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

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) in circulation. After a median treatment of 19.1 weeks (range: 1.7-48.3), three of 40 patients (7.5%) had confirmed partial responses (15.0% (6/40) unconfirmed), all at DLs ≥2.4 mg kg^-1. mPFS was 5.9 months (95% confidence interval: 4.6-7.2); at DLs ≥2.4 mg kg^-1 (n = 34), mPFS was 6.7 months (95% confidence interval: 4.6-8.8). Four patients (10.0%) remained on treatment at cutoff. These early clinical data corroborate preclinical findings, showing predictable safety and encouraging antitumor activity of Precem-TcT at DLs ≥2.4 mg kg^-1, with no interstitial lung disease or ocular toxicity. The dose-optimization part at the RDEs of 2.4 mg kg^-1 and 2.8 mg kg^-1 (both every 3 weeks) in PROCEADE-CRC-01 is ongoing. ClinicalTrials.gov identifier: NCT05464030 .