Author of

• 20167

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  P2.03 - Chemotherapy/Targeted Therapy (ID 704)

  • Event: WCLC 2017
  • Type: Poster Session with Presenters Present
  • Track: Chemotherapy/Targeted Therapy
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)

  • 23283

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    P2.03-012 - Characterization of the Efficacies of Osimertinib and Nazartinib against Cells Expressing Epidermal Growth Factor Receptor Mutations (ID 8067)

    09:30 - 09:30  |  Presenting Author(s): Keita Masuzawa
    • Abstract

    Background:
    A significant subgroup of non-small cell lung cancers harbor epidermal growth factor receptor (EGFR) mutations. Third-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs) were developed to overcome EGFR T790M-mediated resistance to first- and second-generation EGFR-TKIs. Third-generation EGFR-TKIs, such as osimertinib and nazartinib, are effective for patients with EGFR T790M mutation. However, there are no direct comparison data to guide the selection of a third-generation EGFR-TKI for patients with different EGFR mutations. We previously established an in vitro model to estimate the therapeutic windows of EGFR-TKIs by comparing their relative efficacies against cells expressing mutant or wild type EGFRs. The present study used this approach to characterize the efficacies of third-generation EGFR-TKIs and compare them with those of other EGFR-TKIs such as erlotinib and afatinib.
    
    Method:
    We evaluated the drug sensitivity and EGFR downstream signals of human lung cancer cell lines (PC9, H3255, H1975, PC9ER, BID007) and Ba/F3 cells harboring clinically relevant EGFR mutants for first (erlotinib), second (afatinib) and third (osimertinib and nazartinib) generation EGFR-TKIs with MTS assay and western blotting. An in vitro model of mutation specificity was created by calculating the ratio of IC50 values between mutated and wild type EGFR.
    
    Result:
    Among various mutation types, sensitivities to EGFR-TKI were different. For classic EGFR mutations, exon 19 deletion and L858R, with or without T790M osimertinib showed lower IC50 values and wider therapeutic windows than nazartinib. Afatinib, osimertinib and nazartinib inhibited the phosphorylation of EGFR, AKT, and ERK for human cell lines and Ba/F3 cells harboring these EGFR mutations. For uncommon EGFR mutations, G719S or L861Q, afatinib showed lowest IC50 values. For G719S+T790M or L861Q+T790M, the IC50 values of osimertinib and nazartinib were around 100 nM, 10 to 100 fold higher than those of classic+T790M mutations. On the other hand, osimertinib and nazartinib showed similar efficacies in cells expressing EGFR exon 20 insertions. For C797S mutations, no EGFR-TKIs demonstrated efficacy.
    
    Conclusion:
    The present study provides fundamental osimertinib and nazartinib sensitivity/resistance data in cells expressing a range of EGFR mutations, including uncommon EGFR mutations. The findings highlight the diverse mutation selective sensitivity pattern of EGFR-TKIs. These data may help to inform the selection of EGFR-TKIs for non-small cell lung cancer patients harboring EGFR mutations.