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

Abstract

Antibody-drug conjugate; Metastatic colorectal cancer

Conjugado anticuerpo-fármaco; Cáncer colorrectal metastásico

Conjugat d'anticòs-fàrmac; Càncer colorectal metastàtic

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.

This study was funded by the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945). The healthcare business of Merck KGaA, Darmstadt, Germany provided the study drug and collaborated with investigators during trial design and planning, data collection and analysis and interpretation of results. The authors would like to acknowledge the contributions of K. Dueker, N. Piske and R. Martello in biomarker and ADA data analyses. Medical writing support was provided by A. Singh of Merck Specialities Pvt. Ltd., Bangalore, India, an affiliate of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945), in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3). Medical writing and editorial support were funded by the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945).