April 23, 2026 | Chris Ryan
The novel bispecific antibody EPI-326 generated robust tumor regressions in models of EGFR-driven solid tumors, including a 90% complete response rate in an EGFR-mutant non–small cell lung cancer (NSCLC) model, according to preclinical data presented at the 2026 AACR Annual Meeting 2026.1
Findings from preclinical studies showed that EPI-326 monotherapy is active in both EGFR-mutant and wild-type models in NSCLC, colorectal cancer (CRC), and head and neck squamous cell carcinoma (HNSCC). Notably, single-agent EPI-326 yielded significant regressions in NSCLC models with EGFR exon 19 deletions, exon 21 L858R/T790M mutations, and exon 20 C797S mutations, along with osimertinib (Tagrisso)–resistant models.
The agent also demonstrated superior antitumor activity compared with standard blocking antibodies such as cetuximab (Erbitux) and amivantamab-vmjw (Rybrevant), effectively driving tumor regressions in both wild-type HNSCC and CRC models using patient-derived xenografts (PDX). Additionally, the combination of EPI-326 with KRAS inhibitors such as sotorasib (Lumakras) elicited synergistic activity, highlighting its potential in expanded therapeutic settings.
“We believe we created something really distinct with EPI-326. It’s able to degrade all oncogenic forms of EGFR and do this really safely,” Shyra J. Gardai, PhD, chief scientific officer of EpiBiologics, said in a presentation of the preclinical data. “We’re excited about the opportunity to head to clinic as we think about being able to develop [this agent] in NSCLC, as well as HNSCC and potentially CRC.”
What is EPI-326?
EPI-326 is a mutation-independent agent developed via EpiTAC platform, which is designed to leverage bispecific antibodies and a novel atlas of tissue-selective degrader receptors to selectively degrade EGFR in diseased tissue and spare healthy tissue.
Gardai explained that current EGFR-directed therapies are limited by mutation dependence and resistance mechanisms, which limit single-agent activity. Additionally, current agents are limited by the inability of these agents to differentiate between EGFR on healthy cells and tumor cells.
With EPI-326 demonstrating activity in EGFR-mutant and wild-type cancer models, Gardai explained that the bispecific antibody is mutation independent, and the removal of target receptor downstream signaling generates durable monotherapy activity. EPI-326 also avoids blocking EGFR signaling in normal tissues to minimize associated off-target toxicities, and the safety and activity profile position it as a candidate for combination therapies.
How was the research on EPI-326 in cancer conducted?
The development of EPI-326 involved evaluation in multicenter, open-label preclinical cell line–derived (CDX) and PDX models, focusing on EGFR-driven solid tumors, including NSCLC, HNSCC, and CRC. Some models specifically utilized cetuximab-experienced or osimertinib-resistant phenotypes to test efficacy in refractory disease states.
What’s next for the evaluation of EPI-326 in EGFR-driven solid tumors?
A phase 1, first-in-human dose-escalation clinical trial (NCT07462377) is currently evaluating EPI-326 as monotherapy in patients with locally advanced or metastatic, EGFR-mutated NSCLC or HNSCC, with the goal of assessing safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity in the form of overall response rate and duration of response.2 Gardai noted that the first patient has been dosed.1
The phase 1 trial investigators are enrolling patients at least 18 years of age who have a life expectancy of more than 12 weeks, an ECOG performance status of 0 to 2, and adequate organ function.2 Patients with symptomatic brain metastases are being excluded from the study. The multicenter study is expected to enroll approximately 110 patients, and it is currently open at 5 center centers in the United States.
Disclosures: Gardai is an employee of EpiBiologics.
References
Sitrin J, Marshall L, Tran H, et al. EPI-326: a novel mutation-independent and normal tissue-sparing EGFR bispecific antibody that degrades EGFR for the treatment of EGFR-driven solid tumors. Presented at: 2026 AACR Annual Meeting; April 17-22, 2026; San Diego, CA. Abstract ND04.
A phase 1 study of EPI-326 in EGFR-mutant NSCLC and HNSCC. ClinicalTrials.gov. Updated March 25, 2026. Accessed April 22, 2026. https://clinicaltrials.gov/study/NCT07462377
