sirexatamab (DKN-01) / Eli Lilly, Cypherpunk Technologies - LARVOL DELTA

Overcoming antigen tolerance to develop GB22-45-2, an anti-DKK1 antibody for gastric cancer. (PubMed, Antib Ther) - "In vivo, GB22-45-2 showed a modest tumor growth inhibition (31.03%) that is significant (P = 0.0175), while DKN-01 did not reach significance, in the MKN-45-Balb/c-nude mouse model. Additionally, GB22-45-2 exhibited a satisfactory developability profile, including good thermal stability, low aggregation propensity, high structural integrity, and excellent stability under various stress conditions. In summary, these preclinical results suggest that GB22-45-2 is a potential therapeutic candidate for GC, laying the foundation for its future drug development."

Journal • Gastric Cancer • Oncology • Solid Tumor • DKK1

Phase 2 Study Evaluating the Efficacy of the Combination of DKN-01 (DKK1 Inhibitor, Leap Therapeutics) and Pembrolizumab in the Treatment of Advanced or Recurrent Endometrial Cancer (clinicaltrials.gov) - P2 | N=8 | Active, not recruiting | Sponsor: M.D. Anderson Cancer Center | Recruiting ➔ Active, not recruiting | N=60 ➔ 8

Enrollment change • Enrollment closed • Endometrial Cancer • Oncology • Solid Tumor • AXIN1 • CTNNB1 • RSPO2 • ZNRF3

Cypherpunk Technologies (formerly Leap Therapeutics) Reports Third Quarter 2025 Financial Results (PRNewswire) - "The Company is in the process of engaging with regulatory agencies in the United States and Europe to discuss the registrational pathway for sirexatamab in CRC. The Company is also working with a leading diagnostics research laboratory to optimize the DKK1 biomarker diagnostic test that could be used to identify CRC patients with poor prognosis and to select patients for treatment with sirexatamab. The Company expects to provide an update on the next steps in sirexatamab development and on the registrational pathway in the first quarter of 2026."

Clinical • Colorectal Cancer

DeFianCe trial: A randomized phase II 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) (ESMO 2025) - P2 | "84% received FOLFIRI on study...Conclusions Sirexa in combination with standard of care (SOC) was well tolerated and demonstrated a promising early signal in DKK1-high MSS CRC pts with significant advantage of PFS and OS compared to SOC alone. Further investigation of sirexa in 2L DKK1-high CRC is warranted."

Clinical • Late-breaking abstract • Metastases • P2 data • Colorectal Cancer • Gastrointestinal Cancer • Oncology • BRAF • DKK1

Leap Therapeutics Presents Final Data from DeFianCe Study at ESMO 2025 (PRNewswire) - "Across the DKK1-high (upper median) patients (n=88): ORR was 38.0% in the Sirexatamab Arm compared to 23.7% ORR in the Control Arm. mPFS 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. mOS was not reached in the Sirexatamab Arm compared to 14.39 months in the Control Arm, HR 0.42, p-value = 0.0118."

P2 data • Colorectal Cancer

DisTinGuish: A Study of DKN-01 in Combination With Tislelizumab ± Chemotherapy in Patients With Gastric or Gastroesophageal Cancer (clinicaltrials.gov) - P2 | N=247 | Terminated | Sponsor: Leap Therapeutics, Inc. | Trial completion date: Dec 2025 ➔ Mar 2025 | Active, not recruiting ➔ Terminated; experimental treatment will not be more efficacious than its comparator in the primary endpoint of PFS

Trial completion date • Trial termination • Esophageal Cancer • Gastric Adenocarcinoma • Gastric Cancer • Gastroesophageal Cancer • Gastroesophageal Junction Adenocarcinoma • Oncology • Solid Tumor • DKK1 • PD-L1

Leap Therapeutics Announces Closing of $58.88 Million Private Placement in Cash Led by Winklevoss Capital to Initiate a Digital Asset Treasury Strategy (PRNewswire) - "A portion of the capital will be used to continue development of Leap's therapeutic programs, including FL-501 and sirexatamab, which has recently completed a randomized controlled Phase 2 trial in patients with colorectal cancer that is being presented in a Mini Oral Session at the European Society for Medical Oncology (ESMO) Congress 2025 on October 19 in Berlin, Germany."

