Abstract 1196: Combination of neuregulin with EGFR activation signatures predict activity of the anti-ErbB3 antibody KTN3379 in SCCHN

ErbB3, the kinase-dead member of the EGFR/ErbB family, has been implicated as an oncogenic driver in a number of solid tumor types, including squamous cell carcinoma of the head and neck (SCCHN). However, clinical trials have demonstrated limited responses with certain single agent anti-ErbB3-directed therapies, suggesting that multiple ErbB inhibition and/or biomarker-directed patient selection may be beneficial. The anti-EGFR antibody cetuximab has demonstrated improved overall survival in SCCHN, but the overall response rate is relatively low. Several preclinical studies have suggested that pan-ErbB inhibition may result in improved clinical benefit and additionally, may overcome cetuximab resistance. Here we show that ErbB3 and its ligand neuregulin (NRG) are widely expressed in SCCHN, and that ErbB2, but not EGFR, drives ErbB3 activation in the presence of NRG. Although NRG is required for ErbB3 activation, it is not sufficient to fully predict activity of the anti-ErbB3 antibody KTN3379 in SCCHN models. Metadata analysis of human SCCHN tumors revealed that NRG expression is significantly associated with expression of EGFR ligands amphiregulin (AREG) (P