Cambridge, Massachusetts, August 12, 2026
Leap Therapeutics has announced the publication of final results from its randomized Phase 2 DeFianCe clinical trial evaluating sirexatamab (DKN-01) in combination with chemotherapy and bevacizumab for patients with advanced colorectal cancer. The peer-reviewed findings, published in Clinical Cancer Research, provide additional evidence that baseline plasma DKK1 levels may serve as a predictive biomarker for identifying patients most likely to benefit from sirexatamab. The research is particularly significant for patients with second-line metastatic colorectal cancer (mCRC), where treatment options remain limited.
DKK1 Emerges as a Potential Predictive Biomarker
The DeFianCe study evaluated whether DKK1, a secreted protein associated with aggressive cancer biology, could help identify patients who may derive greater benefit from sirexatamab. In Part B of the randomized, open-label, multicenter Phase 2 study, 188 patients were assigned to receive sirexatamab with chemotherapy and bevacizumab or chemotherapy and bevacizumab alone. Progression-free survival (PFS) was the primary endpoint, while objective response rate (ORR) and overall survival (OS) were secondary endpoints. The peer-reviewed analyses found that the benefit of sirexatamab increased as baseline plasma DKK1 levels increased. Three independent statistical approaches consistently supported the relationship between DKK1 levels and treatment benefit. The treatment-by-DKK1 interaction was statistically significant for both PFS and OS, with PFS showing a p-value of 0.0129 and OS a p-value of 0.0027. A separate permutation-tested Biomarker Adaptive Threshold analysis also supported the findings.
Stronger Outcomes in DKK1-High Patients
Among patients with DKK1 levels above the median, sirexatamab produced an objective response rate of 38.0%, compared with 23.7% for standard treatment alone. Median PFS was 9.0 months versus 7.1 months, with a hazard ratio of 0.61, while median overall survival was not reached in the sirexatamab group compared with 14.4 months in the control group. The differences were even more pronounced among patients in the upper DKK1 quartile. ORR reached 44.0% with sirexatamab versus 15.8% with control therapy. Median PFS was 9.4 months compared with 5.9 months, while median OS was not reached versus 9.5 months. These results suggest that patients with particularly high DKK1 levels may represent a population with both aggressive disease and greater potential benefit from targeted treatment.
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Blood-Based Testing Supports Biomarker Selection
The researchers also found that plasma DKK1 was detectable in all patients and showed an approximately eight-fold dynamic range. Measurements were consistent across two different testing platforms, supporting the potential practicality of using a blood-based biomarker for patient selection. The findings also indicated that plasma DKK1 may better reflect systemic DKK1 burden than tumor tissue measurements in this setting. Importantly, the overall intent-to-treat population did not meet the prespecified primary PFS endpoint. Median PFS was 9.2 months with sirexatamab compared with 8.3 months for control therapy. The company noted that the final analysis had fewer PFS events than originally planned, leaving the overall analysis underpowered in a biologically heterogeneous population.
Sirexatamab was generally well tolerated, with Grade 3 or higher treatment-emergent adverse events reported in 59.3% of patients receiving sirexatamab compared with 67.0% in the control group. Leap Therapeutics said the findings provide a scientific foundation for a potential biomarker-selected Phase 3 trial focused on DKK1-high metastatic colorectal cancer. Sirexatamab previously received FDA Fast Track designation in May 2026 for DKK1-high mCRC following progression after one prior systemic therapy.
Source: Leap Therapeutics press release
