Mechanisms of Resistance to the Third-generation Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors in Non-small Cell Lung Cancer

Targeted therapy of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKIs) has been the standard modality as first-line treatment of advanced EGFR-mutated non-small cell lung cancer (NSCLC). The third-generation EGFR-TKIs has been approved to overcome the EGFR T790M mutation in patients resistant to the first-or second-generation TKIs, which brings more survival benefits for patients with advanced NSCLC. Unfortunately, acquired resistance inevitably develops after application of approximately 10 months. Heterogeneities of the tumor determines the diversity of resistance. Mechanisms of resistance to the third-generation TKIs includs EGFR-dependent pathway (such as new EGFR mutations, T790M reduction/disappearance and EGFR amplification, etc.) and EGFR-independent pathway (such as bypass pathway activation and histological transformation, etc.). In this paper, we reviewed principle mechanisms of acquired resistance to third-generation EGFR-TKIs

Crizotinib Treatment Combined with Resection and Whole-brain Radiation Therapy in A ROS1 Rearranged Lung Adenocarcinoma with Brain Metastasis: Case Report and Literature Review

Background and objective Lung cancer with brain metastasis had poor prognosis. Crizotinib had been confirmed to be used in ROS1 (C-ros oncogene 1 receptor tyrosine kinase) rearranged lung adenocarcinoma, but its efficacy in lung cancer with brain metastasis was poor due to the blood brain barrier. In the present study, we reported one case of ROS1 fusion lung adenocarcinoma with symptomatic brain matastasis, who was treated with brain metastases resection, crizotinib, and whole brain radiotherapy plus boost to residual brain metastasis. The safety and efficacy was summarized. Methods At first, surgical resection was used to relive mass effect and to biopsy. Then crizotinib (250 mg, bid) was chosen for the existence of ROS1 fusion gene. Whole brain radiotherapy plus boost to residual brain metastasis were used after surgery. Objective response was evaluated by Response Evaluation Criteriation in Solid Tumours (RECIST) v1.1 and brain metastasis were evaluated by computer tomography (CT)/magnetic resonance imaging (MRI) image. Adverse events were evaluated according to Common Terminology Criteria for Adverse Events (CTC AE) v4.0. Results After taking crizotinib for 3 months, the lung lesions were close to complete response (CR), the brain metastasis were partial response (PR), the abdomen metastasis were CR and the symptom of blurred vision relieved. Conclusion Crizotinib combined with palliative operation and radiation therapy (WBRT plus boost to residual brain metastasis) in the treatment of ROS1 fusion gene positive lung adenocarcinoma with symptomatic brain metastases, can effectively control intracranial lesions with good tolerance

Subgroups analysis for EGFR mutation testing (PPS).

<p>Never-smoked means that the subject smoked no cigarettes during his entire lifetime; ex-smoker means that the subject no longer smokes; occasional smoker means that the subject smokes, but not every day; and regular smoker means that the subject smokes every day.</p><p>Subgroups analysis for EGFR mutation testing (PPS).</p

Multivariate analysis using logistic model for EGFR mutation testing (PPS).

<p>OR: odds ratio; CI: confidence interval</p><p>For patients who provided both histology and cytology samples, test results from histology samples were used.</p><p>The significance level for variable selection was 0.01.</p><p>NX in regional lymph nodes were excluded from the analysis.</p><p>The number of patients used for this analysis was 725.</p><p>Multivariate analysis using logistic model for EGFR mutation testing (PPS).</p

Summary of individual mutation types including multiple mutations.

<p>Summary of individual mutation types including multiple mutations.</p

Molecular Epidemiology of EGFR Mutations in Asian Patients with Advanced Non-Small-Cell Lung Cancer of Adenocarcinoma Histology – Mainland China Subset Analysis of the PIONEER study

<div><p>Epidermal growth factor receptor (EGFR) mutations are the strongest response predictors to EGFR tyrosine kinase inhibitors (TKI) therapy, but knowledge of the EGFR mutation frequency on lung adenocarcinoma is still limited to retrospective studies. The PIONEER study (NCT01185314) is a prospective molecular epidemiology study in Asian patients with newly diagnosed advanced lung adenocarcinoma, aiming to prospectively analyze EGFR mutation status in IIIB/IV treatment-naïve lung adenocarcinomas in Asia. We report the mainland China subset results. Eligible patients (≥20 yrs old, IIIB/IV adenocarcinoma and treatment-naïve) were registered in 17 hospitals in mainland China. EGFR was tested for mutations by amplification refractory mutation system using biopsy samples. Demographic and clinical characteristics were collected for subgroup analyses. A total of 747 patients were registered. Successful EGFR mutation analysis was performed in 741, with an overall mutation rate of 50.2%. The EGFR active mutation rate is 48.0% (with 1.3% of combined active and resistance mutations). Tobacco use (>30 pack-year vs. 0–10 pack-year, OR 0.27, 95%CI: 0.17–0.42) and regional lymph nodes involvement (N3 vs. N0, OR 0.47, 95%CI: 0.29–0.76) were independent predictors of EGFR mutation in multivariate analysis. However, even in regular smokers, the EGFR mutation frequency was 35.3%. The EGFR mutation frequency was similar between diverse biopsy sites and techniques. The overall EGFR mutation frequency of the mainland China subset was 50.2%, independently associated with the intensity of tobacco use and regional lymph nodes involvement. The relatively high frequency of EGFR mutations in the mainland China subset suggest that any effort to obtain tissue sample for EGFR mutation testing should be encouraged.</p></div