8-K: Leap Therapeutics' Sirexatamab Excels in CRC Study

Leap Therapeutics announced final positive results from its Phase 2 DeFianCe study, demonstrating sirexatamab significantly improved progression-free and overall survival in DKK1-high colorectal cancer patients.

Summary

• Leap Therapeutics presented final results from Part B of its Phase 2 DeFianCe study for sirexatamab (DKN-01) at the European Society for Medical Oncology (ESMO) Congress 2025 in Berlin, Germany.
• The study evaluated sirexatamab in combination with bevacizumab and chemotherapy against bevacizumab and chemotherapy alone in microsatellite stable (MSS) colorectal cancer (CRC) patients who had received one prior systemic therapy for advanced disease.
• In DKK1-high (upper median, n=88) patients, the Sirexatamab Arm achieved an Objective Response Rate (ORR) of 38.0% compared to 23.7% in the Control Arm.
• Median Progression-Free Survival (mPFS) for DKK1-high (upper median) patients was 9.03 months in the Sirexatamab Arm compared to 7.06 months in the Control Arm (Hazard Ratio (HR) 0.61, p-value = 0.0255).
• Overall Survival (OS) for DKK1-high (upper median) patients was not reached in the Sirexatamab Arm compared to 14.39 months in the Control Arm (HR 0.42, p-value = 0.0118).
• For DKK1-high (upper quartile, n=44) patients, ORR was 44.0% vs. 15.8%, mPFS was 9.36 months vs. 5.88 months (HR 0.46, p-value = 0.0168), and mOS was not reached vs. 9.66 months (HR 0.17, p-value < 0.001).
• In the full intent-to-treat population (n=188), ORR was 35.1% in the Sirexatamab Arm compared to 26.6% in the Control Arm, and mPFS was 9.2 months vs. 8.3 months (HR 0.84, p-value = 0.1712).
• Sirexatamab, in combination with chemotherapy and bevacizumab, was safe and well-tolerated, with a similar overall treatment-emergent adverse effects (TEAE) profile between the two arms.

Sentiment

Score: 9

Explanation: The clinical trial results for sirexatamab in DKK1-high CRC patients are highly positive, showing statistically significant improvements in both PFS and OS, which are critical endpoints in oncology. The safety profile is also favorable. This data strongly supports the drug's potential for regulatory approval and addresses a high unmet medical need. The only slight detractor is the non-significant result in the full ITT population, but the focus on the biomarker-selected group is a strong positive.

Positives

• Sirexatamab demonstrated statistically significant improvement in Progression-Free Survival (PFS) and Overall Survival (OS) in DKK1-high colorectal cancer patients.
• For DKK1-high (upper median) patients, median PFS was 9.03 months versus 7.06 months in the control arm (HR 0.61, p=0.0255), representing a significant clinical benefit.
• For DKK1-high (upper median) patients, median OS was not reached versus 14.39 months in the control arm (HR 0.42, p=0.0118), indicating a substantial survival advantage.
• Increasing DKK1 levels further improved PFS, OS, and Objective Response Rate (ORR) advantage for the Sirexatamab Arm, with DKK1-high (upper quartile) patients showing particularly strong results (mPFS 9.36 months vs 5.88 months, mOS not reached vs 9.66 months).
• Sirexatamab was safe and well-tolerated, with a similar adverse event profile to the control arm, suggesting it did not negatively impact the safety of the standard of care combination.
• The company plans to engage with regulatory authorities for a registrational path for sirexatamab in CRC, supported by recently completed financing.

Negatives

• In the full intent-to-treat population (n=188), the improvement in median Progression-Free Survival (PFS) was not statistically significant (9.2 months vs. 8.3 months, HR 0.84, p-value = 0.1712), indicating the benefit is primarily observed in the biomarker-selected DKK1-high group.

Risks

• Potential failure to realize the anticipated benefits of the digital asset treasury strategy.
• Changes in business, market, financial, political, and regulatory conditions, particularly concerning digital assets.
• Risks related to the highly volatile nature of cryptocurrency prices.
• The risk that the price of the company's common stock may be highly correlated to the price of the digital assets it holds.
• Increased competition in the industries in which the company operates.
• Significant legal, commercial, regulatory, and technical uncertainty regarding pharmaceutical development and digital assets generally.
• Risks relating to the treatment of crypto assets for U.S. and foreign tax purposes.
• Uncertainty regarding regulatory feedback that may be received from the U.S. Food and Drug Administration (FDA) or equivalent foreign regulatory agencies.

