Abstract EGFR is an oncogenic driver in lung, head and neck, and colorectal cancers, but clinical success has been limited by EGFR having multiple oncogenic forms, acquired drug resistance, and on-target/off-tumor dose-limiting toxicities such as rash and diarrhea. A therapeutic that can robustly antagonize EGFR independent of form (wild type or mutant), avoid the TKI resistance cycle, and act in a tumor-specific manner would be highly differentiated and have distinct advantages over current treatments. EPI-326 is a novel therapeutic for wild type and mutant EGFR-driven cancers that is designed to drive deep, prolonged, and tumor-enriched EGFR degradation while avoiding normal healthy tissue toxicities. Extracellular targeted protein degradation (eTPD) has emerged as a promising new drug modality focused on the elimination of transmembrane and soluble extracellular proteins. EPI-326 is a humanized IgG1 bispecific antibody that leverages a novel degrader receptor, which was identified from a proprietary eTPD degrader receptor atlas screen. Whereas EGFR is broadly expressed in tumors and normal tissues such as the gastrointestinal tract and skin, the degrader receptor is enriched in EGFR-driven tumors and has limited expression in normal tissues. The EGFR and degrader receptor binding arms of EPI-326 were engineered to enable tumor enriched binding, internalization, and lysosomal EGFR degradation resulting in inhibition of oncogenic signaling from EGFR and its heterodimer partners. Deep and sustained EGFR degradation is achieved with EPI-326 bispecificity, and results in robust preclinical in vivo efficacy in classical and drug-resistant (T790M, C797S) EGFR mutant NSCLC models, as well as in wild type HNSCC and CRC tumor models. EPI-326 monotherapy drove a high complete response rate in an EGFR mutant NSCLC model, and had stronger activity compared to other EGFR inhibitors. When combined with front line standard of care therapies, EPI-326 increased the depth and duration of response. EPI-326 was well tolerated in multi-dose rodent and non-human primate toxicology studies to a maximal feasible dose of 200 mg/kg and showed no evidence of stereotypical EGFR-related toxicities. EPI-326 represents a promising and differentiated novel therapeutic approach to address the limitations of current EGFR drugs. An IND was submitted in early 2026 and the first-in-human Phase I study is expected to start in the first half of 2026 to assess the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of EPI-326 in patients with advanced/metastatic EGFR mutant NSCLC and HNSCC. Citation Format: Jonathan Sitrin, Lisa Marshall, Hai Tran, Kenneth Ng, Shruti Yadav, Kimberly Hoi, Zhong Huang, Andy Goodrich, Filomena Housley, May Dayao, Jacob Cohen, Lichao Zhang, Brian Hillier, Josef Gramespacher, Noah Solomon, Maia Vinogradova, Isaac J. Rondon, Shyra J. Gardai. EPI-326: A novel mutation-independent and normal tissue-sparing EGFR bispecific antibody that degrades EGFR for the treatment of EGFR-driven solid tumors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr ND04.
Sitrin et al. (Fri,) studied this question.