Evaluation of Biomarkers for HER3-targeted Therapies in Cancer

Integration of biomarkers into the majority of drug development programs has led to a need for robust measurements and assay validation techniques for analyses of biological samples. The importance of solid methodologies for biomarker assessment is heightened by the fact that new drugs frequently only offer modest benefit and that many potential biomarkers are continuous variables, the application of which relies on data interpretation, with the risk of subjectivity bias, to establish thresholds. Patritumab is a fully human anti-human epidermal growth factor receptor 3 (HER3) antibody that inhibits HER3 from binding to HRG (Mendell et al., 2015). In the HERALD phase II trial, before data unblinding but after subject enrollment, heregulin (HRG) was prospectively declared to be the predictive biomarker for patritumab efficacy. Advanced non-small cell lung cancer (NSCLC) patients previously treated with at least one chemotherapy regimen were randomized to erlotinib plus patritumab (highor low-dose) or erlotinib plus placebo (Mendell et al., 2015). Testing a single primary predictive biomarker hypothesis to identify those patients most likely to benefit from patritumab was a secondary objective of the trial and HRG was identified as a continuous biomarker to predict outcome. Members of the HER family of receptor tyrosine kinases (RTK) and their respective ligands constitute a robust biologic system that plays a key role in the regulation of cell-proliferative growth, survival, and differentiation (Ma et al., 2014). HER3 transactivation via dimerization with other RTKs is frequently observed in various malignancies, including NSCLC. Binding of the alpha and beta forms of neuregulin 1, collectively known as HRG, exposes a dimerization arm in the extracellular domain of HER3 and promotes receptor–receptor interactions (Ma et al., 2014; Carraway et al., 1994). HER3 contains six phosphotyrosine binding sites for the p85 subunit of PI3K, the greatest number of all HER familymembers, and is amajor cause of treatment failure in cancer therapy (Ma et al., 2014; Fedi et al., 1994). Recently, the role of HER3 in primary and acquired resistance to EGFR-targeted or other targeted therapies in NSCLC patients has attracted considerable attention (Ma et al., 2014; Torka et al., 2014). Since HER3 lacks or has weak intrinsic kinase activity, targeting it with blocking antibodies that inhibit HRG binding is one strategy currently being investigated in order to overcome therapeutic resistance (Ma et al., 2014). In the study by Mendell et al., although no progression-free survival (PFS) benefit was observed overall with the addition of patritumab to