Fatal Disease Progression Driven by Acquired MET Amplification After EGFR-TKI Therapy in EGFR- and RBM10-Mutant Lung Adenocarcinoma

Abstract: Although mesenchymal–epithelial transition proto-oncogene ( MET) amplification is a common resistance mechanism in targeted therapy for lung cancer, rapid disease progression associated with this resistance mechanism in patients with epidermal growth factor receptor ( EGFR ) mutation has scarcely been reported. Herein, we report a fatal case of lung adenocarcinoma that rapidly progressed after failure of EGFR-tyrosine kinase inhibitor treatment following the emergence of MET amplification. A 62-year-old man was diagnosed with metastatic lung adenocarcinoma containing mutations in EGFR exon L858R and RNA-binding motif 10. He received afatinib as frontline treatment and showed a partial response; however, the right lung lesion progressed after 14 months of treatment. Although the drug was maintained after salvage segmentectomy of the lesion, lung nodules and pleural effusion developed shortly thereafter. Because EGFR testing using resected tissue showed only the original mutation, we switched his regimen to pemetrexed and carboplatin. However, the disease rapidly progressed with a very large mass in the right lung and massive pleural effusion, which led to death within 7 weeks of treatment. Next-generation sequencing was performed at the time of first progression and second progression revealed acquired MET amplification (copy number gain 15.5 and 9.1, respectively) in addition to baseline mutations. Although an association between MET amplification and rapidly progressive lung cancer has been predicted previously, to the best of our knowledge, this is the first report on the potential contribution of other mutations, such as those in RNA-binding motif 10, during MET -driven rapid progression. Our report highlights the importance of more active utilization of molecular profiling for the emergence of resistance during tyrosine kinase inhibitor use and the early identification of MET amplification and timely initiation of MET-targeted therapy, such as MET inhibitors in combination with EGFR-TKIs, to potentially mitigate rapid disease progression and clinical deterioration. Keywords: lung cancer, EGFR-TKI , MET amplification, RBM10, next-generation sequencing