Translating pre-clinical hypotheses into the clinic – a tale of two kinases


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Nigel Brooks
AstraZeneca, Macclesfield, UK

Abstract

A focus on finding drugs that target genetic drivers has led to the development of a number of new medicines that benefit patients whose tumours harbour that particular genetic aberration. The development path for these agents can vary depending on the strength of the pre-clinical hypothesis. For example, development of gefitinib (IRESSATM), was initially based on targeting epidermal growth factor receptor (EGFR) tyrosine kinase due to its over-expression in numerous tumours. Whilst early clinical activity with gefitinib in Phase 1 & 2 trials was encouraging it was not until the discovery of activating mutations in the kinase domain of EGFR, that subsequent development focused on demonstrating that EGFR mutation positivity is a strong predictive biomarker of response. In contrast, clinical development of AZD4547, a potent and selective inhibitor of fibroblast growth factor receptor (FGFR) 1, 2 and 3 (IC50 values of 0.2, 2.5 and 1.8nM respectively; in vitro kinase assays; >120 fold selective vs. KDR) was predicated on a compelling pre-clinical hypothesis. In cell lines, anti-proliferative responses to AZD4547 are almost exclusively confined to those in which FGFR signalling is de-regulated by either gene amplification, mutation or translocation. Profound tumour regressions are seen in FGFR gene amplified in vivo patient-derived explants models, after treatment with AZD4547. In clinical samples, FGFR1 gene is amplified in approximately 15% of squamous NSCLC and 10% of estrogen receptor positive breast tumours whereas FGFR2 is amplified in 5-7% of gastric tumours. Contrasting the development of gefitinib, for AZD4547, a compelling pre-clinical hypothesis and an ability to prospectively select patients has allowed an early focus on evaluating clinical efficacy in Phase 1 trials in solid tumours with FGFR1 and 2 amplifications. Comparing the development of gefitinib, for AZD4547, new clinically testable hypotheses continue to emerge, requiring a similar flexible and adaptive approach to clinical drug development.

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