Author of

• 11515

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  P2.05 - Poster Session 2 - Preclinical Models of Therapeutics/Imaging (ID 158)

  • Event: WCLC 2013
  • Type: Poster Session
  • Track: Biology
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/29/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 11537

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    P2.05-022 - Therapeutic potential of the FGFR Tyrosine Kinase Inhibitor, AZD4547 in Squamous non-small cell lung cancer (ID 3218)

    09:30 - 09:30  |  Author(s): N. Brooks
    • Abstract

    Background
    Background: As a result of the recent deep molecular profiling of NSCLC samples, FGF receptor inhibition has emerged as a promising strategy for targeting a sub-set of squamous NSCLC (Sq NSCLC) tumours that carry FGFR gene amplifications, mutations and fusions. AZD4547 is a potent, orally available and selective inhibitor of FGFR 1, 2 and 3 and is currently in phase II clinical development.

    Methods
    not applicable

    Results
    Results: In pre-clinical patient derived models of FGFR1 amplified Sq NSCLC, AZD4547 is able to induce dose dependent tumour growth inhibition and tumour regression and this is correlated to FGFR1 protein expression and inhibition of signalling pathways downstream of FGFR1. Since the FGFR2 mutations described in Sq NSCLC do not present as clear codon hot-spots we also investigated a sub-set of the FGFR2 mutations using inducible expression in non-transformed cells. We found these mutations to be constitutively active and capable of inducing 3D colony formation in non-transformed cells. Both FGFR signalling and 3D colony growth were inhibited potently by AZD4547 treatment. We have developed a number of biomarker assays that enable both patient selection and exploratory analysis of patient samples. We found that FGFR1 gene amplified samples are enriched for those expressing both FGFR1 mRNA and protein. AZD4547 is currently being tested as a monotherapy in Sq NSCLC patients whose tumours carry FGFR1 amplification and we will describe preliminary observations from this trial including a comprehensive molecular profile of the tumour from a patient who experienced a durable partial response following AZD4547 treatment.

    Conclusion
    Conclusion: In view of the strong and emerging platform of evidence that implicates dis-regulated FGFR signalling in Sq NSCLC and the early evidence of clinical activity, FGFR inhibition warrants continued clinical investigation in patients whose tumours carry FGFR genetic lesions including amplification, mutation and gene fusions.