Abstract ND07: HER2-TTC: A Targeted thorium conjugate to treat HER2 expressing cancers with potent alpha radiation

Abstract

Abstract HER2-TTC (BAY 2701439) is a new representative of the Targeted Thorium Conjugates (TTCs), a novel class of radiotherapeutics for the treatment of cancer. It is comprised of the α-particle emitter thorium-227 complexed to a 3,2-HOPO chelator and conjugated to a human epidermal growth factor receptor 2 (HER2) targeted monoclonal antibody derived from trastuzumab. The targeted binding of HER2-TTC exposes tumor cells that express HER2 to a cytotoxic dose of alpha radiation. The high energy alpha-particles induce clustered double-strand DNA damage in targeted and adjacent tumor cells, which have a high likelihood to result in cell death in a cell cycle-independent fashion. Alpha particles have a short range of < 100 μm (less than 10 cell diameters), which minimizes damage to surrounding healthy tissue. The mechanism of action for TTCs is not dependent on any specific tumor type or affected by known resistance mechanisms provided that the target tumor epitope continues to be expressed. Potential combinations with inhibitors of DNA damage response (DDR) pathways may lead to synergistic anti-tumor activity. Preclinically, HER2-TTC has demonstrated substantial and selective anti-tumor activity in different models including breast, gastric, lung, bladder, colorectal cancer, with a range of HER2 expressions (IHC scores of 1+ to 3+). These included trastuzumab and T-DM1 resistant models, and models with low HER2 expression (IHC2+/ISH- or IHC1+). HER2-TTC has also demonstrated synergistic efficacy in combination with olaparib in a BRCAmut model. Preclinical data also support potential combinations with immune oncology agents, likely due to immunogenic cell death induced by alpha radiation. HER2-TTC has recently entered a First in Human study (NCT04147819) in patients with advanced tumors that express HER2. These include HER2 high expressing (IHC3+ or ISH+) breast and gastric/gastroesophageal carcinoma relapsed/refractory to trastuzumab/T-DM1, cancers with low HER2 expression, and other tumors that express HER2 such as colorectal cancer, non-small cell lung cancer, salivary, bladder and endometrial tumors. Citation Format: Jenny Karlsson. HER2-TTC: A Targeted thorium conjugate to treat HER2 expressing cancers with potent alpha radiation [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 ND07.