Financing • Colorectal Cancer

THE EMERGING ROLE OF DKK1 IN GASTRIC CARCINOGENESIS AND TARGETING DKK1 BY APTAMER-BASED PROTAC (UEGW 2025) - "Dickkopf-1 (DKK1), frequently overexpressed in GC, is implicated in critical oncogenic processes such as tumorigenesis, epithelial-mesenchymal transition (EMT), cisplatin resistance, and immune evasion...However, clinical outcomes from therapeutic antibodies targeting extracellular DKK1 (e.g., DKN-01, BHQ880) have been disappointing, highlighting the potential importance of intracellular DKK1 functions in cancer progression and underscoring the need for innovative therapeutic strategies addressing both extracellular and intracellular roles... Intracellular DKK1 promotes the progression of GC through the stabilization of β-catenin. Apc102, a novel aptamer-based PROTAC, which has recently been granted the FDA Orphan Drug Designation (DRU-2024-10338), exhibits potent anti-tumor efficacy and safety. This offers a breakthrough for DKK1 - positive gastric cancer."

Dyslipidemia • Gastric Cancer • Oncology • Targeted Protein Degradation • CRBN • DKK1

Leap Therapeutics to Present Final Clinical Data from Part B of the DeFianCe Study at the ESMO Congress 2025 (PRNewswire)

P2 data • Colorectal Cancer

DeFianCe: Phase 2 Study of DKN-01 in Colorectal Cancer (clinicaltrials.gov) - P2 | N=188 | Completed | Sponsor: Leap Therapeutics, Inc. | Active, not recruiting ➔ Completed | Trial completion date: Oct 2025 ➔ Jul 2025 | Trial primary completion date: Oct 2025 ➔ Jul 2025

Trial completion • Trial completion date • Trial primary completion date • Colorectal Adenocarcinoma • Colorectal Cancer • Oncology • Solid Tumor

DKN-01 and atezolizumab as second or third-line therapy in advanced mismatch repair proficient (MMRp) oesophagogastric adenocarcinoma (OGA): WAKING trial (ESMO-GI 2025) - P1/2, P2 | "DKN-01 and atezolizumab did not meet the target ORR of 25%. One pt with high baseline PD-L1 CPS had prolonged disease control. Further translational analyses with serial blood and tissue samples are ongoing."

Metastases • Mismatch repair • pMMR • Esophageal Cancer • Gastric Adenocarcinoma • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Oncology • Solid Tumor • DKK1

DKN-01 and tislelizumab as second-line therapy in DKK1-high gastroesophageal adenocarcinoma: DisTinGuish trial part B. (PubMed, Nat Commun) - P2 | "The median OS was 8.2 months, median PFS 1.4 months, and DCR rate 34.8% in the overall population. Although exploratory, the results of this trial compare favorably against second-line benchmarks of Keynote-061 and RAINBOW and support the safety and tolerability of DKN-01 combined with tislelizumab."

Biomarker • IO biomarker • Journal • Esophageal Adenocarcinoma • Esophageal Cancer • Fatigue • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Oncology • Solid Tumor • DKK1

DKN-01 and tislelizumab as second-line therapy in DKK1-high gastroesophageal adenocarcinoma: DisTinGuish trial part B (Nat Commun, Nature) - P2 | N=232 | DisTinGuish (NCT04363801) | Sponsor: Leap Therapeutics, Inc. | "The trial met the prespecified primary endpoint. In the safety population (n = 52), 21 (40.4%) patients reported at least 1 DKN-01-related adverse event, most of which were low-grade, with fatigue (15.4%) and nausea (9.6%) being most common. The ORR was 21.7% in the overall population (n = 46) and 31.8% in the programmed death-ligand 1 (PD-L1) ≥ 5% population. The median OS was 8.2 months, median PFS 1.4 months, and DCR rate 34.8% in the overall population."

P2 data • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma

DKN-01 and tislelizumab as second-line therapy in DKK1-high gastroesophageal adenocarcinoma: DisTinGuish trial part B (Nat Commun, Nature) - P2 | N=232 | DisTinGuish (NCT04363801) | Sponsor: Leap Therapeutics, Inc. | "The trial met the prespecified primary endpoint. In the safety population (n = 52), 21 (40.4%) patients reported at least 1 DKN-01-related adverse event, most of which were low-grade, with fatigue (15.4%) and nausea (9.6%) being most common. The ORR was 21.7% in the overall population (n = 46) and 31.8% in the programmed death-ligand 1 (PD-L1) ≥ 5% population. The median OS was 8.2 months, median PFS 1.4 months, and DCR rate 34.8% in the overall population."