Future Outlook

Leap Therapeutics plans to engage with regulatory authorities to define the registrational path for sirexatamab in colorectal cancer and to optimize the DKK1 biomarker diagnostic test for identifying high-risk CRC patients. The company also aims to build long-term shareholder value through its digital asset treasury strategy, supported by a recent $58.88 million private placement.

Management Comments

• "Sirexatamab has significant potential to provide a survival benefit for CRC patients who have high DKK1 levels and who are likely to have poor outcomes receiving the current standard of care alone." (Zev Wainberg, MD, Professor of Medicine and Co-Director of the GI Oncology Program at UCLA)
• "Sirexatamab has the potential to be a valuable addition to the CRC treatment paradigm as a targeted therapeutic for patients with high DKK1 and should move forward to be evaluated in a biomarker-focused registrational trial." (Zev Wainberg, MD)
• "The DeFianCe study results demonstrate the significant potential of sirexatamab in patients with advanced CRC. Patients with this aggressive cancer, particularly those with high DKK1 levels, have poor overall survival outcomes and few promising second-line or later options." (Douglas E. Onsi, President and Chief Executive Officer of Leap Therapeutics)
• "Sirexatamab has repeatedly demonstrated its potential as a novel, first-in-class antibody targeting DKK1 that provides deep and durable benefit for patients in desperate need of new therapies." (Douglas E. Onsi, President and Chief Executive Officer of Leap Therapeutics)

Industry Context

The positive results for sirexatamab in DKK1-high colorectal cancer patients highlight a growing trend towards biomarker-driven precision medicine in oncology. Colorectal cancer remains a significant challenge, especially for patients with advanced, metastatic disease and limited second-line options. The identification of DKK1 as a prognostic factor and a target for therapy positions sirexatamab as a potential novel treatment in a high-unmet-need population, aligning with the industry's focus on personalized cancer treatments.

Stakeholder Impact

• Shareholders: Positive impact due to strong clinical data for a key pipeline asset, potentially increasing company valuation and future revenue prospects. The digital asset strategy introduces new risk/reward dynamics.
• Patients: Significant potential benefit for advanced colorectal cancer patients, particularly those with high DKK1 levels, who currently have limited treatment options and poor prognoses.
• Regulatory Authorities: Will be engaged by Leap Therapeutics to discuss the registrational path for sirexatamab, indicating potential for a new approved therapy.
• Medical Community: Provides new data supporting a biomarker-driven approach to treating advanced CRC, potentially influencing future treatment guidelines.

Next Steps

• Engage with regulatory authorities (e.g., FDA) regarding the registrational path for sirexatamab in colorectal cancer.
• Optimize the DKK1 biomarker diagnostic test to identify CRC patients with poor prognosis who could benefit from sirexatamab.
• Continue supporting the development of sirexatamab in DKK1-high CRC patients.
• Continue the development of FL-501.
• Build long-term shareholder value through the digital asset treasury strategy.

Key Dates

Recommendation

The final results from the DeFianCe study for sirexatamab are exceptionally strong, particularly in the DKK1-high patient population, demonstrating statistically significant and clinically meaningful improvements in both progression-free survival and overall survival. The favorable safety profile further enhances its appeal. This data significantly de-risks the asset and positions sirexatamab for a potential registrational path, addressing a high unmet medical need in advanced colorectal cancer. While the company's digital asset strategy introduces some unique risks, the core clinical data for sirexatamab represents a substantial value driver and warrants a strong buy recommendation for investors seeking exposure to innovative oncology therapeutics.

Keywords

Leap Therapeutics, LPTX, Sirexatamab, DKN-01, DeFianCe study, Colorectal Cancer, CRC, DKK1, Oncology, Biotechnology, Phase 2, Clinical Trial, ESMO, Progression-Free Survival, Overall Survival, Biomarker, MSS CRC