Author of

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  P2.13 - Targeted Therapy (Not CME Accredited Session) (ID 962)

  • Event: WCLC 2018
  • Type: Poster Viewing in the Exhibit Hall
  • Track:
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall

  • 25706

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    P2.13-32 - TAK-788 is a Novel and Potent Tyrosine Kinase Inhibitor with Selective Activity Against EGFR/HER2 (ID 12643)

    16:45 - 18:00  |  Author(s): Rachael Brake
    • Abstract
    • Slides

    Background
    

    Dysregulation of the EGFR family member HER2 (human epidermal growth factor receptor 2) plays an important role in many cancers. HER2 exon 20 in-frame insertion mutations occur in 2−4% of non-small cell lung carcinomas (NSCLC). Despite current HER2-directed treatments, no approved therapies exist for patients with cancers harboring HER2 mutations. Unlike other activating mutations, exon 20 insertions induce a conformational change leading to significant homology to the ATP-binding pocket of WT proteins. As such, clinical development of tyrosine kinase inhibitors (TKIs) against these insertions has been challenging, as inhibition of WT-EGFR is associated with clinical dose-limiting toxicities, such as diarrhea and skin rash. TAK-788 was designed to potently inhibit oncogenic variants with desirable selectivity over WT-EGFR. TAK-788 inhibits mutant EGFR and HER2 via covalent modification of EGFR-Cys797 and HER2-Cys805. Here, we characterized the non-clinical activity of TAK-788 in HER2 exon 20 insertion and substitution mutants and contrasted it with other TKIs.

    a9ded1e5ce5d75814730bb4caaf49419 Method
    

    In vitro activity was assessed by measuring viability in engineered Ba/F3 lines expressing different HER2 mutation variants (substitutions and insertions). Inhibition of WT-EGFR was assessed by measuring EGFR phosphorylation in A431 cells that overexpress WT-EGFR. In vivo activity was assessed by monitoring tumor volume.

    4c3880bb027f159e801041b1021e88e8 Result
    

    TAK-788 inhibited all HER2 mutations tested, including exon 20 insertions and point mutations, more potently than it inhibits WT-EGFR (Figure), suggesting an acceptable therapeutic window compared with other TKIs. TAK-788 in vitro potency in these mutations has also been confirmed in vivo with tumor xenograft models and in a phase 1 clinical trial.

    

    8eea62084ca7e541d918e823422bd82e Conclusion
    

    The favorable selectivity and potency observed in these in vitro experiments for HER2 exon 20 insertions/point mutations supports the ongoing exploration of TAK-788 in NSCLC patients with HER2 mutations (NCT02716116) as well as in other HER2 mutant−driven cancer patients.

    6f8b794f3246b0c1e1780bb4d4d5dc53

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