653P - A phase I dose escalation study of EBC-129, a first-in class, anti N-glycosylated CEACAM5 & CEACAM6 antibody-drug conjugate (ADC) in patients with solid tumors

Background

EBC-129 is a humanised IgG1 linked to monomethyl auristatin E (MMAE) via the clinically validated MC-vc-PAB linker. It targets a conformational epitope specific for N256-glycosylated CEACAM5 & CEACAM6 (N256 C5/C6) which is highly tumour specific. This study evaluates safety and preliminary efficacy of EBC-129 in advanced solid tumors.

Methods

The multicentre Phase 1A dose escalation study used a Bayesian design to establish the recommended Phase 2 dose (RP2D) of EBC-129. Patients (pts) failing standard therapies, with adequate organ function and ECOG 0-1 were eligible and received doses between 0.3 and 2.2 mg/kg every 3 weeks, until disease progression. The primary endpoint is safety; secondary endpoints include efficacy and PK. Prospective central assessment of archival tissue to determine IHC positivity (≥20% at 2+ or 3+) was performed in ≥30% of pts (NCT05701527) using a validated assay.

Results

As of 24 Apr 2024, 16 pts received ≥1 dose of EBC-129. Most pts were male (75%) and Asian (63%), with a median (range) age of 59 (53-76) and 3 (1-9) lines of prior therapy. The RP2D is 2.2 mg/kg, the MTD was not reached and back-filling at lower doses is ongoing. One DLT was observed at 2.2 mg/kg (G4 febrile neutropenia). The most common TRAEs were Gr 1-2 infusion-related reactions. Transient Gr 3/4 neutropenia occurred in 5 pts (at 1.8 and 2.2 mg/kg). Treatment-related neuropathy was not seen. Of 14 evaluable pts, there were 2 PRs (oesophageal and pancreatic adenocarcinoma at 1.2 mg/kg and 1.8 mg/kg respectively), 7 pts are currently ongoing. IHC positivity for N256 C5/6 in archival tissues was most frequent in colorectal (94%), followed by gastric (64%), pancreatic (57%), oesophageal and lung cancers (53% each).

Conclusions

EBC-129 is the first ADC to target N256C5/6 and has shown promising early activity in a heavily pre-treated population. Additional targeting of C6 did not increase toxicity seen with MMAE-linked ADCs. Three expansion cohorts (n=15 each) in IHC positive gastroesophageal or other cancers, and in pancreatic cancer (IHC positive or ≥ 1% expression at 3+) are ongoing.

Clinical trial identification

NCT05701527.

Editorial acknowledgement

Legal entity responsible for the study

Experimental Drug Development Centre (EDDC), A∗STAR.

Funding

National Research Foundation (NRF), Singapore.

Disclosure

M.C.H. Ng: Financial Interests, Personal, Speaker, Consultant, Advisor: AstraZeneca, BeiGene, BMS, Merck, MSD, Novartis, Pfizer; Financial Interests, Institutional, Financially compensated role: Amgen, BMS, Eli Lilly, MSD, Taiho; Non-Financial Interests, Personal, Non financial benefits, travel support: AstraZeneca, BMS; Non-Financial Interests, Personal, Non financial benefits, travel support: MSD; Financial Interests, Personal, Stocks/Shares: AstraZeneca. F. Meric-Bernstam: Financial Interests, Personal, Other, Consultant: AstraZeneca, OnCusp Therapeutics, Zymeworks; Financial Interests, Personal, Other, Consulting: Calibr, Ecor1, Exelixis, GT Aperion, Infinity Pharmaceuticals, Loxo Oncology, LegoChem Bio, Lengo Therapeutics, Tallac Therapeutics, Becton Dickinson, eFfector Therapeutics, Jazz Pharmaceuticals; Financial Interests, Personal, Advisory Board: Daiichi Sankyo, Incyte, Karyopharm, Protai, TheraTechnologies, Zentalis, FogPharma, Harbinger Health, Mersana Therapeutics, Sanofi Pharmaceuticals; Financial Interests, Personal, Other, Consulting: Menarini Group; Financial Interests, Personal, Advisory Board/Consultant: Seagen; Financial Interests, Personal, Invited Speaker: Dava Oncology; Financial Interests, Institutional, Other, Local PI / Research Grant: Aileron Therapeutics, Bayer Healthcare, CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., eFfector Therapeutics, Taiho Pharmaceutical Co.; Financial Interests, Institutional, Other, Local PI / Research Grant / Coordinating PI: AstraZeneca; Financial Interests, Institutional, Local PI: Calithera Biosciences, Curis Inc., Debiopharm International, Guardant Health Inc., Klus Pharma, Novartis, Jazz Pharmaceuticals, Zymeworks; Financial Interests, Institutional, Other, Local PI / Steering Committee Member: Genentech Inc.; Financial Interests, Institutional, Research Grant: Takeda Pharmaceutical Co., Puma Biotechnology Inc., Repare; Other, Travel support: European Organisation for Research and Treatment of Cancer (EORTC), European Society for Medical Oncology (ESMO); Other, Travel Support: Cholangiocarcinoma Foundation, Dava Oncology. R.W. Lentz: Financial Interests, Institutional, Research Funding: ALX Oncology, Merck, Eli Lilly, Guardant, EDDC; Financial Interests, Personal, Speaker, Consultant, Advisor: Boehringer Ingelheim, Agenus. All other authors have declared no conflicts of interest.