Sirexatamab Combo Shows Positive Activity in Advanced MSS Colorectal Cancer

Data from the DeFianCe study support a registrational phase 3 trial intended to assess sirexatamab plus bevacizumab/chemotherapy as second-line therapy for patients with MSS CRC, high levels of DKK1, and no prior receipt of anti-VEGF therapy.

Combining an investigational anti-DKK1 monoclonal antibody, sirexatamab (DKN-01), with bevacizumab (Avastin) and chemotherapy elicited improved outcomes vs bevacizumab/chemotherapy alone among patients with previously treated, 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

Among patients with high DKK1 levels in the sirexatamab arm (n = 25) and the control arm (n = 19), the respective overall response rates (ORRs) were 48.0% vs 15.8% per investigator assessment (P = .0067) and 40.0% vs 5.3% based on blinded independent central review (BICR; P <.001). Additionally, the median progression-free survival (PFS) was 9.36 months vs 5.88 months (HR, 0.46; 95% CI, 0.21-1.02; P = .0248), and the median overall survival (OS) was not reached (NR) vs 9.49 months (HR, 0.09; 95% CI, 0.01-0.69; P = .0018).

In the subgroup of patients without prior exposure to anti-VEGF therapy who received treatment with the sirexatamab combination (n = 49) or bevacizumab plus chemotherapy (n = 46), the ORR per investigator assessment was 55.1% vs 32.6%, respectively (P = .0116); based on BICR, these rates were 44.9% vs 21.7% (P = .0066). Study treatment yielded a median PFS of 10.94 months vs 8.34 months (HR, 0.59; 95% CI, 0.32-1.07; P = .0386) and a median OS of NR vs NR in this subgroup (HR, 0.22; 95% CI, 0.03-2.01; P = .0719). OS data were not yet mature at the time of analysis for this patient subgroup.

Across the sirexatamab (n = 94) and control arms (n = 94) in the intent-to-treat population, the ORR was 36.2% vs 25.5% based on investigator assessment (P = .0536) and 33.0% vs 16.0% per BICR (P = .0023). Additionally, the median PFS was 7.82 months vs 8.31 months in each respective arm, although these data were immature due to the higher number of patients remaining on treatment with sirexatamab driving separation following the median (HR, 0.83; 95% CI, 0.56-1.24; P = .1809).

Findings showed that the sirexatamab-based regimen was well tolerated, demonstrating a safety profile that was comparable with prior reports. Data from the DeFianCe study support a registrational phase 3 trial intended to assess sirexatamab plus bevacizumab/chemotherapy as second-line therapy for patients with MSS CRC, high levels of DKK1, and no prior receipt of anti-VEGF therapy.

“The updated data from part B of the DeFianCe study presented today confirms that sirexatamab can generate significantly higher ORR and longer PFS in [patients with] CRC who have high levels of DKK1 or who have not had prior anti-VEGF therapy, 2 exploratory populations with strong scientific rationale. In the full intent-to-treat population, sirexatamab demonstrated a higher ORR and a tail population with longer PFS that continues to mature,” Cynthia Sirard, MD, chief medical officer at Leap Therapeutics, the developer of sirexatamab, stated in the press release.¹ “With more [patients who received sirexatamab] currently continuing on study drug than patients [in the control arm], there is potential for the dataset to continue to strengthen over the coming months.”

In the open-label, multicenter, phase 2 DeFianCe study, 188 patients in the intent-to-treat population were randomly assigned to receive chemotherapy with irinotecan plus leucovorin and fluorouracil (FOLFIRI) or oxaliplatin plus folinic acid and fluorouracil (FOLFOX) in combination with bevacizumab alone, or chemotherapy plus bevacizumab and sirexatamab.² Investigators administered sirexatamab at 400 mg intravenously every 2 weeks with an additional loading dose during the first treatment cycle and bevacizumab at 5 mg intravenously.

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.

Patients 18 years and older with progressive disease following frontline systemic therapy with any fluoropyrimidine-based combination for advanced disease apart from folinic acid plus fluorouracil, oxaliplatin, and irinotecan (FOLFOXIRI) were eligible for enrollment. Other eligibility criteria included having 1 or more measurable tumors per RECIST v1.1 guidelines and an ECOG performance status of 0 or 1.

References

1. Leap Therapeutics reports positive updated data from sirexatamab colorectal cancer study. News release. March 26, 2025. Accessed March 27, 2025. https://tinyurl.com/5jb8js2n
2. Phase 2 study of DKN-01 in colorectal cancer (DeFianCe). ClinicalTrials.gov. Updated September 27, 2024. Accessed March 27, 2025. https://shorturl.at/3TLVk