EBC-129 Is Active and Safe in Heavily Pretreated mPDAC

EBC-129 in Heavily Pretreated mPDAC

| Image Credit: © Image by Ashling Wahner

& MJH Life Sciences Using AI

EBC-129 monotherapy demonstrated antitumor activity and had a manageable safety profile in patients with heavily pretreated metastatic pancreatic ductal adenocarcinoma (mPDAC), according to early findings from a phase 1 trial (NCT05701527) that were presented at the 2025 ASCO Annual Meeting.1

Among the 20 evaluable patients with mPDAC, the objective response rate (ORR) was 20%, the disease control rate was 71.4%, and the median progression-free survival (PFS) was 12.9 weeks. Among evaluable patients treated at the 1.8-mg/kg dose (n = 8), the ORR was 25%, and the median PFS was 19.1 weeks. Among those treated at the 2.2-mg/kg dose (n = 10), the ORR was 20.0%, and the median PFS was 12.1 weeks.

“EBC-129 monotherapy is active in heavily pretreated [patients with] mPDAC and has a manageable safety profile,” Robert W. Lentz, MD, an assistant professor in the Division of Medical Oncology in the Department of Medicine at the University of Colorado Anschutz School of Medicine in Aurora, said during his presentation of the data.

About EBC-129

EBC-129 is a first-in-class antibody-drug conjugate (ADC) that targets N256-glycosylated CEACAM5 and CEACAM6, 2 antigens that are highly prevalent in PDAC and associated with aggressive tumor biology. EBC-129 uses a fully humanized monoclonal antibody linked to monomethyl auristatin E (MMAE) via a cleavable linker, with a drug-to-antibody ratio of 4. The molecule also has inherent antibody-dependent cellular cytotoxicity activity. The preclinical rationale for the dual targeting of CEACAM5 and CEACAM6 rests in the roles of these targets in cell migration and invasion, as well as their collective overexpression in gastrointestinal tumors.

Behind the Phase 1 Study in PDAC

The study enrolled patients 18 years of age and older in the United States and 21 years of age and older in Singapore who had measurable disease by RECIST 1.1 criteria on imaging, an ECOG performance status of 0 or 1, and histologically or cytologically confirmed unresectable locally advanced or metastatic solid tumors. Patients needed to have confirmed CEACAM5/6 expression on archival tissue and cell staining per immunohistochemistry (IHC) of at least 20% at 2+/3+ intensity or at least 1% at 3+ intensity. No clear correlation was seen between IHC expression levels and response.

Patients enrolled in the study (n = 21) received EBC-129 every 3 weeks at doses of 1.8, 2.0, or 2.2 mg/kg, with 1.8 and 2.2 mg/kg established as the recommended phase 2 doses. The median age of the 21 patients included was 63.0 years (range, 44.0-81.0), 52% of patients were male, 11 patients were Asian, and 10 patients were White. Seventeen patients (81.0%) had received prior taxanes. Five patients had stage I disease at diagnosis, 3 patients had stage II disease, 3 patients had stage III disease, 8 patients had stage IV disease, and 2 had unknown disease stages. In total, 47.6% of patients had received at least 3 prior lines of therapy, and 81.0% had previously received taxanes.

“Among the 4 partial responses, 1 was confirmed, 3 were unconfirmed due to subsequent progression, and 3 of these patients had prior taxane exposure,” said Lentz. “Three patients experienced stable disease for longer than 6 months, with a disease control rate of 71.4% in the entire group. There was no apparent correlation between IHC score and treatment response, including in 1 partial responder with 1% of cells at 3+ expression. Three patients continue on the trial.”

Safety Results and Biomarker Analysis

EBC-129 was generally well tolerated, with a safety profile consistent with that of other MMAE-based ADCs. Overall, the most common treatment-related adverse effects (TRAEs) were infusion-related reactions (13.8%), which were predominantly grade 1 or 2 and effectively mitigated with premedication; and neutropenia (31.0%), which was typically manageable with growth factor support.

There were no grade 5 AEs observed in the study, and no ocular events were reported. Neuropathy was infrequent, seen in only 6% of patients, and no patients discontinued treatment due to toxicity.

“EBC-129 has a manageable safety profile, with neutropenia and infusion-related reactions as the primary TRAEs,” added Lentz.

A biomarker analysis revealed that most patients had higher baseline serum levels of CEACAM6 than CEACAM5 (n = 18/21; 86%), a finding that was consistent with prior observations in PDAC biology.

Future Directions

“The EBC-129 antigen [N256-glycosylated CEACAM5/6] has a high prevalence of IHC positivity in patients with metastatic pancreatic adenocarcinoma,” said Lentz.

Given these results, EBC-129 has received FDA fast track designation for the treatment of patients with PDAC.

Furthermore, a phase 2 trial furthering this research in patients with mPDAC is planned to launch in 2026 through the Academic GI Cancer Consortium.2 The study will explore EBC-129 both as monotherapy and in combination with gemcitabine in patients with second-line mPDAC. If the efficacy of EBC-129 is confirmed in later-phase trials, this agent could be a novel treatment option for a patient population with few effective therapies and a historically poor prognosis.

References

1. Lentz RW, Ng MC, Yong WP, et al. 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. J Clin Oncol. 2025;43(suppl 17):4018. doi:10.1200/JCO.2025.43.16_suppl.4018
2. Experimental Drug Development Centre granted U.S. FDA fast track designation for antibody-drug conjugate EBC-129 to treat pancreatic ductal adenocarcinoma. News release. Experimental Drug Development Centre. May 28, 2025. Accessed June 2, 2025. https://www.eddc.sg/experimental-drug-development-centre-granted-u-s-fda-fast-track-designation-for-antibody-drug-conjugate-ebc-129-to-treat-pancreatic-ductal-adenocarcinoma/