Precemtabart tocentecan

Table of contents

• What is precemtabart tocentecan?
• How does precemtabart tocentecan work?
• Which conditions is it studied for?
• How is precemtabart tocentecan given?
• What do the clinical trials show?
• What side effects are known?

What is precemtabart tocentecan?

Precemtabart tocentecan, previously known by the development code M9140, is an investigational antibody–drug conjugate (ADC).^[4] An ADC is a type of medicine that combines an antibody — a protein designed to recognise a specific target on cells — with a cell-killing drug attached to it. The antibody part of precemtabart tocentecan targets a protein called CEACAM5, which is overexpressed on the surface of many colorectal cancer cells and other solid tumours.^[4] The cell-killing payload is exatecan, a topoisomerase 1 inhibitor.^[4] Precemtabart tocentecan is not yet an authorised medicine; it remains under investigation in clinical trials. The European Medicines Agency (EMA) has granted a product-specific waiver for a paediatric investigation plan, meaning the company is not required to study the drug in children for all malignant neoplasms except central nervous system tumours and haematopoietic and lymphoid tissue neoplasms.^[3]

How does precemtabart tocentecan work?

The drug works by binding to CEACAM5 on the surface of cancer cells. Once bound, the ADC is taken inside the cell, where the linker between the antibody and the payload is broken down, releasing exatecan. Exatecan inhibits topoisomerase 1, an enzyme that helps cancer cells copy their DNA during division. By blocking this enzyme, the drug causes DNA damage and cell death.^[4] In preclinical models, precemtabart tocentecan also showed a bystander effect, meaning the released drug can affect neighbouring cancer cells that may not express CEACAM5 themselves.^[4] The linker–payload combination (β-glucuronide–exatecan) was shown to be stable in the bloodstream, with total and conjugated antibody profiles largely overlapping in pharmacokinetic measurements.^[4]

Which conditions is it studied for?

• Metastatic colorectal cancer — cancer of the colon or rectum that has spread to other parts of the body; the Phase 3 trial enrols participants whose disease has progressed after previous treatment.^[1]
• Gastric cancer — advanced cancer of the stomach, studied in a Phase 1 substudy with 91 participants.^[2]
• Non-small cell lung cancer (NSCLC) — the most common form of lung cancer, studied in a Phase 1 substudy with 78 participants.^[2]
• Pancreatic ductal adenocarcinoma — the most common type of pancreatic cancer, studied in a Phase 1 substudy with 73 participants.^[2]

How is precemtabart tocentecan given?

Precemtabart tocentecan is given by intravenous infusion, meaning it is administered directly into a vein.^[3] The pharmaceutical form listed in the EMA paediatric investigation plan is a powder for concentrate for solution for infusion.^[3] In the earlier Phase 1 dose-escalation trial, the drug was given every 3 weeks, and the maximum tolerated dose was determined to be 2.8 mg per kilogram of body weight every 3 weeks.^[4] The ongoing Phase 3 trial also uses a 2.8 mg/kg intravenous dose.^[1]

What do the clinical trials show?

Four clinical trial records are currently listed for precemtabart tocentecan, all with Authorised status, meaning regulatory approval has been granted for the studies to proceed.^[2][1] The largest and most advanced is a Phase 3 trial (PROCEADE-CRC-03) in metastatic colorectal cancer with 1,020 participants. This trial compares precemtabart tocentecan alone, and in combination with bevacizumab, against trifluridine/tipiracil plus bevacizumab, which is a standard treatment option for previously treated metastatic colorectal cancer. The primary endpoint is overall survival, meaning how long participants live.^[1]

The other three records are Phase 1 substudies of a single trial protocol (NCT06710132) in advanced gastric cancer (91 participants), non-small cell lung cancer (78 participants), and pancreatic ductal adenocarcinoma (73 participants). These substudies measure objective response according to RECIST v1.1, a standard way of assessing whether tumours shrink in response to treatment, as assessed by investigators.^[2][2][2]

Earlier clinical data from the Phase 1 dose-escalation trial (PROCEADE-CRC-01) in 40 heavily pretreated patients with irinotecan-refractory metastatic colorectal cancer were published in Nature Medicine. At the analysis cutoff, three of 40 patients (7.5%) had confirmed partial responses, with an additional three unconfirmed responses (15.0% total unconfirmed). The median progression-free survival was 5.9 months overall and 6.7 months in patients treated at dose levels of 2.4 mg/kg or higher. Four patients (10.0%) remained on treatment at the cutoff.^[4]

What side effects are known?

In the Phase 1 dose-escalation trial, seven patients experienced dose-limiting toxicities, primarily haematologic events — side effects affecting the blood and bone marrow — at the two highest dose levels of 3.0 mg/kg and 3.2 mg/kg. A treatment-related death, which was also deemed disease-related, was reported in a patient with multiple comorbidities and grade 3 obesity. The maximum tolerated dose was therefore set at 2.8 mg/kg every 3 weeks.^[4] The toxicity profile observed in cynomolgus monkeys during preclinical testing was consistent with that of exatecan, the cell-killing payload.^[4] Detailed side effect data from the ongoing Phase 3 and Phase 1 substudies have not yet been published in the sources provided.