Sirexatamab Regimen May Improve PFS, OS in DKK1-High Colorectal Cancer

Adding sirexatamab (DKN-01) to bevacizumab (Avastin) and chemotherapy did not improve progression-free survival (PFS), overall survival (OS), and overall response rate (ORR) in patients with metastatic colorectal cancer (CRC) who progressed during or after 1 line of prior systemic therapy, according to results from the phase 2 DeFianCe trial (NCT05480306) published in Clinical Cancer Research and announced in a press release from Leap Therapeutics, Inc.^1,2 Notably, exploratory analyses did demonstrate that greater sirexatamab benefit was achieved in patients with higher baseline plasma DKKI.

What were the key efficacy findings from the DeFianCe trial?

In the intent-to-treat (ITT) population, the prespecified primary end point of investigator-assessed PFS was not met, with a median PFS of 9.2 months (95% CI, 7.3-10.9) in the sirexatamab arm vs 8.3 months (95% CI, 7.2-9.5) in the control arm (HR, 0.84; 95% CI, 0.58-1.21; P = .1712). Furthermore, the median OS was not reached in either arm (HR, 0.83; 95% CI, 0.46-1.48; P = .2632), and the ORR was 35.1% with sirexatamab vs 26.6% with control (P = .1009).

In patients with baseline plasma DKK1 above the median (n = 88), sirexatamab was associated with an ORR of 38.0% (95% CI, 24.7%-52.8%) vs 23.7% (95% CI, 11.4%-40.2%) with control, a median PFS of 9.0 months (95% CI, 7.0-10.9) vs 7.1 months (95% CI, 5.2-8.3; HR, 0.61; 95% CI, 0.37-1.00), and a median OS that was not reached vs 14.4 months (95% CI, 9.7-not applicable [NA]; HR, 0.42; 95% CI, 0.19-0.91; P = .0118). In the upper-quartile DKK1 subgroup (n = 44), the ORR was 44.0% (95% CI, 24.4%-65.1%) vs 15.8% (95% CI, 3.4%-39.6%), median PFS was 9.4 months (95% CI, 5.8-NA) vs 5.9 months (95% CI, 3.5-8.3; HR, 0.46; 95% CI, 0.22-0.96; P = .0168), and a median OS that was not reached vs 9.5 months (95% CI, 7.1-12.6; HR, 0.17; 95% CI, 0.05-0.53; P <.001).

How does baseline plasma DKK1 predict sirexatamab benefit?

Three independent statistical approaches—a continuous treatment-by-DKK1 interaction model, a permutation-tested biomarker-adaptive threshold analysis, and median- and upper-quartile subgroup analyses—converged on the same conclusion that sirexatamab benefit rises with baseline plasma DKK1. The treatment-by-DKK1 interaction was significant for both PFS (P = .0129) and OS (P = .0027). Baseline plasma DKK1 was detectable in 100% of patients across an approximately 8-fold dynamic range and was concordant between 2 assay platforms (Spearman r = 0.77).

Tumoral DKK1 mRNA expression was low in most tissue samples, supporting plasma, rather than tissue, as the more relevant readout of systemic DKK1 burden and a practical blood-based selection biomarker. Higher DKK1 also tracked with worse outcomes on standard of care alone, a pattern consistent with prior evidence linking elevated DKK1 to more aggressive CRC.

Interim DeFianCe data were previously presented at the 2025 European Society for Medical Oncology Congress, where the DKK1-high subgroup showed early signals of improved PFS and OS with sirexatamab.³

“In second-line [CRC], we urgently need novel biomarkers that inform patients’ treatment options. The final data from the DeFianCe study show that baseline plasma DKK1 identifies patients with more aggressive disease, and it identifies the patients who benefit most from adding sirexatamab. 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,” stated Zev Wainberg, MD, professor of medicine at UCLA and co-director of the UCLA GI Oncology Program, in the press release.²

What was the DeFianCe trial design?

DeFianCe was a 2-part, randomized, open-label, multicenter phase 2 study. Part B randomly assigned 188 patients with metastatic CRC 1:1 to sirexatamab plus investigator-choice folinic acid plus 5-fluorouracil and irinotecan (FOLFIRI) or folinic acid plus 5-fluorouracil and oxaliplatin (mFOLFOX6) and bevacizumab, or to chemotherapy and bevacizumab alone, following progression on 1 prior systemic therapy line. Sirexatamab was given intravenously on day 1 of each 14-day cycle at 400 mg, with an additional 400-mg loading dose on day 8 of cycle 1.

Eligible patients had measurable disease per RECIST v1.1 guidelines, an ECOG performance status of 0 or 1, and histologically confirmed colorectal adenocarcinoma.

The primary end point was investigator-assessed PFS in the ITT population; secondary endpoints included OS and ORR, with baseline plasma DKK1 as a prespecified exploratory biomarker. The final analysis included 119 investigator-assessed PFS events, which was fewer than the 145 planned.

What was the safety profile of sirexatamab?

Sirexatamab combined 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 events were comparable between arms (19.8% vs 19.3%). TEAEs led to discontinuation of sirexatamab in 4.4% of patients. Across both arms, the most frequent TEAEs were decreased neutrophil count, nausea, and diarrhea.

“These data support the utility of baseline plasma DKK1 as a liquid biomarker for improving response rates and survival with sirexatamab, making a compelling case for a biomarker-selected phase 3 registrational trial,” stated Markus Moehler, MD, PhD, head of gastrointestinal oncology and senior physician of gastroenterology and endosonography at Mainz University Clinic, in the press release.²

In May 2026, the FDA granted fast track designation to sirexatamab in combination with chemotherapy and bevacizumab for patients with DKK1-high metastatic CRC whose disease progressed following 1 prior systemic therapy. These results are intended to support planning for a biomarker-selected phase 3 registrational trial.

References

1. Wainberg ZA, Lee KW, Kim JG, et al. Sirexatamab in combination with bevacizumab and chemotherapy as second-line therapy for advanced colorectal adenocarcinoma: the phase II DeFianCe trial. Clin Cancer Res. 2026;XX:XX-XX. doi:10.1158/1078-0432.CCR-26-1456
2. Leap Therapeutics announces publication of DeFianCe study results in Clinical Cancer Research. News release. Leap Therapeutics, Inc. August 12, 2026. Accessed August 12, 2026. https://tinyurl.com/47688c4w
3. Wainberg ZA, Han SW, Kim JG, et al. DeFianCe Trial: a randomized phase 2 trial of sirexatamab (DKN-01) plus bevacizumab and chemotherapy versus bevacizumab and chemotherapy as second-line therapy in advanced microsatellite stable (MSS) colorectal cancer (CRC). Presented at: 2025 European Society for Medical Oncology Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA34.