Abstract CT049: ACR246, a novel anti-5T4 antibody-drug conjugate: Updated phase I/IIa study results in advanced solid tumors

Abstract Background: ACR246 is a novel anti-5T4 antibody-drug conjugate (ADC) composed of a fully human monoclonal antibody, a proprietary topoisomerase I inhibitor payload, and an innovative stable cleavable linker, with a drug-to-antibody ratio (DAR) of 8. Preclinical studies demonstrated excellent antitumor efficacy, high tolerability, and a favorable therapeutic window. Methods: This phase I/IIa, open-label, multicenter study evaluated ACR246 in patients (pts) with advanced solid tumors. The phase I dose-escalation utilized an accelerated titration followed by a BOIN design to assess doses from 0.6 to 4.5 mg/kg administered intravenously every 3 weeks. Primary objectives were to evaluate safety, tolerability, pharmacokinetics (PK), immunogenicity, preliminary efficacy, and determine the recommended phase II dose (RP2D). The phase IIa expansion will further assess ACR246 in 5T4-positive patients. Results: As of December 10, 2025, 22 pts with various solid tumors, including esophageal squamous cell carcinoma (ESCC), gastric cancer (GC), ovarian cancer (OV), colorectal cancer (CRC), and non-small cell lung cancer (NSCLC),etc., were enrolled across six dose levels: 0.6 mg/kg (n=1), 1.2 mg/kg (n=3), 2.4 mg/kg (n=5), 3.0 mg/kg (n=3), 3.6 mg/kg (n=7), and 4.5 mg/kg (n=3). The median age was 58 years (range 35-72). Pts had received a median of 2-6 prior lines of therapy. Treatment-related adverse events (TRAEs) of any grade occurring in >20% of pts included leukopenia (90.9%), nausea and anemia (86.4% each), neutropenia (68.2%), vomiting (59.1%), thrombocytopenia and asthenia (50.0% each), hyponatremia, decreased appetite, and constipation (45.5% each), hypokalemia and stomatitis (36.4% each), increased ALT and increased blood bilirubin (31.8% each), hypertriglyceridemia and rash (27.3% each), and hypocalcemia and pyrexia (22.7% each). Notably, no Grade ≥3 TRAEs were reported at the 2.4 and 3.0 mg/kg dose levels. Among efficacy-evaluable pts, the objective response rate (ORR) was 35.0% (7/20), with partial responses (PRs) observed in GC (n=2), OV (n=1), ESCC(n=2), and NSCLC (n=2), per RECIST v1.1; the disease control rate (DCR) was 80.0%. In the biomarker-evaluable subset of 9 pts with 5T4-positive tumors confirmed by IHC, the DCR reached 88.9% (8/9). In the 2.4-3.6 mg/kg dose range (n=13), efficacy was more pronounced, with an ORR of 46.2% (6/13), a DCR of 92.3% (12/13: 6 PRs and 6 SD). PK analysis showed nearly overlapping concentration-time profiles for conjugate antibody and total antibody, with very low free payload levels in plasma, confirming high linker stability in circulation. Conclusions: ACR246 continues to demonstrate a manageable safety profile and promising antitumor activity in heavily pretreated pts with advanced solid tumors. Encouraging efficacy signals were observed in pts with ESCC, GC, OV, and NSCLC. Enrollment and dose exploration are ongoing. Clinical trial identification: NCT06238401 Citation Format: Panpan Zhang, Yuping Sun, Zhengbo Song, Zhenwei Miao, Lina Chen, Feng Wang, Yang Li, Lin Shen. ACR246, a novel anti-5T4 antibody-drug conjugate: Updated phase I/IIa study results in advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT049.