Merus N.V. has announced the dosing of the first patient in its Phase 2 clinical trial evaluating petosemtamab monotherapy for heavily pretreated (3L+) metastatic colorectal cancer (mCRC). This open-label trial aims to assess the safety and antitumor activity of petosemtamab in patients who have progressed following anti-EGFR therapy and lack specific mutations (KRAS, NRAS).
Petosemtamab: A Novel Bispecific Antibody
Petosemtamab, also known as MCLA-158, is a Biclonics® low-fucose human full-length IgG1 antibody. It is designed to target the epidermal growth factor receptor (EGFR) and the leucine-rich repeat containing G-protein-coupled receptor 5 (LGR5). Petosemtamab exhibits three independent mechanisms of action:
- Inhibition of EGFR-dependent signaling
- LGR5 binding leading to EGFR internalization and degradation in cancer cells
- Enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) activity
Preclinical Evidence
According to John de Kruif Ph.D., Chief Technology Officer at Merus, petosemtamab was discovered through an unbiased screen of over 500 bispecific antibodies. Preclinical studies in CRC models demonstrated that petosemtamab consistently showed superior activity compared to cetuximab, a standard therapy in mCRC.
Trial Design and Objectives
The Phase 2 trial is an open-label study that will evaluate the safety and antitumor activity of petosemtamab monotherapy in heavily pretreated mCRC patients who have progressed after anti-EGFR therapy. Patient eligibility requires the absence of certain mutations, including KRAS and NRAS, as detected in plasma by ctDNA NGS.
