Blood Test May Identify Who Benefits From Sirexatamab in Colorectal Cancer

Adding the investigational drug sirexatamab to standard second-line treatment did not delay cancer growth for patients with metastatic colorectal cancer overall, according to results from the phase 2 DeFianCe trial published in Clinical Cancer Research. But patients who started treatment with higher levels of a blood protein called Dickkopf-related protein 1 (DKK1) went longer without their cancer growing and lived longer.

Median progression-free survival, meaning the time patients lived without their cancer growing or spreading, was 9.2 months for patients who received sirexatamab plus chemotherapy and Avastin (bevacizumab), compared with 8.3 months for those who received chemotherapy and Avastin alone. That difference was not large enough to meet the trial's main goal. The two groups also showed no meaningful difference in how long patients lived overall or in how often tumors shrank.

"Sirexatamab plus chemotherapy and bevacizumab did not improve [progression-free survival] in the intent-to-treat population but was generally well tolerated," the researchers wrote.

What is DKK1, and why did the DeFianCe trial measure it?

DKK1 is a protein released into the bloodstream that influences tumor growth, immune activity and the formation of blood vessels that feed tumors. Earlier research has linked higher DKK1 levels with more aggressive colorectal cancer and poorer outcomes. Sirexatamab is an antibody designed to block it.

Researchers measured DKK1 in blood samples drawn before treatment began. It showed up in every patient, and levels varied widely, with the highest roughly eight times the lowest. Most tumor samples showed little or no DKK1 activity, which supports the idea that the DKK1 circulating in the blood comes from several places in the body rather than from the tumor alone.

Did patients with higher DKK1 levels benefit more from sirexatamab?

Among the 88 patients whose DKK1 levels fell above the midpoint for the group, those who received sirexatamab went a median of 9 months without their cancer growing or spreading, compared with 7.1 months for those who received chemotherapy and Avastin alone. Tumors shrank in 38% of the sirexatamab group and 23.7% of the comparison group.

The gap was wider among the 44 patients with the highest DKK1 levels. Those who received sirexatamab went a median of 9.4 months without their cancer growing or spreading, compared with 5.9 months in the comparison group, and tumors shrank in 44% and 15.8% of patients, respectively.

In both groups, median overall survival could not be calculated for patients who received sirexatamab because more than half were still alive when researchers analyzed the data. In the comparison group, it was 14.4 months and 9.5 months.

Patients whose DKK1 levels fell below those cutoffs showed no clear benefit from sirexatamab. Researchers checked the pattern three different ways and found the same direction each time: the higher the DKK1 level, the greater the estimated benefit.

"The consistent association between higher baseline plasma DKK1 and greater sirexatamab benefit suggests that DKK1-directed therapy may require biomarker-selected evaluation rather than all-comer development," the researchers wrote.

How was the phase 2 DeFianCe trial designed?

The randomized portion of the trial enrolled 188 patients at sites in the United States, South Korea and Germany. Patients were assigned by chance to receive either sirexatamab plus chemotherapy and Avastin or chemotherapy and Avastin alone.

Patients in the sirexatamab group received 400 milligrams through an IV on day 1 of each 14-day cycle, plus an extra 400-milligram dose on day 8 of the first cycle. Both groups received one of two standard chemotherapy regimens, FOLFIRI or mFOLFOX6, chosen by their physician and given with Avastin. Treatment continued until the cancer worsened, side effects became unmanageable or patients or their physicians chose to stop.

Patients were eligible if their colorectal cancer had spread and had grown during or after one prior treatment. Median age was 59.5 years, 61.7% were male and 75% had tumors on the left side of the colon.

What are the side effects associated with sirexatamab?

Every patient in both groups had at least one side effect during treatment, and adding sirexatamab did not raise the overall rate. The most common across both groups were a drop in neutrophils, a type of infection-fighting white blood cell, along with nausea and diarrhea.

Among patients who received sirexatamab, 57.1% had side effects their physicians linked to the drug itself, most often nausea (25.3%), fatigue (18.7%) and a drop in neutrophils (14.3%). Severe or life-threatening side effects occurred in 59.3% of the sirexatamab group and 67% of the comparison group.

Four patients (4.4%) stopped sirexatamab because of side effects, and 63 patients (69.2%) paused it temporarily, most often for a drop in neutrophils. One patient in the sirexatamab group died of cardiac arrest, which researchers determined was not related to the drug.

What are the limitations of the DeFianCe results?

The trial recorded fewer instances of cancer growth or death than planned by the time of the analysis, which made it harder to detect a difference between the two groups.

The DKK1 findings were exploratory, meaning they were meant to raise a question for future research rather than set a cutoff for treatment decisions, and they came from small groups of patients. Larger studies pairing blood and tissue samples will be needed to define what sets DKK1-high disease apart and who is most likely to respond to treatment aimed at it.

Reference

1. "Sirexatamab in Combination with Bevacizumab and Chemotherapy as Second-line Therapy for Advanced Colorectal Adenocarcinoma: The Phase II DeFianCe Trial." Wainberg ZA, et al. Clinical Cancer Research. Published July 23, 2026.

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