Adlai Nortye Advances First-in-Class Pan-RAS(ON) ADC AN4035 into Phase I Trial for RAS-Addicted Solid Tumors
核心洞察
Adlai Nortye received HREC approval and submitted a CTN in Australia to begin a Phase I trial of AN4035 (搜索), the first pan-RAS (搜索)(ON) inhibitor-based ADC to enter clinical development globally.
AN4035 (搜索) targets CEACAM5 (搜索)-expressing tumors and delivers a pan-RAS (搜索)(ON) inhibitor payload designed to localize activity to tumors while minimizing systemic toxicity.
The global Phase I study will evaluate AN4035 (搜索) as monotherapy and in combination with cetuximab in approximately 288 patients with colorectal, pancreatic, and lung cancers harboring RAS (搜索) mutations.
Adlai Nortye Ltd. (NASDAQ: ANL), a clinical-stage biotechnology company, announced today that it has submitted a Clinical Trial Notification (CTN) to Australia's Therapeutic Goods Administration (TGA) and received approval from the Human Research Ethics Committee (HREC) to commence a Phase I clinical trial evaluating AN4035 (搜索), a first-in-class CEACAM5 (搜索)-targeting, pan-RAS (搜索)(ON) inhibitor-based antibody drug conjugate (ADC). The trial will enroll patients with CEACAM5-enriched, RAS-addicted solid tumors, marking the first time a pan-RAS(ON) ADC has entered clinical development globally.
"AN4035 (搜索) is a first-in-class CEACAM5 (搜索)-targeting ADC armed with a pan-RAS (搜索)(ON) inhibitor payload, and is our first drug candidate to demonstrate proof-of-concept of our RASiCA™ (RAS Inhibitor Conjugated Antibody) platform," said Dr. Archie Tse, President, Head of Research & Development at Adlai Nortye. "To our knowledge, AN4035 is the first pan-RAS(ON) ADC to enter the clinic globally."
Addressing a Persistent Unmet Need in RAS (搜索)-Driven Cancers
RAS (搜索) mutations are among the most common oncogenic drivers, occurring in approximately 30% of human cancers and at particularly high frequency in colorectal, pancreatic, and non-small cell lung cancers. While recent approvals of KRAS G12C inhibitors have demonstrated that mutant RAS can be therapeutically targeted, most RAS alterations remain without effective targeted treatment options. Systemic pan-RAS inhibition has raised concerns about toxicity in normal tissues, a challenge AN4035 (搜索) seeks to address through targeted delivery.
CEACAM5 (搜索) is an antigen overexpressed in colorectal, pancreatic, and lung cancers, which frequently harbor RAS (搜索) mutations. By using a CEACAM5-directed antibody to selectively deliver a pan-RAS(ON) inhibitor payload into tumor cells, AN4035 (搜索) is designed to localize pan-RAS(ON) inhibitor activity to the tumor while minimizing systemic RAS pathway inhibition. Dr. Tse noted that this approach "could potentially both widen the therapeutic window and enable rational combinations."
Phase I Trial Design and Scope
The open-label global Phase I trial (NCT07686445) will evaluate AN4035 (搜索) both as monotherapy and in combination with the EGFR inhibitor cetuximab. According to the clinicaltrials.gov listing, the study is expected to begin recruiting in September 2026 at sites in Sydney and Perth, Australia. Approximately 288 patients with advanced colorectal cancer (搜索), pancreatic ductal adenocarcinoma (搜索), non-small cell lung cancer (搜索), and other CEACAM5 (搜索)-positive solid tumors harboring KRAS, NRAS, or HRAS mutations are expected to enroll.
Dose escalation will employ a Bayesian Optimal Interval (BOIN) design to establish the maximum tolerated dose and recommended Phase II dose, after which expansion cohorts will assess preliminary antitumor activity. The trial will evaluate safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy. Notably, patients previously treated with KRAS G12C inhibitors are eligible for enrollment, allowing evaluation of AN4035 (搜索) in a population that may already have received mutation-specific RAS (搜索)-targeted therapy.
The decision to combine AN4035 (搜索) with cetuximab reflects growing interest in simultaneously targeting complementary signaling pathways in colorectal cancer (搜索), though the clinical benefit of this combination remains to be established.
Preclinical Evidence Supporting Clinical Advancement
Preclinical data presented by Adlai Nortye at the 2026 AACR Annual Meeting provided the scientific rationale for advancing AN4035 (搜索) into the clinic. The ADC demonstrated nanomolar to picomolar cytotoxicity in CEACAM5 (搜索)-positive, RAS (搜索)-addicted cancer cell lines, along with a robust bystander killing effect. In cell line-derived and patient-derived xenograft (CDX/PDX) models, AN4035 exhibited potent anti-tumor activity with deep and durable tumor regressions.
In a patient-derived xenograft study, the company reported an objective response rate of 73%. Non-human primate studies supported a safety profile that the company considered suitable for clinical development. The payload is designed to remain largely inactive in circulation and become concentrated within CEACAM5 (搜索)-expressing tumors following ADC internalization, potentially improving the therapeutic index of pan-RAS (搜索) inhibition.
Regulatory Pathway and Next Steps
In parallel with the Australian CTN and HREC approval, Adlai Nortye is filing investigational new drug (IND) applications for AN4035 (搜索) with the U.S. Food and Drug Administration (FDA) and China's National Medical Products Administration (NMPA). Patient dosing with AN4035 is expected to begin in the second half of 2026.
AN4035 (搜索) occupies a differentiated position in the rapidly evolving competitive landscape for RAS (搜索)-mutated cancers by pairing targeted drug delivery with pan-RAS(ON) inhibition rather than attempting systemic blockade of RAS signaling. As a first-in-human study, the trial is intended primarily to establish safety, tolerability, and appropriate dosing. Whether this approach can generate meaningful clinical activity while maintaining an acceptable safety profile remains the central question the Phase I study is designed to address.