Sirexatamab Combo Shows Promise in Advanced Colorectal Cancer

A new therapeutic approach is offering hope for patients with a specific type of advanced colorectal cancer. Recent findings indicate that adding sirexatamab (DKN-01) to a standard treatment regimen can significantly improve survival outcomes for patients whose tumors have high levels of DKK1 protein.

These promising results come from the phase 2 DeFianCe clinical trial, which were presented at the 2025 ESMO Congress. The study evaluated the combination of sirexatamab, bevacizumab (Avastin), and standard-of-care chemotherapy against the standard treatment alone in patients with metastatic colorectal cancer (mCRC).

A Targeted Approach Shows Promise

In the overall study population, the addition of sirexatamab led to a slightly higher overall response rate (ORR) of 35.1% compared to 26.6% in the control group. The median progression-free survival (PFS) was also slightly longer at 9.2 months versus 8.3 months. However, lead author Dr. Zev A. Wainberg noted that neither of these initial findings reached statistical significance.

The DKK1-High Biomarker: A Game Changer

The true potential of the therapy became clear when researchers focused on a specific subgroup of patients with high levels of the DKK1 biomarker. In this DKK1-high group, the benefits were substantial and statistically significant.

"Looking at the DKK1-high population, defined as the upper median, the improvement started to bear fruit," explained Dr. Wainberg, a professor of medicine at UCLA.

Key outcomes for the DKK1-high patients on the sirexatamab regimen included:

• Progression-Free Survival (PFS): A median of 9.03 months, compared to just 7.06 months for the control group. This represents a 39% reduction in the risk of progression or death.
• Overall Survival (OS): The median OS was not yet reached in the sirexatamab group, while it was 14.39 months in the control group. This translates to a remarkable 58% reduction in the risk of death.
• Overall Response Rate (ORR): The response rate was 38.0% in the sirexatamab arm versus 23.7% in the control arm.

Inside the DeFianCe Trial Design

The DeFianCe trial was a randomized phase 2 study involving 188 patients with microsatellite stable (MSS) metastatic colorectal cancer who had received one prior line of therapy. Patients were randomly assigned to receive either sirexatamab combined with standard chemotherapy (FOLFIRI or FOLFOX) and bevacizumab, or the standard therapy alone. The primary goal was to measure investigator-assessed PFS, with secondary endpoints including safety, ORR, and OS.

Patient Profile and Safety

The study arms were well-balanced, with most patients having left-sided tumors and a high incidence of liver metastases. Importantly, the addition of sirexatamab did not significantly increase the side effects of the treatment. The rate of treatment-emergent adverse events was similar across both groups. Discontinuation rates, dose reductions, and treatment interruptions were also comparable, suggesting the combination is well-tolerated.

What This Means for the Future

The compelling data from the DeFianCe trial strongly supports the continued investigation of sirexatamab as a targeted therapy for patients with DKK1-high mCRC. As Dr. Wainberg concluded, these findings pave the way for further development that could potentially establish a new standard of care for this specific patient population.