Elevated baseline DKK1 plasma is a biomarker for sirexatamab treated colorectal cancer patients

Sirexatamab is an IgG4 monoclonal antibody that potently neutralizes dickkopf-related protein 1 (DKK1). DKK1 is a secreted protein that has been implicated as a poor prognostic marker and as an oncogenic driver for colorectal cancer (CRC). The DeFianCe (NCT05480306) Phase 2 randomized, global, open-label, multicenter study was conducted to evaluate the efficacy and safety of sirexatamab plus the current standard of care (SOC) treatment regimen (FOLFIRI/FOLFOX and bevacizumab) versus SOC as second-line treatment for participants with advanced CRC (n=188). A retrospective analysis of baseline plasma levels of DKK1 using a research assay identified a significant improvement in progression free and overall survival favoring the experimental arm in patients with elevated levels of DKK1. In order to enable future prospective patient selection, an optimized DKK1 assay using the Meso Scale Discovery (MSD) platform was developed and underwent feasibility at a central laboratory. DeFianCe samples were retested with the optimized assay. Consistent with the research assay, patients whose DKK1 levels were above the median showed improved clinical outcomes in the experimental arm compared to SOC. Furthermore, approximately 500 commercial CRC plasma samples were evaluated to determine the prevalence of patients with elevated DKK1 in a real-world data set and understand the association between demographics and DKK1 levels. Future work will include completing the development and validation of the assay as a potential companion diagnostic and determining the appropriate threshold of DKK1 plasma levels for CRC patients who would be most likely to derive clinical benefit from a sirexatamab-based therapy.