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

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

DKN-01 and atezolizumab as second- or third-line therapy in advanced oesophagogastric adenocarcinoma: the WAKING trial. (PubMed, ESMO Gastrointest Oncol) - "DKN-01/atezolizumab was well tolerated. However, efficacy in MMRp/microsatellite stable OGA in an otherwise biomarker-unselected population did not meet the primary efficacy endpoint."

IO biomarker • Journal • Gastric Adenocarcinoma • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Oncology • Solid Tumor • DKK1 • PD-L1

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

Randomized phase 2 study of DKN-01 plus FOLFIRI/FOLFOX and bevacizumab versus FOLFIRI/FOLFOX and bevacizumab as second-line treatment of advanced colorectal cancer (DeFianCe). (ASCO-GI 2023) - P2 | "Recruitment is ongoing. Clinical trial information: NCT05480306."

Clinical • Metastases • P2 data • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BRAF • DKK1

Leap Therapeutics Announces Publication of DeFianCe Study Results in Clinical Cancer Research (PRNewswire) - "Sirexatamab benefit increased as baseline plasma DKK1 rose: Three independent analyses — a continuous treatment-by-DKK1 interaction model, a permutation-tested Biomarker Adaptive Threshold (BAT) analysis, and median- and upper-quartile subgroup analyses — converged on the same conclusion: benefit rises with baseline plasma DKK1...DKK1-high patients above the median (n=88): ORR was 38.0% in the Sirexatamab Arm compared with 23.7% in the Control Arm; Median PFS was 9.0 months versus 7.1 months; HR 0.61 (95% CI, 0.37–1.00); p=0.0255....DKK1-high patients in the upper quartile (n=44): ORR was 44.0% in the Sirexatamab Arm compared with 15.8% in the Control Arm; p=0.0149; Median PFS was 9.4 months versus 5.9 months; HR 0.46 (95% CI, 0.22–0.96); p=0.0168...Results in the overall intent-to-treat (ITT) population: The prespecified primary endpoint of PFS in the ITT population was not met."

P2 data • Colorectal Cancer

Leap Therapeutics held a Type C meeting with the FDA to discuss the DeFianCe results and proposed registrational path for sirexatamab in DKK1-high, second-line mCRC. (PRNewswire) - "Leap presented its proposed Phase 3 trial design, and the FDA provided feedback supporting key elements of that design, including the use of a DKK1 biomarker-selected patient population and a dual-endpoint structure intended to support both accelerated and full approval....Approximately 270 patients with mCRC whose disease has progressed following one prior line of systemic therapy prospectively identified as DKK1-high using a baseline plasma DKK1 assay cut point are expected to be enrolled and randomized 1:1. Potential accelerated approval in the United States could be determined by objective response rate (ORR) in an initial group of approximately 160 patients, and overall survival (OS) will be evaluated in the full study population intended to support a filing for full approval in the United States and to support registration in markets outside the United States."

FDA event • New P3 trial • Colorectal Cancer

Sirexatamab in Combination with Bevacizumab and Chemotherapy as Second-Line Therapy for Advanced Colorectal Adenocarcinoma: the Phase II DeFianCe Trial. (PubMed, Clin Cancer Res) - "Sirexatamab plus chemotherapy and bevacizumab did not improve PFS in the intent-to-treat population but was generally well tolerated. However, the consistent association between higher baseline plasma DKK1 and greater sirexatamab benefit suggests that DKK1-directed therapy may require biomarker-selected evaluation rather than all-comer development in mCRC."

Journal • P2 data • Colorectal Adenocarcinoma • Colorectal Cancer • Oncology • Solid Tumor • DKK1

Presented new plasma DKK1 biomarker assay and results based on Part B of the DeFianCe study of sirexatamab plus bevacizumab and chemotherapy in colorectal cancer ("CRC") patients at the American Association for Cancer Research (AACR) 2026 (PRNewswire) - "The new plasma DKK1 biomarker assay was used to test the patient samples from Part B of the DeFianCe study, a Phase 2 study of sirexatamab in combination with bevacizumab and chemotherapy compared to bevacizumab and chemotherapy in patients with microsatellite stable CRC who have received one prior systemic therapy for advanced disease...50% of patients had DKK1-high levels > 380 pg/ml, and in this subgroup of patients (n=87): ORR was 42% (including one complete response) in the Sirexatamab Arm vs. 16% ORR in the Control Arm, p-value = 0.003.; mOS was not reached in the Sirexatamab Arm vs. 14.39 months in the Control Arm, HR 0.47, p-value = 0.0244."

P2 data • Colorectal Cancer

Sirexatamab received Fast Track designation from FDA (PRNewswire) - "In May 2026, the U.S. Food and Drug Administration (FDA) granted Fast Track designation to sirexatamab in combination with fluoropyrimidine plus oxaliplatin- or irinotecan-based chemotherapy and bevacizumab, for the treatment of patients with DKK1-high metastatic colorectal cancer whose disease has progressed following one prior systemic therapy."

Fast track • Colorectal Cancer

The Dickkopf-1 (DKK1) Dichotomy in Oncology: New Insights on Tumor Progression and Immune Regulation. (PubMed, Int J Mol Sci) - "Given its intricate impact on malignancy, DKK1 has become a promising therapeutic target, with ongoing clinical trials investigating neutralizing antibodies such as DKN-01 to disrupt its oncogenic and immunosuppressive signaling. Understanding the context-dependent nature of DKK1 signaling remains essential for refining its application as both a biomarker and a component of emerging precision immunotherapy strategies. By prioritizing the literature from the last decade, this review characterizes DKK1 as a key mediator of tumor progression and immune reprogramming, while assessing its clinical potential as a biomarker and therapeutic target."

IO biomarker • Journal • Review • Hematological Disorders • Hematological Malignancies • Oncology • CAFs • CD8 • CKAP4 • DKK1

Elevated baseline DKK1 plasma is a biomarker for sirexatamab treated colorectal cancer patients (AACR 2026) - P2 | "The DeFianCe (NCT05480306) Phase 2 randomized, global, open-label, multicenter study was conducted to evaluate the efficacy and safety of sirexatamab plus the current standard of care (SOC) treatment regimen (FOLFIRI/FOLFOX and bevacizumab) versus SOC as second-line treatment for participants with advanced CRC (n=188)...Furthermore, approximately 500 commercial CRC plasma samples were evaluated to determine the prevalence of patients with elevated DKK1 in a real-world data set and understand the association between demographics and DKK1 levels. Future work will include completing the development and validation of the assay as a potential companion diagnostic and determining the appropriate threshold of DKK1 plasma levels for CRC patients who would be most likely to derive clinical benefit from a sirexatamab-based therapy."

Biomarker • Clinical • Colorectal Cancer • 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

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

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 (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