Author of

• 18974

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  P3.02 - Biology/Pathology (ID 620)

  • Event: WCLC 2017
  • Type: Poster Session with Presenters Present
  • Track: Biology/Pathology
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)

  • 23989

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    P3.02-041 - EGFR Amplification Mediates Resistance to TAS121, A Third-Generation EGFR-TKI, in EGFR T790M-Positive Non-Small Cell Lung Cancer (ID 9168)

    09:30 - 09:30  |  Author(s): S. Kanda
    • Abstract

    Background:
    Third-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have shown promising efficacy in EGFR T790M-mutation-positive non-small cell lung cancer (NSCLC). However, acquired resistance to third-generation EGFR-TKIs has been reported in EGFR T790M-positive NSCLC. The mechanism of resistance to these third-generation EGFR-TKIs has not been fully elucidated. We report a case of metastatic NSCLC harboring an EGFR T790M mutation in which EGFR amplification mediated acquired resistance to TAS121, a novel third-generation EGFR-TKI.
    
    Method:
    A 68-year-old woman with metastatic lung adenocarcinoma, harboring an EGFR L858R mutation, received gefitinib in September 2013. Although the patient achieved a partial response, the tumor progressed and she was treated with 4 cycles of chemotherapy using cisplatin and pemetrexed followed by pemetrexed maintenance therapy. In April 2015, computed tomography (CT) showed disease progression (PD) with liver metastases, and re-biopsy of hepatic lesions was performed. Tumor genotyping with the PNA LNA PCR-Clamp method revealed an original mutation of EGFR L858R in exon 21 and a secondary mutation of EGFR T790M in exon 20. Tumor progression was noted after completion of one cycle of docetaxel, and she was enrolled into a phase 1 trial of TAS121 in June 2015. Although she showed a partial response to TAS121, PD was confirmed on CT, which indicated progression of liver metastases. She discontinued TAS121 and received supportive care. She died in October 2015, and an autopsy was performed. To determine the mechanism of resistance to TAS121, we performed next-generation sequencing (NGS) (NCC OncoPanel, Agilent) with post-TAS121 samples obtained from progressing liver lesions during TAS121 treatment. We also conducted fluorescence in situ hybridization (FISH) analysis for EGFR in pre-TAS121 liver lesions, post-TAS121 liver lesions, and autopsy samples from the lung and liver. The study protocol was approved by the Ethical Review Committee of the National Cancer Center Hospital.
    
    Result:
    NGS with the post-TAS121 liver samples showed EGFR amplification in the tumor cells (log2 ratio 2.2). On FISH analysis, EGFR amplification was not detected in the pre-TAS121 liver lesions (the ratio of EGFR signals to CEP signals 1.7), but was detected in the post-TAS121 liver lesions (2.1) and those obtained at autopsy (3.0). EGFR amplification was not detected in the autopsy samples of the lung lesions (1.0), which remained stable during TAS121 treatment.
    
    Conclusion:
    Our case revealed that genomic instability of the EGFR domain contributed to the development of resistance to TAS121. Further molecular analysis is warranted to understand the role of EGFR amplification in acquired resistance to third-generation EGFR-TKIs.