Development And Validation Of A Biomarker For Prospective Selection Of Notch1 Activation In Patients With Certain Advanced Solid Tumors In A First-In-Human Phase1 Study Of The Cancer Stem Cell Targeting Antibody Omp-52m51 (Anti-Notch1)

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PAThe Notch pathway plays a key role in embryonic development, the regulation of stem and progenitor cells, and is implicated centrally in many forms of human cancer. Notch1 is known to be frequently activated in certain solid tumor types. OMP-52M51 is a humanized IgG2 antibody that inhibits the signaling function of the Notch1 receptor. Mouse xenograft studies using minimally-passaged, patient-derived xenografts have shown that OMP-52M51 impedes tumor growth and selectively eliminates CSCs in a range of tumor types particularly in tumors with activated Notch1 signaling.We previously reported the frequency of Notch pathway activation across a large panel of human tumors (nu003e600) by an Immunohistochemistry (IHC) assay that detects the activated form of Notch1 using an antibody that specifically recognizes the Notch1 intracellular domain (ICD). Using this test and a rigorous H-score cut-off, we found elevated Notch1 ICD in 7-53% of the following cancers: chemo-resistant breast (29%), gastric (13%), cholangiocarcinoma (20%), esophageal (27%), hepatacellular carcinoma (HCC, 7%), small cell lung cancer (SCLC, 12%), pancreatic (12%) and colorectal cancer (53%).Here we developed a specific CLIA-validated IHC assay capable of identifying patients with Notch1 activation. The assay has a rapid turn-around time and shows robust precision, reproducibility and accuracy. The sensitivity of the method was confirmed by comparing results obtained on xenograft tumor tissue samples with known levels of Notch1 expression and response to anti-Notch1 therapy. From these results, the cut-off of the assay was set. This predictive biomarker was specifically designed to screen patients for prospective selection in the first-in-human Phase1 study of OMP-52M51 (anti-Notch1) in certain advanced solid tumors ([NCT01778439][1]). Detailed assay validation data and its application to the analysis of clinical trial samples will be highlighted.Citation Format: Belinda Cancilla, Raymond Tam, Chun Zhang, Steve Anderson, John Lewicki, Tim Hoey, Bryan McCune, Lori Johnson, Esohe Idusogie, Ann M. Kapoun. Development and validation of a biomarker for prospective selection of Notch1 activation in patients with certain advanced solid tumors in a first-in-human phase1 study of the cancer stem cell targeting antibody OMP-52M51 (anti-Notch1). [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 1549. doi:10.1158/1538-7445.AM2015-1549 [1]: /lookup/external-ref?link_type=CLINTRIALGOVu0026access_num=NCT01778439u0026atom=%2Fcanres%2F75%2F15_Supplement%2F1549.atom