P3.01-60 A Novel MET D1246H Mutation After Progression of EGFR-TKI/MET Inhibitor Combined Therapy in a NSCLC Patient with Acquired MET Amplification

Abstract

MET amplification was the second common acquired resistance mechanism to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) in patients with advanced non-small cell lung cancer (NSCLC). It may be benefited by combinations of EGFR TKIs and the MET inhibitor. However, the acquired resistance mechanism to this combination therapy remains to be identified. A patient with advanced lung adenocarcinoma harboring both EGFR L858R mutation and acquired MET amplification, progressed after the combination of MET inhibitor gefitinib and EGFR-TKI crizotinib. The next generation sequencing (NGS) based circulating tumor DNA (ctDNA) assay was performed. Results were applied to discover a novel mutation after resistance to target therapy. A 52-year-old Chinese never-smoking woman with EGFR L858R mutant adenocarcinoma had systemic progression after gefitinib, pemetrexed/platinum-pemetrexed maintenance, and SBRT local progressed lung metastasis. The NGS-based ctDNA analysis revealed that the MET amplification was found besides continually present EGFR L858R mutation. The patient started treatment with crizotinib (250mg Bid) and gefitinib (250mg/d). The NGS was performed after progression of this combined therapy. It revealed two novel mutations of MET D1246H (MAF 0.9%) and EGFR T790M mutation (MAF 0.2%), in addition to the initial presence of EGFR L858R mutation (MAF 9.8%) and MET amplification (LR 6.7). The patient started to receive osimertinib (80mg/d) and cabozantinib (20mg/d and later increased to 40mg/d). The patient tolerated this combination well while the symptoms did not relief. After 8 weeks, the re-scan CT showed pulmonary lesions progressed. The NGS-based ctDNA assay performed again and it showed that L858R mutation (MAF 11.4%) and MET amplification (LR 4.9) presented while the EGFR T790 mutation and MET D1246H disappeared. Then the patient received osimertinib (80mg/d) and crizotinib (250mg Bid). The patient felt symptoms improved greatly after 1 week’s administration and CT scan after 2 months showed good response. However, one more month later, the patient felt deteriorative symptoms of dyspnea and chest X-ray showed increasing pleural effusion, progressing pulmonary lesions. The NGS-based ctDNA assay at that time revealed that MET D1246H (MAF 14.4%) appeared again, in addition to the initial presence of EGFR L858R mutation (MAF 22.4%) and MET amplification (LR 8.2) while the EGFR T790 mutation was not existed. However, the patient died because of respiratory failure. MET mutations might be a potential acquired resistance mechanism after progression during EGFR-TKI /MET inhibitor combined therapy in advanced NSCLC patient with primary EGFR mutation and secondary acquired MET amplification.