P2 data • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma

Leap Therapeutics Reports Updated Clinical Data from Sirexatamab Colorectal Cancer Study and Announces Exploration of Strategic Alternatives (PRNewswire) - P2 | N=188 | DeFianCe (NCT05480306) | Sponsor: Leap Therapeutics, Inc. | "Leap Therapeutics...reported updated results from Part B of the DeFianCe study (NCT05480306), a Phase 2 study of sirexatamab (DKN-01), an anti-DKK1 monoclonal antibody, in combination with bevacizumab and chemotherapy (Sirexatamab Arm) compared to bevacizumab and chemotherapy (Control Arm) in patients with advanced microsatellite stable (MSS) colorectal cancer (CRC) who have received one prior systemic therapy for advanced disease...In the updated analysis as of May 22, 2025, sirexatamab demonstrated a positive trend on overall response rate (ORR), by investigator assessment (IA) and blinded independent central review (BICR), and progression-free survival (PFS) in the full second-line CRC population, driven by the statistically significant benefit in patients with high levels of DKK1, no prior exposure to anti-VEGF therapy, or liver metastasis."

P2 data • Colorectal Cancer

Leap Therapeutics to Host Virtual KOL Event to Discuss Sirexatamab (DKN-01) in Second-line Patients with Advanced Microsatellite Stable Colorectal Cancer (PRNewswire) - "Dr. Wainberg will connect with Leap's Chief Medical Officer, Cynthia Sirard, MD, to discuss the unmet need and how sirexatamab (DKN-01) may improve upon the current treatment landscape for previously treated patients with advanced microsatellite stable (MSS) colorectal cancer (CRC). The event will focus on reviewing the positive data from Part B of the Phase 2 DeFianCe study of sirexatamab in second-line patients with advanced MSS CRC."

P2 data • Colorectal Cancer

WaKING: Wnt and checKpoint INhibition in Gastric Cancer (clinicaltrials.gov) - P1/2 | N=52 | Active, not recruiting | Sponsor: Royal Marsden NHS Foundation Trust | Trial completion date: Sep 2025 ➔ Dec 2025 | Trial primary completion date: Dec 2024 ➔ Mar 2025

Checkpoint inhibition • Mismatch repair • pMMR • Trial completion date • Trial primary completion date • Esophageal Adenocarcinoma • Esophageal Cancer • Gastric Cancer • Gastroesophageal Cancer • Oncology • Solid Tumor

Leap Therapeutics Reports Positive Updated Data from Sirexatamab Colorectal Cancer Study (PRNewswire) - P2 | N=189 | DeFianCe (NCT05480306) | Sponsor: Leap Therapeutics, Inc. | "In patients with high DKK1 levels (upper quartile, n=44), the sirexatamab Experimental Arm has a statistically significant 32% higher ORR, 3.5 month longer PFS, and OS compared to the Control Arm; In patients who had not received prior anti-VEGF therapy (n=95), the sirexatamab Experimental Arm has a statisticially significant 22% higher ORR and 2.6 month longer PFS compared to the Control Arm, with OS not mature but favoring the sirexatamab Experimental Arm; Across the intent-to-treat population (n=188), the sirexatamab Experimental Arm has improved ORR compared to the Control Arm, with the primary endpoint of PFS still to mature due to the higher number of patients remaining on sirexatamab driving separation after the median."

P2 data • Colorectal Cancer

Leap Therapeutics Reports Initial Clinical Data from Part B of the DeFianCe Study (PRNewswire) - P2 | N=189 | DeFianCe (NCT05480306) | Sponsor: Leap Therapeutics, Inc | "Patients treated with sirexatamab plus bevacizumab and chemotherapy (Experimental Arm, n=94) had ORR of 35% and disease control rate (DCR) of 86%, compared to an ORR of 23% and DCR of 84% in patients treated with bevacizumab and chemotherapy alone (Control Arm, n=94); Patients treated in the Experimental Arm (n=71) had an ORR of 38%, compared to an ORR of 25% in the Control Arm (n=73); Patients in the Experimental Arm with DKK1 levels above the median (n=49) had an ORR of 39%, compared to 22% ORR in the Control Arm (n=36); With only 3 months follow-up on the final patients enrolled and mean duration on study of approximately 6 months, PFS is not yet mature."

