Precemtabart tocentecan, an anti-CEACAM5 antibody–drug conjugate, in metastatic colorectal cancer: a phase 1 trial

作者：Scott Kopetz, Valentina Boni, Ken Kato, Kanwal Raghav, María Vieito, Athanasios Pallis, Christina Habermehl, Abdul Siddiqui, Perrine Courlet, Willem Sloot, Sabine Raab-Westphal, Felix Hart, Ildefonso Rodriguez-Rivera · 发表于：Nature Medicine · 年份：2025 · DOI：10.1038/s41591-025-03843-z · 被引用次数：19 · 研究领域：Radiopharmaceutical Chemistry and Applications、Colorectal Cancer Treatments and Studies、HER2/EGFR in Cancer Research

Abstract CEACAM5, a cell surface protein, is overexpressed in colorectal cancer (CRC). Precemtabart tocentecan (Precem-TcT, previously M9140) is an anti-CEACAM5 antibody–drug conjugate with the topoisomerase 1 inhibitor exatecan as payload. Precem-TcT demonstrated strong antitumor activity and potent bystander activity in preclinical models. Its toxicity profile in cynomolgus monkeys was consistent with that of exatecan. In the dose-escalation stage of the phase 1 trial of Precem-TcT (PROCEADE-CRC-01), 40 heavily pretreated patients with irinotecan-refractory metastatic CRC received Precem-TcT every 3 weeks across seven dose levels (DLs, 0.6–3.2 mg kg −1 ). Primary endpoints were dose-limiting toxicities (DLTs), adverse events and preliminary clinical activity to establish the recommended dose(s) for expansion (RDEs). Secondary endpoints included pharmacokinetic parameters, objective response and median progression-free survival (mPFS). At the planned, end-of-dose-escalation analysis with extended follow-up (cutoff: 1 August 2024), seven patients had experienced DLTs, primarily hematologic events at 3.0 mg kg −1 and 3.2 mg kg −1 . A treatment-related death, also deemed disease related, was reported in a patient with multiple comorbidities and grade 3 obesity. The maximum tolerated dose was determined to be 2.8 mg kg −1 every 3 weeks. Total and conjugated antibody pharmacokinetic profiles largely overlapped, indicating stability of the linker–payload (β-glucuronide–exatecan) i...