EP1.14-10 Investigation of Mechanisms of Acquired Resistance to Afatinib with Plasma DNA in Non-Small Cell Lung Cancer Patients

Abstract

Afatinib, the 2nd generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) has been evidenced better efficacy compared to 1st generation EGFR-TKI by phase III studies, but the problem is to acquire resistance approximately one year after treatment. The detail mechanisms of acquired resistance to afatinib has not clarified, although T790M was also detected at time to acquired resistance. Recently, the 3rd generation EGFR-TKI, osimertinib has been approved as the first line setting. As for the mechanisms of acquired resistance to osimertinib as 1st line, various kinds of pathway beside EGFR contributed, suggesting difficulty to select next treatment strategy after osimertinib. Considering how to use 1st, 2nd and 3rd approximately, it has been reported that longer PFS was shown among the patients who were treated with osimertinib following afatinib, compared to 1st generation EGFR-TKI. Based on these evidences, we hypothesize that mechanisms of acquired resistance to afatinib may be less genetic alterations compared to osimertinib, and these alterations could be limited to EGFR pathway, resulting in EGFR-TKI sequencing, from afatinib to osimertinib showed better prognosis. Because the concept of tumor evolution showed that the number and kind of genetic alterations were increased after treatment modifications, comprehensive assay system is indispensable for evaluation of acquired resistance. Moreover, non-invasive assay system such as liquid biopsy is needed since distant metastases are often observed in advanced lung cancer patients. Guardant360™, a high sensitive digital sequencing system with plasma DNA has been developed by Guardant Health, enable to detection of SNV of 73 genes, in/del of 23 genes, amplification of 18 genes, and fusions of 6 genes. The assay system enables us to detect 0.03% allele fraction. The purpose of this study is to clarify mechanism of acquired resistance to afatinib with liquid biopsy to determine best EGFR-TKI sequencing. Study Design Prospective observational study Primary objective To determine mechanisms of acquired resistance to afatinib with plasma DNA Target sample size 40. We are planning to compare with the results of patients who acquired resistance to osimertinib with liquid biopsy performed in FLAURA. So far, 29 patients acquired resistance to afatinib, and we collected these blood samples. Sample preparation Collection of samples 1. before afatinib treatment and at PD to afatnib 2. collection of 5ml blood with sodium citrate collection tube Genomic examinations NGS is performed in Guardant Health. This study had finished enrollment and under analysis now. Comprehensive analysis are needed to clarify the mechanisms of acquired resistance to afatinib to facilitate consideration of the best sequence of EGFR-TKI.