P2 data • Colorectal Cancer

Leap Therapeutics Reports Initial Clinical Data from…Part C of the DisTinGuish Study (PRNewswire) - P2 | N=232 | DisTinGuish (NCT04363801) | Sponsor: Leap Therapeutics, Inc | "While demonstrating activity in biomarker populations, the study did not generate a clear positive signal and will be negative on the primary PFS endpoints when the study completes, resulting in the decision not to move forward with Phase 3 studies in gastric cancer...Part C enrolled 170 first-line, HER2-negative patients...Across the ITT population (n=170), patients treated with sirexatamab plus tislelizumab and chemotherapy (Experimental Arm, n=85) had a confirmed ORR of 52% by both IA and BICR, while patients treated with tislelizumab and chemotherapy alone (Control Arm, n=85) had a confirmed ORR of 56% by IA and 42% by BICR; In the ITT population, preliminary median PFS in the Experimental Arm was 9.72 months by BICR and 7.66 months by IA compared to 11.99 months by BICR and 10.41 months by IA in the Control Arm; Sirexatamab plus tislelizumab and chemotherapy was well tolerated."

P2 data • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma

Leap Therapeutics Reports Third Quarter 2024 Financial Results (PRNewswire) - "Leap Highlights: Completed enrollment in the expanded randomized controlled Part B of the Phase 2 DeFianCe study evaluating DKN-01, Leap's anti-DKK1 monoclonal antibody, in combination with standard of care bevacizumab and chemotherapy in second-line patients with advanced colorectal cancer (CRC); data expected in mid-2025; Patient follow-up continuing in the randomized controlled Part C of the Phase 2 DisTinGuish study evaluating DKN-01 in combination with tislelizumab and chemotherapy in first-line patients with advanced gastroesophageal junction (GEJ) and gastric cancer; data expected in late 2024 or early 2025."

P2 data • Trial status • Colorectal Cancer • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma

Leap Therapeutics Reports Third Quarter 2024 Financial Results (PRNewswire) - "Research and development expenses were $14.9 million for the third quarter 2024, compared to $11.5 million for the same period in 2023. The increase of $3.4 million was primarily due to an increase of $1.7 million in manufacturing costs related to clinical trial material and manufacturing campaigns, and an increase of $0.8 million in clinical trial costs due to patient enrollment, the duration of patients on study, the enhancement of correlative studies, increase in site activity associated with Part C of the DisTinGuish study, and the expansion of the size of Part B of the DeFianCe study."

Commercial • Colorectal Cancer • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma

DKN-01 in Combination With Tislelizumab and Chemotherapy as First-Line Therapy in Advanced Gastric or Gastroesophageal Junction Adenocarcinoma: DisTinGuish (J Clin Oncol) - P2 | N=232 | DisTinGuish (NCT04363801) | Sponsor: Leap Therapeutics, Inc. | "Between September 18, 2020, and April 8, 2021, 25 patients were enrolled....The ORR was 73% (95% CI, 49.8 to 89.3), with a disease control rate of 95%. The ORR was 90% (95% CI, 55.5 to 99.7) in the DKK1-high tumor patients and 67% (95% CI, 29.9 to 92.5) in the DKK1-low tumor patients. The median PFS was 11.3 months (95% CI, 5.8 to 12.0) and the 12-month PFS rate was 33%. The median OS was 19.5 months (95% CI, 15.2 to 24.4) with a 12-month OS rate of 76% and an 18-month OS rate of 55%."

P2 data • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma

DKN-01 in Combination With Tislelizumab and Chemotherapy as First-Line Therapy in Advanced Gastric or Gastroesophageal Junction Adenocarcinoma: DisTinGuish. (PubMed, J Clin Oncol) - P2 | "DKN-01 can be safely combined with frontline fluoropyrimidine/oxaliplatin and tislelizumab and demonstrates encouraging activity independent of PD-L1 expression levels. A randomized phase II trial is ongoing (ClinicalTrials.gov identifier: NCT04363801)."

Combination therapy • IO biomarker • Journal • Metastases • Esophageal Adenocarcinoma • Esophageal Cancer • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • DKK1 • HER-2 • PD-L1

Characterization of cell states in biliary tract cancers identifies mechanisms of therapeutic resistance in a phase II trial of DKN-01/nivolumab. (PubMed, medRxiv) - P2 | "Malignant cell states co-varied with distinct immune cell states, revealing diverse mechanisms of myeloid and T-cell mediated immune suppression, including M2 myeloid and terminally exhausted T cell programs that were induced by DKN-01/nivolumab. Here, we provide the first systematic classification of functionally annotated cell states in biliary tract cancer and provide new insight into resistance mechanisms to an immunotherapy combination that can inform the next generation of trials."

Journal • P2 data • Biliary Cancer • Biliary Tract Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • DKK1