Leap Therapeutics Publishes DeFianCe Study Results: Plasma DKK1 Emerges as Predictive Biomarker for Sirexatamab Benefit in Second-Line Colorectal Cancer
核心洞察
The randomized Phase 2 DeFianCe study demonstrated that baseline plasma DKK1 (搜索) levels predict deepening benefit from sirexatamab when added to bevacizumab and chemotherapy in second-line metastatic colorectal cancer (搜索) patients.
In DKK1 (搜索)-high patients above the median, sirexatamab improved median PFS to 9.0 months versus 7.1 months (HR 0.61; p=0.0255) and median OS was not reached versus 14.4 months (HR 0.42; p=0.0118).
Among upper-quartile DKK1 (搜索)-high patients, the OS hazard ratio was 0.17 (p<0.001), with median OS not reached versus 9.5 months, while ORR reached 44.0% compared with 15.8% in the control arm.
Leap Therapeutics, the biotechnology subsidiary of Cypherpunk Technologies (搜索) Inc., announced the publication of complete results from the randomized Phase 2 DeFianCe study of sirexatamab (DKN-01) in Clinical Cancer Research, establishing baseline plasma DKK1 (搜索) as a continuous quantitative biomarker that predicts deepening therapeutic benefit in patients with second-line metastatic colorectal adenocarcinoma (mCRC).
The publication, titled "Sirexatamab in Combination with Bevacizumab and Chemotherapy as Second-Line Therapy for Advanced Colorectal Adenocarcinoma: the Phase II DeFianCe Trial," reports comprehensive efficacy, safety, and biomarker analyses and details the statistical basis for the DKK1 (搜索) biomarker finding. The peer-reviewed analyses demonstrate that the benefit of sirexatamab increases as a patient's baseline plasma DKK1 level rises — a relationship confirmed by three independent statistical approaches.
"In second-line colorectal cancer, we urgently need novel biomarkers that inform patients' treatment options. The final data from the DeFianCe study show that baseline plasma DKK1 (搜索) identifies patients with more aggressive disease, and it identifies the patients who benefit most from adding sirexatamab," said Zev Wainberg, MD, Professor of Medicine at UCLA and co-director of the UCLA GI Oncology Program. "Patients with high DKK1 do worse on standard of care, and they are the patients who gained the most in response and survival when sirexatamab was added."
Markus Moehler, MD, PhD, Head of GI Oncology at the Mainz University Clinic, added: "Microsatellite-stable colorectal cancer remains one of the most difficult settings in gastrointestinal oncology, as patients whose disease progresses after first-line therapy have quite limited options. These data support the utility of baseline plasma DKK1 (搜索) as a liquid biomarker for improving response rates and survival with sirexatamab, making a compelling case for a biomarker-selected Phase 3 registrational trial."
Study Design and Overall Results
DeFianCe (NCT05480306) was a two-part, randomized, open-label, multicenter Phase 2 study. Part B randomized 188 patients 1:1 to receive sirexatamab plus FOLFIRI or mFOLFOX6 and bevacizumab (Sirexatamab Arm) or chemotherapy and bevacizumab alone (Control Arm). The primary endpoint was investigator-assessed progression-free survival (PFS), with secondary endpoints including objective response rate (ORR) and overall survival (OS). Baseline plasma DKK1 (搜索) was a prespecified candidate biomarker.
The prespecified primary endpoint of PFS in the intent-to-treat (ITT) population was not met. Median PFS was 9.2 months in the Sirexatamab Arm versus 8.3 months in the Control Arm (HR 0.84; 95% CI, 0.58–1.21). ORR was 35.1% versus 26.6%, and median OS was not reached in either arm (HR 0.83; 95% CI, 0.46–1.48). The final analysis included 119 investigator-assessed PFS events against the 145 events planned, leaving the ITT analysis underpowered in a biologically heterogeneous population.
DKK1 (搜索) as a Predictive Biomarker
Three independent analyses — a continuous treatment-by-DKK1 (搜索) interaction model, a permutation-tested Biomarker Adaptive Threshold (BAT) analysis, and median- and upper-quartile subgroup analyses — converged on the conclusion that sirexatamab benefit rises with baseline plasma DKK1. The treatment-by-DKK1 interaction was statistically significant for both PFS (p=0.0129) and OS (p=0.0027), with DKK1 modeled as a continuous variable. The BAT analysis with permutation testing reached the same conclusion (PFS p=0.018; OS p<0.001).
In DKK1 (搜索)-high patients above the median (n=88), ORR was 38.0% in the Sirexatamab Arm compared with 23.7% in the Control Arm. Median PFS was 9.0 months versus 7.1 months (HR 0.61; 95% CI, 0.37–1.00; p=0.0255). Median OS was not reached versus 14.4 months (HR 0.42; 95% CI, 0.19–0.91; p=0.0118).
Among DKK1 (搜索)-high patients in the upper quartile (n=44), the benefit was even more pronounced. ORR was 44.0% in the Sirexatamab Arm compared with 15.8% in the Control Arm (p=0.0149). Median PFS was 9.4 months versus 5.9 months (HR 0.46; 95% CI, 0.22–0.96; p=0.0168). Median OS was not reached versus 9.5 months (HR 0.17; 95% CI, 0.05–0.53; p<0.001).
Prognostic Value of DKK1 (搜索)
Higher baseline DKK1 (搜索) was also prognostic of poor outcome on standard therapy. In the Control Arm, median OS declined as DKK1 rose — not reached in the overall population, 14.4 months above the median, and 9.5 months in the upper quartile — consistent with published evidence linking elevated DKK1 to more aggressive disease. DKK1-high patients therefore represent a population with both poor prognosis on standard therapy and the greatest observed benefit from sirexatamab.
Plasma DKK1 (搜索) as a Practical Biomarker
Baseline plasma DKK1 (搜索) was detectable in 100% of patients across an approximately eight-fold dynamic range. Levels were concordant across two orthogonal platforms — an aptamer-based SomaScan assay and an antibody-based Meso Scale Discovery (MSD) assay (Spearman r=0.77). Tumoral DKK1 mRNA expression was low in most tissue samples, reinforcing that plasma, not tissue, reflects the systemic DKK1 burden relevant to colorectal cancer biology and supporting a blood-based patient-selection test.
Safety Profile
Sirexatamab in combination with chemotherapy and bevacizumab was generally well tolerated. Grade 3 or higher treatment-emergent adverse events (TEAEs) occurred in 59.3% of patients in the Sirexatamab Arm compared with 67.0% in the Control Arm, and serious TEAEs were comparable between arms (19.8% versus 19.3%). TEAEs leading to discontinuation of sirexatamab occurred in 4.4% of patients, indicating that adding sirexatamab did not meaningfully change the tolerability of standard of care.
Regulatory Context and Next Steps
Sirexatamab is a humanized monoclonal antibody that binds and neutralizes Dickkopf-related protein 1 (DKK1 (搜索)), a secreted modulator of Wnt signaling associated with more aggressive disease, immune suppression, angiogenesis, and poorer outcomes in colorectal and other cancers. In May 2026, the FDA granted Fast Track designation to sirexatamab in combination with fluoropyrimidine plus oxaliplatin- or irinotecan-based chemotherapy and bevacizumab for the treatment of patients with DKK1-high metastatic colorectal cancer (搜索) whose disease has progressed following one prior systemic therapy.
The findings define DKK1 (搜索)-high mCRC as a biologically distinct population with high unmet need and provide the scientific foundation for a biomarker-selected Phase 3 registrational trial.