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.
Robert W. Lentz, Matthew Chau Hsien Ng, Wei Peng Yong, Funda Meric-Bernstam, Inderjeet Singh, Venkateshan Srirangam, Julienne Cometa, Stéphanie Blanchard, Ranjani Nellore, Kunal J. Shah, Y.Y. Lee, Chek Shik Lim, Bong Hwa Gan, Allison Tan, Nurul Rozaini, Claudia Koh, Nur Quraishah Adanani, Joe Yeong, V. Diermayr
Abstract
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 .