Abstract 985: BI 905711 selectively induces apoptosis and anti-tumor response in TRAILR2/CDH17- expressing pancreatic cancer models
Authors: Han Jing , Machado Annette A. , Mahendra Mikhila , Daniele Joseph R. , Bristow Christopher A. , Huang Justin Kwang-Lay , Carugo Alessandro , Mullinax Robert A. , Bivona Benjamin J. , Feng Ningping , Gandhi Poojabahen , Schweifer Norbert , Chetta Paolo Maria , Garcia-Martinez Juan Manuel , Hilberg Frank , Vellano Christopher P. , Heffernan Timothy P. , Marszalek Joseph R. 
Published: July 2021

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal adult cancers with an average 5-year survival rate of less than 10% due in part to the limited number of effective therapies. Activation of TRAILR2 (Tumor necrosis factor (TNF)-Related Apoptosis-Inducing Ligand Receptor 2) has emerged as an important therapeutic concept in cancer treatment. Traditional TRAILR2 agonists have had limited clinical success due to lack of efficacy or, importantly, severe hepatotoxicity. Here we present anti-tumor activity in preclinical PDAC models for BI 905711, a first-in-class tetravalent bispecific antibody specifically designed to overcome the disadvantages of previous strategies targeting TRAILR2.
BI 905711 serves as a uniquely specific, and liver-sparing therapeutic by targeting tumors that co-express TRAILR2 and another cell surface protein CDH17, which has ~40% prevalence in PDAC and is not expressed in normal liver. Working from a large cohort of molecularly characterized PDAC PDX models, we provide the first preclinical evidence of BI 905711 exhibiting robust anti-tumor activity in difficult to treat PDAC PDX models. Anti-tumor efficacy in responding models correlated with strong induction of Caspases 3/7 and 8 activation in tumors 24 hours after a single dose of BI 905711, and was associated with the presence and expression levels of TRAILR2 and CDH17 proteins. Evaluation of models with differential TRAILR2 and CDH17 expression profiles helped define the expression threshold for each target that is associated with response, upon which clinical assay development is in process for future patient stratification. Additionally, response was also associated with PDAC molecular subtypes utilizing a novel proprietary gene co-expression network developed from a curated cohort of PDAC PDX tumors. Responders to BI 905711 were identified primarily within the classical and quasi-basal/hybrid subtypes when TRAILR2 was adequately co-expressed. This correlates with an enrichment pattern of CDH17 gene expression that is mostly within the classical gene cluster and strongly anti-correlated with basal-like cluster enrichment.
Robust preclinical anti-tumor activity of BI 905711 in TRAILR2 and CDH17-expressing PDAC PDX models, along with this antibody's potential for a favorable safety profile, has justified the enrollment of pancreatic cancer patients in the ongoing BI 905711 FIH Phase I clinical trial (NCT04137289).
Citation Format: Jing Han, Annette A. Machado, Mikhila Mahendra, Joseph R. Daniele, Christopher A. Bristow, Justin Kwang-Lay Huang, Alessandro Carugo, Robert A. Mullinax, Benjamin J. Bivona, Ningping Feng, Poojabahen Gandhi, Norbert Schweifer, Paolo Maria Chetta, Juan Manuel Garcia-Martinez, Frank Hilberg, Christopher P. Vellano, Timothy P. Heffernan, Joseph R. Marszalek. BI 905711 selectively induces apoptosis and anti-tumor response in TRAILR2/CDH17- expressing pancreatic cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 985.