California-based EpiBiologics has posted details of a Phase I clinical trial (NCT07462377) for EPI-326, a tissue-selective bispecific antibody targeting EGFR in patients with locally advanced or metastatic EGFR-mutant non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC). EPI-326 is designed to trigger lysosomal degradation of EGFR rather than block its activity. The antibody binds EGFR and a second cell-surface receptor enriched in tumor tissue, promoting internalization and breakdown of the receptor.
EpiBiologics describes the approach as extracellular targeted protein degradation, an antibody-based strategy intended to remove disease-driving proteins from the cell surface. The molecule was developed using the company’s EpiTAC platform, which traces to work from UCSF chemist Jim Wells. EpiBiologics raised USD 107 million in Series B financing in 2026, co-led by GV and Johnson & Johnson Innovation.
The open-label, multicenter, sequential dose-escalation study plans to enroll approximately 110 adults with confirmed NSCLC harboring any documented EGFR mutation, or pathologically confirmed HNSCC. Disease must be locally advanced or metastatic. The study, set to initiate in Q2 2026, will assess safety, dose-limiting toxicities, PK/PD, and aim to establish maximum dosing. Primary completion is estimated for Q3 2029. Sites include MD Anderson Cancer Center in Houston, Sarah Cannon Research Institute in Nashville, START centers in San Antonio and Los Angeles, and Astera Cancer Care in New Jersey.
Research context
EPI-326’s mechanism diverges from existing EGFR-directed therapies in two respects. First, by inducing degradation of the EGFR protein rather than inhibiting its enzymatic function, the molecule eliminates both kinase-dependent and kinase-independent survival signaling, a limitation of small-molecule TKIs such as osimertinib, erlotinib, and afatinib. Second, the bispecific format engages a second receptor that is enriched in tumor tissue, which in principle confines EGFR degradation to malignant cells and spares normal epithelia in skin and gut, the tissues responsible for the rash and diarrhea that constrain dosing of every approved EGFR-targeting agent. The EpiTAC platform from which EPI-326 emerged traces to academic work on engineered bispecific constructs that co-opt surface receptors for targeted degradation.
EGFR-mutant NSCLC remains one of the most intensively targeted areas of oncology drug development. AstraZeneca’s osimertinib (Tagrisso) remains the leading first-line therapy, while Johnson & Johnson’s amivantamab (Rybrevant) targets both EGFR and MET signaling using a bispecific antibody approach.
Other programs are exploring alternative strategies, including antibody-drug conjugates such as patritumab deruxtecan, which targets HER3, and next-generation EGFR inhibitors designed to overcome resistance mutations.
In head and neck cancer, the EGFR-directed pipeline is smaller. Cetuximab remains the only approved anti-EGFR antibody, while newer bispecific antibodies such as Merus’s petosemtamab are being tested in late-stage trials.
If successful, EPI-326 could represent a different approach by eliminating EGFR protein rather than inhibiting its signaling, potentially offering activity across multiple EGFR mutation types.
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