Patients with advanced non‑small cell lung cancer with EGFR mutations in addition to complex mutations treated with osimertinib have a poor clinical outcome: A real‑world data analysis

Abstract

The present study aimed to investigate the clinical characteristics and outcomes of patients with advanced non-small cell lung cancer (NSCLC) treated with osimertinib, and focused on the resistance mechanism to osimertinib in a real-world setting. Data from 128 patients with advanced NSCLC who were treated with osimertinib between March 2015 and November 2018 at the Chinese People's Liberation Army General Hospital (Beijing, China) were retrospectively collected, and the associations between mutation types and survival were analysed. In patients treated with osimertinib, the objective response rate reached 60.9% (78/128) and the disease control rate reached 81.3% (104/128), with a median progression-free survival (PFS) time of 12.2 months. A number of complex mutations were identified in the re-analysis after the development of osimertinib resistance, including TP53, KRAS and PIK3CA mutations, epidermal growth factor receptor (EGFR) and MYC amplifications, and mutations associated with SCLC transformation, demonstrating that these mutations may account for osimertinib resistance. The median PFS time for patients with the EGFR T790M mutation (n=41) was significantly longer than that for patients with the T790M mutation and the aforementioned complex mutations (n=13) (16.7 vs. 10.8 months; P=0.001). Patients with a single EGFR mutation (n=87) had a longer median PFS time than those with an EGFR mutation and complex mutations (n=24) (14.63 vs. 6.63 months; P<0.0001). In conclusion, the present study analysed the effects of osimertinib in patients with advanced NSCLC with EGFR mutations, particularly T790M mutations. The results indicated that the efficacy of osimertinib was weakened when patients had complex mutations, suggesting that complex mutations may be responsible for resistance to osimertinib.

Coexpression of ΔNp63/p40 and TTF1 Within Most of the Same Individual Cells Identifies Life-Threatening NSCLC Featuring Squamous and Glandular Biphenotypic Differentiation: Clinicopathologic Correlations

“…SMARCA2 and SMARCA4 gene products were both retained, and this phenotype could have contributed to chemotherapy failure and immune system anergy, 30 also exemplified by scantness of tumor-infiltrating lymphocytes, PD-L1 negativity, ineffectiveness of pembrolizumab (case number 2), or mutanome-derived low neoantigens of the EGFR-altered case number 1. 31 , 32 Furthermore, resistance to EGFR tyrosine kinase inhibitor could have derived from alternative signaling coactivation through IGFR1 , 33 MYC , 34 CCND1 , 35 or CDK2 CNVs, also conferring worse prognosis through TP53 inactivation. 34 , 36 …”

“…31 , 32 Furthermore, resistance to EGFR tyrosine kinase inhibitor could have derived from alternative signaling coactivation through IGFR1 , 33 MYC , 34 CCND1 , 35 or CDK2 CNVs, also conferring worse prognosis through TP53 inactivation. 34 , 36 …”

Pretreatment Neutrophil-to-Lymphocyte Ratio and Smoking History as Prognostic Factors in Advanced Non–Small Cell Lung Cancer Patients Treated with Osimertinib

“…However, it is worth noting that the factors that were non-significant in our multivariate analysis but tended to be prognostic factors in univariate analysis were consistent with those previously reported. Interestingly, Chang et al recently reported that osimertinib efficacy was diminished in a group of patients who had a complex mutation apart from the T790M mutation 23 .…”

Case Report: Outcome of Osimertinib Treatment in Lung Adenocarcinoma Patients With Acquired KRAS Mutations

“…Ortiz et al described a patient who acquired a KRAS G12S mutation with the administration of Osimertinib. Cellular investigation showed that, compared to KRAS wild type transduced cells (PC9 KRAS-wt ), G12S mutation cells (PC9 KRAS G12S ) appeared less sensitive to Osimertinib (9), suggesting that KRAS mutations underlie the resistance to Osimertinib (10)(11)(12). Although KRAS and EGFR mutations are thought to exist in a mutually exclusive manner (13), with the introduction of high-sensitivity large-scale mutation analysis, multiple studies have unveiled the co-existence of EGFR mutations and other dominant mutations such as those of KRAS (14).…”