Association Of Erbb/Her Biomarkers With Antitumor Activity Of The Anti-Erbb3/Her3 Monoclonal Antibody Ktn3379 In Scchn

Aberrant regulation of the HER family of receptor tyrosine kinases (RTK) has proven to be a driver for promoting tumor growth and progression in a number of solid tumors. HER3 is a unique RTK; it is a pseudo-kinase and requires heterodimerization with HER2 or other RTKs to signal. KTN3379 is a human anti-HER3 monoclonal antibody currently being evaluated in clinical studies. It potently inhibits HER3 by locking the receptor in an inactive conformation, providing a structural model for KTN3379 inhibition of both ligand-dependent and independent activation of HER3. Tumor expression of neuregulin 1 (NRG1), a high affinity HER3 ligand, is not well defined. An in silico survey of 29,049 human tumor samples, identified squamous cell carcinoma of the head and neck cancer (SCCHN) as having the highest prevalence of NRG1 over-expression. We used the VeraTag® technology, a proximity-dependent dual-antibody immunoassay, to quantify total receptor levels (HER1, HER2 and HER3) and dimerization/activation (HER1-HER1 homodimer, HER2-HER3 heterodimer, HER3-PI3 kinase (p85) and phospho-HER3) in formalin-fixed paraffin-embedded (FFPE) SSCHN tumors, and in cell lines and xenografts treated with KTN3379. In SSCHN tumors, expression of the HER biomarkers ranged from ∼6 to >300-fold, with the largest range in expression from HER1-HER1 homodimer and phospho-HER3, suggestive of signaling through both the HER1 and HER3 pathways in these tumors. The addition of KTN3379 to a panel of 6 SCCHN cell lines had no or a modest dose-dependent effect on cell growth, but resulted in a reduction of both phospho-HER3 and HER3-PI3K in 4 of the 6 SCCHN cell lines. Elevated levels of phospho-HER3 were predictive of KTN3379 activity. The combination of KTN3379 and cetuximab synergistically inhibited the growth of SCCHN cell lines greater than cetuximab alone, consistent with a reduction of pAKT and pERK by Western blot analyses. In mouse xenograft models, KTN3379 reduced tumor volume by 65% and 43% in Cal27 (SCCHN) and NCI-N87 (gastric), respectively. Tumor growth inhibition correlated with significant reductions in both phospho-HER3 (p = 0.0063) and HER3-PI3K (p = 0.0220) in the Cal27 model and phospho-HER3 (p = 0.0247) in the NCI-N87 model. In summary, we found that basal phospho-HER3 correlated with KTN3379 antitumor activity in SCCHN cell lines, and KTN3379 treatment of xenografts and cell lines resulted in a significant decrease of phospho-HER3 and HER3-PI3K suggesting phopho-HER3 may be useful as both a predictive and pharmacodynamic marker for KTN3379 activity. Collectively, these data support the evaluation of KTN3379 as an anti-tumor agent in NRG1-driven SCCHN cancer. A SCCHN window study evaluating the effects of KTN3379 in SCCHN cancer patients on phospho-HER3 and other biomarkers before and after treatment is planned. Citation Format: Diego Alvarado, Jerry Wallweber, Scott Seibel, Ahmed Chenna, Roy Ravanera, Weidong Huang, David Stathas, Paul Theobald, Theresa M. LaVallee. Association of ErbB/HER biomarkers with antitumor activity of the anti-ErbB3/HER3 monoclonal antibody KTN3379 in SCCHN. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1558. doi:10.1158/1538-7445.AM2015-1558