elderly patients.
Results
We enrolled 676 patients; 137 (20.3%) were assigned to the elderly group. The median age of the elderly and younger groups was 78 (range, 75–85) and 66 (range, 34–74) years. The median progression‐free survival (4.8 months vs. 3.3 months, p = 0.1589) and median overall survival (12.3 months vs. 13.0 months, p = 0.5587) were similar between the elderly and younger groups. Multivariate analysis revealed that a significantly better OS in the elderly group was associated with better responses to first‐ or second‐line ICI treatment (p = 0.011) and more immune‐related adverse events (irAEs) (p = 0.02). IrAEs that led to ICI discontinuation occurred in 34 of 137 patients (24.8%) in the elderly group, and their survival was significantly higher than that in those who did not have irAEs.
Conclusion
ICI is also effective in elderly NSCLC patients, and treatment discontinuation due to irAEs may be a good prognostic marker.
PCR testing of nasopharyngeal swab samples is used for the diagnosis of coronavirus disease 2019 (COVID-19) and for determining timing of discharge. The viral load usually declines at convalescent phase, but sometimes remained positive for a long time even after relief of symptoms. In this study, we identified older age is associated with sustained detection of SARS-CoV-2 in nasopharyngeal swab samples.
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