China-based Adlai Nortye Ltd. (Nasdaq: ANL) has advanced AN4035, a CEACAM5-targeted antibody-drug conjugate (ADC) carrying a proprietary pan-RAS(ON) inhibitor payload, into first-in-human clinical testing in patients with advanced RAS-mutated solid tumors. As per a clinicaltrials.gov listing, the Phase I study (NCT07686445) is expected to begin recruiting in September 2026 at sites in Sydney and Perth, Australia, and marks the clinical debut of a strategy designed to selectively deliver pan-RAS inhibition to CEACAM5-expressing tumors while potentially reducing the systemic toxicity that has challenged broader RAS-targeting approaches.
RAS mutations remain 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, and systemic pan-RAS inhibition has raised concerns about toxicity in normal tissues. AN4035 seeks to address this challenge by using a CEACAM5-directed antibody to selectively deliver a pan-RAS(ON) inhibitor payload into tumor cells expressing the surface antigen.
The open-label Phase I trial will evaluate AN4035 both as monotherapy and in combination with the EGFR inhibitor cetuximab. Approximately 288 patients with advanced colorectal cancer, pancreatic ductal adenocarcinoma, non-small cell lung cancer and other CEACAM5-positive solid tumors harboring KRAS, NRAS or HRAS mutations are expected to enroll. Dose escalation will use a Bayesian Optimal Interval (BOIN) design to establish the maximum tolerated dose and recommended Phase II dose before expansion cohorts assess preliminary antitumor activity.
The company's decision to combine AN4035 with cetuximab reflects growing interest in simultaneously targeting complementary signaling pathways in colorectal cancer, although the clinical benefit of the combination remains to be established. Patients previously treated with KRAS G12C inhibitors are eligible for enrollment, allowing evaluation of AN4035 in a population that may already have received mutation-specific RAS-targeted therapy.
Preclinical data presented by Adlai Nortye at the 2026 AACR Annual Meeting provided the scientific rationale for advancing AN4035 into the clinic. According to the company, the ADC demonstrated potent antitumor activity across multiple colorectal cancer cell lines, induced bystander killing of neighboring tumor cells, and produced deep and durable tumor regressions in colorectal cancer cell line-derived and patient-derived xenograft models. In a patient-derived xenograft study, the company reported an objective response rate of 73%, while 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-expressing tumors following ADC internalization, potentially improving the therapeutic index of pan-RAS inhibition.