AUTHOR=Takamori Shinkichi , Seto Takashi , Yamaguchi Masafumi , Kinoshita Fumihiko , Fujishita Takatoshi , Ito Kensaku , Toyozawa Ryo , Shoji Fumihiro , Okamoto Tatsuro 

TITLE=Case report: Success of tepotinib therapy in overcoming resistance to osimertinib in a patient with EGFR-mutant lung adenocarcinoma with a potential acquired MET exon 14 skipping mutation

JOURNAL=Frontiers in Oncology

VOLUME=12

YEAR=2022

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.965741

DOI=10.3389/fonc.2022.965741

ISSN=2234-943X

ABSTRACT=<p>Osimertinib is a standard therapy for the treatment of advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor gene (<italic>EGFR</italic>) mutations, but most patients with <italic>EGFR</italic>-mutant NSCLC develop secondary resistance to osimertinib. Mesenchymal-epithelial transition gene (<italic>MET</italic>) alterations and oncogene fusions have been identified as the most common mechanisms of resistance to osimertinib. However, <italic>MET</italic> exon 14 skipping mutation (<italic>MET</italic>ex14del) as an acquired resistance to osimertinib has rarely been reported. A non-smoking 76-year-old woman was diagnosed with lung adenocarcinoma in the right lower lobe (cT2bN2M1c [pulmonary and bone metastases], cStage IVB). The primary tumor was submitted to cobas<sup>®</sup> EGFR Mutation Test v2 (Roche Diagnostics Ltd.), next generation sequencing (Oncomine Comprehensive Assay v3; Thermo Fisher Scientific), the AmoyDx<sup>®</sup> Essential NGS panel (Amoy Diagnostics, Xiamen, China), all of which were positive for <italic>EGFR L858R</italic> and <italic>de novo T790M</italic>. We administered daily osimertinib (80 mg/day), and achieved a partial response. However, after 14.0 months, computed tomography showed progression of the primary tumor and lung metastases. Re-biopsy of the primary tumor was conducted, and the specimen was submitted to Archer<sup>®</sup>MET companion diagnostic for detection of <italic>MET</italic>ex14del. Although the primary tumor was negative for <italic>MET</italic>ex14del, the re-biopsy specimen was positive for <italic>MET</italic>ex14del. We validated that the biopsy specimen of the primary tumor at diagnosis before osimertinib administration was negative for <italic>MET</italic>ex14del using local reverse transcription PCR. We administered daily tepotinib (500 mg/day) to the patient as a further-line treatment, and achieved a partial response (tumor shrinkage rate: 34.5%) after 2.0 months, who responded to tepotinib therapy for 8.0 months. We described a patient with lung adenocarcinoma harboring <italic>MET</italic>ex14del as a potential acquired resistance to osimertinib, who responded to subsequent tepotinib therapy. Re-biopsy and re-analysis of genetic profiles should be considered in NSCLC patients who develop osimertinib resistance.</p>