Sirexatamab Combo Significantly Improves PFS in MSS CRC Subgroups

In the open-label, 2-part, multi-center phase 2 DeFianCe study (NCT05480306), 188 patients with advanced MSS CRC were assigned to receive chemotherapy plus bevacizumab at 5 mg intravenously alone or in combination with sirexatamab at 400 mg every 2 weeks with an additional loading dose in the first treatment cycle.

Combining sirexatamab (DKN-01) with bevacizumab (Avastin) and chemotherapy conferred statistically significant improvements in progression-free survival (PFS) across various subgroups of patients with advanced microsatellite stable (MSS) colorectal cancer (CRC), according to a press release on findings from part B of the phase 2 DeFianCe study (NCT05480306).¹

However, developers at Leap Therapeutics noted that they have begun to explore strategic alternatives to reduce internal expenses and maximize value to shareholders.

With a data cutoff of May 22, 2025, the median PFS across the intent-to-treat (ITT) population (n = 188) was 9.2 months in the sirexatamab arm (n = 94) vs 8.31 months with bevacizumab and chemotherapy alone (n = 94; HR, 0.84; 95% CI, 0.57-1.22; P = .1749). Additionally, the objective response rate (ORR) in this population was 35.1% vs 26.6% by investigator assessment and 33.0% vs 20.2% per blinded independent central review (BICR).

Among patients with high DKK1 levels (n = 44), the median PFS was 9.36 months in the investigational arm and 5.88 months in the control arm (HR, 0.47; 95% CI, 0.22-1.01; P = .0237). The median overall survival (OS) was not yet reached and 9.66 months in each respective arm (HR, 0.19; 95% CI, 0.05-0.73; P = .0037). Additionally, data showed an ORR of 44.0% vs 15.8% per investigator evaluation (P = .0149) and 40.0% vs 15.8% via BICR (P = .0301).

In a subgroup of patients with DKK1 levels exceeding the median (n = 88), sirexatamab-based treatment yielded a median PFS of 9.03 months vs 7.23 months with bevacizumab/chemotherapy alone (HR, 0.56; 95% CI, 0.33-0.94; P = .0146). The study treatment produced a median OS that was not yet reached vs 14.39 months, respectively (HR, 0.48; 95% CI, 0.2-1.16; P = .0475). The ORR was 38.0% vs 23.7% based on investigator assessment (P = .0706) and 40.0% vs 15.8% per BICR (P = .0039).

Among patients who did not receive prior anti-VEGF therapy (n = 95), the median PFS was 11.2 months in the sirexatamab arm vs 8.34 months in the control arm (HR, 0.61; 95% CI, 0.35-1.06; P = .0383), and the median OS was not yet reached in both arms (HR, 0.47; 95% CI, 0.14-1.6; P = .1069). Additionally, the ORR was 55.1% vs 32.6% per investigator evaluation (P = .0116) and 44.9% vs 26.1% based on BICR (P = .0252).

Regarding those with liver metastases (n = 138), the median PFS was 9.03 months vs 7.26 months in the investigational and control arms, respectively (HR, 0.7; 95% CI, 0.46-1.06; P = .0443). Data also showed that the median OS was not yet reached and 15.74 months in each arm (HR, 0.69; 95% CI, 0.33-1.43; P = .1584). The study therapy yielded an ORR of 37.0% vs 27.7% per investigator assessment (P = .1203) and 30.1% vs 24.6% per BICR (P = .233).

“Sirexatamab demonstrated a statistically significant benefit in patients with high levels of DKK1, no prior exposure to anti-VEGF therapy, or liver metastasis, with a positive trend on ORR and PFS in the full second-line CRC population. With the additional patient follow-up, we believe that the objectives of the DeFianCe study have been achieved,” Douglas E. Onsi, president and chief executive officer of Leap Therapeutics, stated in the press release.¹ “However, due to current market conditions, we have decided to wind-down the DeFianCe clinical trial and further reduce internal expenses.”

In the open-label, 2-part, multi-center phase 2 DeFianCe study, 188 patients with advanced MSS CRC were assigned to receive chemotherapy plus bevacizumab at 5 mg intravenously alone or in combination with sirexatamab at 400 mg every 2 weeks with an additional loading dose in the first treatment cycle.² Chemotherapy consisted of irinotecan plus leucovorin and fluorouracil (FOLFIRI) or oxaliplatin plus folinic acid and fluorouracil (FOLFOX).

The trial’s primary end point was PFS. Secondary end points included ORR, duration of response, OS, and grade 3 or higher treatment-related adverse effects (TRAEs).

References

1. Leap Therapeutics reports updated clinical data from sirexatamab colorectal cancer study and announces exploration of strategic alternatives. News release. Leap Therapeutics, Inc. June 23, 2025. Accessed June 26, 2025. https://tinyurl.com/48wrrau4
2. Phase 2 study of DKN-01 in colorectal cancer (DeFianCe). ClinicalTrials.gov. Updated April 2, 2025. Accessed June 26, 2025. https://shorturl.at/3TLVk