HER1/EGFR-targeted agents: predicting the future for patients with unpredictable outcomes to therapy

Abstract

Therapeutic agents that target the epidermal growth factor receptor (HER1/EGFR) signal pathway, such as small-molecule tyrosine kinase inhibitors and monoclonal antibodies are now advanced in clinical development and two are already licensed for use. Complete/ongoing phase II studies with these agents clearly demonstrate that a small, but significant proportion of patients respond to HER1/EGFR inhibition. However, with our current understanding of tumour biology and genetics, we cannot explain why some patients respond well and others less so or not at all. These differences may be a result of many factors, such as patients' genotype and phenotype, pharmacological and pharmacokinetic differences between agents or the inherent molecular heterogeneity of tumours. In this article, we explore current strategies to identify patients who respond differently and ways to maximise the clinical benefit of these therapies. This includes defining optimal dose and dosing schedules, identifying appropriate combination partners and finding predictive and surrogate markers of response. The association between HER1/EGFR gene mutations in non-small cell lung cancer (NSCLC) tumours and response to HER1/EGFR-targeted agents is also discussed. This may help us to preselect responsive patients, tailor the dose according to the individual's tolerability, or monitor these agents to optimise/interrupt therapy at an early stage.