Clinical activity of EBC-129, a first-in class, anti N256-glycosylated CEACAM5 and CEACAM6 antibody-drug conjugate (ADC), in patients with pancreatic ductal adenocarcinoma (PDAC) in a phase 1 study.

4018 Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with limited treatment options. EBC-129 is a first in class MMAE-linked ADC against N256-glycosylated CEACAM5/6 antigen. Pre-screening data shows 73% of PDAC express surface antigen (IHC positive cut-off ≥20% at 2+ or 3+) or 82% (≥1% at 3+). Previously reported dose escalation data identified 1.8 and 2.2 mg/kg every 3 weeks as the RP2Ds. Here we report pooled safety and efficacy data of the PDAC patients enrolled in the dose escalation (DEs) and expansion (DEx) cohorts of the phase 1 study. Methods: This study consisted of DEs and DEx cohorts. Previously treated histologically confirmed, locally advanced or metastatic PDAC patients with antigen expression levels of ≥20% at 2+ or 3+ intensity or ≥1% at 3+ intensity (IHC on archival samples) were enrolled. Objectives were to evaluate safety, efficacy, and PK of EBC-129, administered every 3 weeks. Results: A total of 21 PDAC patients were enrolled (6 in DEs and 15 in DEx). Patients received 1.8 (n = 8), 2.0 (n = 2) or 2.2 (n = 11) mg/kg EBC-129 every 3 weeks. 52% were male; mean age 63 years; median 3 (range 1-7) lines of previous treatments with 81% prior taxane treated. At data cut-off (Jan 16th, 2025), 5 patients are continuing treatment, 12 patients had radiological progression, 3 had clinical progression, and 1 patient withdrew treatment. The overall response rate, disease control rate (first assessment), and median PFS, at 1.8 mg/kg, 2.2 mg/kg and overall group, respectively, were 25.0%, 18.2% and 19.0% (unconfirmed), 87.5%, 63.6% and 71.4%, and 18, 12 and 12 weeks. 43% of patients had any tumour shrinkage overall. Infusion related reactions (IRR) were seen in 57% of patients; most were grade 1/2, more frequent at 2.2 mg/kg, and resolved or reduced with premedication. Grade ≥3 treatment related adverse events included neutropenia (50.0% and 81.8%) and anaemia (12.5% and 18.2%) at 1.8 and 2.2mg/kg, respectively; amylase/lipase increase, vomiting, and aspartate aminotransferase increase occurred in 1 patient each. Grade ≤2 peripheral neuropathy was seen in 2 patients. No drug related discontinuations occurred in this cohort. In this cohort, selected for target antigen expression, no apparent correlation was seen between IHC score and treatment response. Based on a cut-off of > 25% CEA decrease (either local or central), biomarker response was seen 42.9% at 1.8 mg/kg and 36.4% at 2.2 mg/kg. Conclusions: EBC-129 shows promising clinical activity in heavily treated PDAC patients with a manageable tolerability profile, consistent with MMAE-based ADCs. Further evaluation of EBC-129 in PDAC, both as monotherapy and in combination with chemotherapy, is planned. Clinical trial information: NCT05701527 .