Patritumab is a fully human anti HER monoclonal antibody

Patritumab is a fully human anti-HER3 monoclonal antibody that demonstrates antitumor activity when used alone or with anti-EGFR inhibitors in preclinical cancer models (Freeman et al., 2009). Patritumab inhibits HRG-mediated HER3 signaling by binding to the extracellular domain of HER3 (thus preventing HRG from binding) and promoting the internalization and degradation of the receptor (Freeman et al., 2008; Treder et al., 2008a, 2008b). Patritumab was assessed in the phase 2 HERALD study in which patients with advanced NSCLC were randomized to either patritumab in combination with erlotinib or placebo with erlotinib (von Pawel et al., 2014). While patritumab had been previously studied in a phase 1 study as a monotherapy in patients with solid tumors refractory to prior treatments (LoRusso et al., 2013), a predictive biomarker for response to patritumab had not yet been identified before initiation of the phase 2 study. Therefore, the phase 2 study had a secondary objective of defining a biomarker for a primary biomarker hypothesis (Beckman et al., 2011), based on preclinical data available after patient enrollment was completed in the clinical study and prior to data unblinding and statistical analysis (a prospective–retrospective approach (Simon, 2005)).
Materials and Methods
Results
Discussion After study initiation, a validated assay method to measure HRG mRNA mmp inhibitor from FFPE tissue was developed to assess a single primary biomarker hypothesis, which stated that patients with high HRG mRNA expression levels would more likely benefit from the addition of patritumab. The results confirmed that patients with advanced NSCLC and high levels of HRG mRNA expression showed significant clinical benefit for treatment with patritumab plus erlotinib compared with patients receiving erlotinib monotherapy. Interestingly, levels of HRG mRNA expression also appear to be a prognostic biomarker in patients who were treated with erlotinib monotherapy. This is consistent with molecular studies suggesting that HRG upregulation is a resistance mechanism to tyrosine kinase inhibitors and chemotherapy (Hegde et al., 2013; Zhou et al., 2006; Baselga and Swain, 2009; Xia et al., 2013). Given the challenges faced at the onset of the study, the use of a prospective–retrospective approach for this phase 2 study was valuable in provisionally validating HRG mRNA expression levels as a predictive biomarker for patritumab efficacy. These challenges included the possibility of having to evaluate multiple biomarkers and the existence of few validated assays at the start of the study. Preclinical study results became available during the clinical phase 2 study and showed that HRG protein expression is predictive of preclinical patritumab efficacy in cell lines and mouse tumor xenograft models. The finding that HRG—but not HER3 expression—is a predictive biomarker for patritumab clinical efficacy is consistent with the relationship between the HER3 receptor and its ligand and the mechanism of action underlying patritumab activity. Activation of the HER3 pathway appears to be driven by increased HRG expression (Ueno et al., 2008; Zhou et al., 2006; Schoeberl et al., 2009, 2010; Shames et al., 2013), which is associated with therapeutic resistance to a variety of agents, including those inhibiting the PI3K pathway (Zhou et al., 2006; Xia et al., 2013; Sato et al., 2013). These observations indicate that HRG activity is a key regulator of HER3 signaling and support that patritumab inhibits HRG-mediated HER3 activation (Freeman et al., 2008; Treder et al., 2008a, 2008b). Additionally, high HRG expression may result in a decrease in the apparent levels of membrane surface HER3 detectable through IHC owing to the internalization of the receptor (Hettmann et al., 2010). Low levels of this membrane surface receptor were not well detected by an IHC assay method, which may also explain why HER3 expression levels appear uncorrelated with patritumab efficacy in our study.