Adlai Nortye partners with Eli Lilly & Merck KGaA for a Phase I trial evaluating AN4035 (CEACAM5-targeted ADC) with cetuximab in RAS-addicted solid tumors.
Written By: Creola Gonsalves, MS Biotech
Reviewed By: Pharmacally Editorial Team
Adlai Nortye has secured clinical trial collaboration and drug supply agreements with Eli Lilly and Merck KGaA to evaluate cetuximab alongside AN4035, an investigational CEACAM5-targeting antibody-drug conjugate (ADC) carrying a pan-RAS(ON) inhibitor payload. The Phase I study will assess whether targeted delivery of RAS inhibition can support a combination strategy in patients with CEACAM5-enriched, RAS-addicted solid tumors.
Dual Targeting of EGFR and RAS Signaling
The agreements support the evaluation of AN4035 in combination with cetuximab, an anti-EGFR antibody marketed as ERBITUX. Lilly will supply cetuximab at no cost to clinical trial sites in the United States, while Merck KGaA, Darmstadt, Germany, will supply the antibody at no cost to sites in Australia and China.
RAS proteins regulate cellular growth and survival, and mutations that activate RAS signaling are common in several solid tumors, including colorectal, pancreatic and lung cancers. EGFR signaling can also contribute to tumor growth and interact with downstream RAS pathways. Combining EGFR blockade with RAS inhibition could therefore provide a complementary approach to suppressing oncogenic signaling.
However, systemic inhibition of these pathways can produce overlapping toxicities, potentially limiting combination treatment. AN4035 uses an antibody-drug conjugate approach to deliver a potent pan-RAS(ON) inhibitor payload to tumors expressing CEACAM5, a cell-surface protein overexpressed in several cancers.
Phase I Trial to Assess Safety and Preliminary Activity
The ongoing global Phase I trial is evaluating AN4035 as a single agent and in combination with cetuximab in patients with CEACAM5-enriched, RAS-addicted solid tumors.
Investigators will assess safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary antitumor activity. The monotherapy and combination arms will begin on a staggered schedule.
The company has not disclosed clinical efficacy or safety results from the cetuximab combination. The study therefore remains an early-stage investigation of the regimen’s tolerability, biological activity and potential therapeutic value. Its findings will help establish whether the combination warrants further clinical development.
Preclinical Findings Support Targeted RAS Inhibition
AN4035 targets CEACAM5 and carries a highly potent pan-RAS(ON) inhibitor payload through Adlai Nortye’s proprietary RASiCA platform. The approach is intended to concentrate RAS inhibition within CEACAM5-expressing tumors rather than rely solely on systemic exposure to the inhibitor.
According to the company, preclinical studies showed favorable thermal and plasma stability, desirable pharmacokinetic properties and strong intracellular payload retention. AN4035 also demonstrated nanomolar-to-picomolar cytotoxicity in CEACAM5-positive, RAS-addicted cancer cell lines, alongside a bystander-killing effect that could extend activity to nearby tumor cells.
In cell-derived and patient-derived xenograft models, the ADC produced substantial tumor regression. Compared with the payload alone, AN4035 also showed greater tumor retention and selectivity over normal tissues.
These findings provide a rationale for clinical testing but do not establish that the ADC will deliver comparable activity or an improved safety profile in patients.
Clinical Significance and Next Steps
Adlai Nortye’s President and Head of Research and Development, Dr. Archie Tse, described dual EGFR and RAS inhibition as a compelling strategy for RAS-addicted cancers. The company expects targeted payload delivery to help address the tolerability challenges associated with combining these pathways.
The collaboration also provides access to cetuximab across trial sites in three countries without drug supply costs to the participating sites. The source announcement does not disclose additional financial terms or a timeline for reporting clinical results.
The key question is whether AN4035 can achieve sufficient tumor-selective RAS inhibition to support combination treatment without unacceptable overlapping toxicity. Results from the Phase I study will be important in determining the feasibility of this approach and whether it can advance toward broader evaluation in RAS-driven solid tumors.
Reference
Adlai Nortye Enters into Clinical Collaboration with Lilly and Merck KGaA, Darmstadt, Germany to Evaluate Combination of AN4035 and Cetuximab, 15 October 2026
About the Writer
Creola Gonsalves (Linkedin) is an M.S. Biotechnology postgraduate with a strong interest in clinical research, evidence interpretation, and healthcare writing, with a focus on translating life-science knowledge into meaningful real-world insights.
She is trained in Good Clinical Practice (GCP), clinical research principles, and critical interpretation of randomized clinical trials, with certifications from NIH and Stanford University.
Her research background in biotechnological applications and microbial research strengthens her ability to understand scientific evidence and develop clear, accurate, and research-driven healthcare content.