Zev A. Wainberg (Los Angeles, United States of America), Sae-Won Han (Seoul, Republic of Korea), Jong Gwang Kim (Daegu, Republic of Korea), Craig Devoe (Lake Success, United States of America), John H. Strickler (Durham, United States of America), Keun-Wook Lee (Seongnam, Republic of Korea), Jason Baum (Cambridge, United States of America), Calvin Jia (Cambridge, United States of America), Cynthia Sirard (Cambridge, United States of America), Markus Moehler (Mainz, Germany)
Disclosure
Z.A. Wainberg: Financial Interests, Personal, Advisory Board: Amgen, Astellas, Arcus, Bayer, AstraZeneca, Novartis, Roche, Ipsen, Daiichi, Merck, BMS, Alligator, Jannsen, Boehringer Ingelheim, Phanes; Financial Interests, Personal, Other, DMC: Pfizer; Financial Interests, Institutional, Steering Committee Member: Novartis, AstraZeneca; Financial Interests, Institutional, Coordinating PI: Ipsen; Financial Interests, Institutional, Local PI: Merck; Financial Interests, Institutional, Research Grant: BMS, Arcus. S. Han: Financial Interests, Personal, Advisory Board: AstraZeneca, Natera, Ono Pharmaceuticals, AbbVie, Bayer; Financial Interests, Institutional, Other, Consulting: Cell Biotech, BeyondBio; Financial Interests, Institutional, Local PI: Hanmi, Genentech, Roche, Loxo, Mirati, MSD, Janssen, Lilly, Seagen, Arcus, Merck, Leap Therapeutics, Hengrui, GC Pharma, AbbVie, Astellas, AstraZeneca, Jeil Pharmaceutical; Financial Interests, Institutional, Coordinating PI: BeyondBio, Cell Biotech, Boryung, IMBdx. C. Devoe: Non-Financial Interests, Other, Site PI on clinical trial CBP-1019-101.: Coherent Biopharma; Non-Financial Interests, Other, Site PI on clinical trial DEK-DKK1-P207 (DEFIANCE trial): Leap Therapeutics; Non-Financial Interests, Other, Site PI for MK-7684A-010: Merck; Non-Financial Interests, Other, Site PI for ELI-002-001 (AMPLIFY-201) & ELI-002-201 (AMPLIFY-7P): Elicio Therapeutics. J.H. Strickler: Financial Interests, Personal, Advisory Board: AbbVie, Amgen, Astellas, AstraZenca, BMS, Bayer, BeiGene, Cytovation, Daiichi Sankyo, Eli Lilly, GE Healthcare, Incyte, Ipsen, Jazz Pharmaceuticals, Johnson and Johnson, Leap Therapeutics, Merck, Natera, Pfizer, Quanta Therapeutics, Regeneron, Roche Genentech, Sanofi, Taiho, Takeda, Xilio Therapeutics; Financial Interests, Personal, Other, Consulting: GSK; Financial Interests, Personal, Stocks/Shares, Stock options: Triumvira Therapeutics; Financial Interests, Institutional, Local PI: AbbVie, Apollo Therapeutics, Bayer, BeiGene, Curegenix, Daiichi Sankyo, Eli Lilly, GSK, Leap Therapeutics, Novartis, Revolution Medicine, Roche Genentech; Financial Interests, Institutional, Coordinating PI: Amgen; Financial Interests, Personal and Institutional, Steering Committee Member: Pfizer; Financial Interests, Personal and Institutional, Local PI: Quanta Therapeutics. K. Lee: Financial Interests, Personal, Advisory Board: AbbVie (Korea), Astellas, Daiichi Sankyo (Korea), Merck Sharp & Dohme (Korea), Metafines, Ono Pharmaceuticals (Korea), BeiGene (Korea), PIN therapeutics, Takeda (Korea); Financial Interests, Personal, Invited Speaker: Bayer (Korea), Merck KCaA (Korea), Celltrion; Financial Interests, Institutional, Local PI, For conducting clinical trials: ALX Oncology, Amgen, Arcus Biosciences, Astellas Pharma, AstraZeneca, Avelos Therapeutics, Bayer, BeiGene, Boehringer Ingelheim, Bolt therapeutics, Daiichi Sankyo, Erasca, Inc, Exelixis, Genome & Company, GSK, Hanmi, IDRx, IgM Biosciences, Ildong Pharmaceutical, InventisBio, Jazz Pharmaceuticals, Jiangsu Hengruii, Leap therapeutics, MedPacto, Medicenna, Merck KGaA, Merck Sharp & Dohme, Metafines, Ono pharmaceutical, Panolos Bioscience, Pfizer, Roche, Taiho Pharmaceutical, Torl Biotherapeutics, Trishula therapeutics, Wellmarker Bio; Non-Financial Interests, Leadership Role, SMC chair of ASPEN-06 study: ALX Oncology. J. Baum: Financial Interests, Personal, Full or part-time Employment: Leap Therapeutics. C. Jia: Financial Interests, Personal, Full or part-time Employment: Leap Therapeutics. C. Sirard: Financial Interests, Personal, Full or part-time Employment: Leap Therapeutics. M. Moehler: Financial Interests, Personal, Advisory Board: BMS, Servier, Amgen, Lilly, BeiGene, Novartis, Taiho, Daiichi, Amgen, MD; Financial Interests, Personal, Invited Speaker: MSD, BMS, Falk foundation, AIO, BeiGene, Amgen; Financial Interests, Institutional, Advisory Board: Bayer, Sanofi; Financial Interests, Personal, Other, Chair: EORTC. All other authors have declared no conflicts of interest.
Background
Metastatic CRC is highly associated with alterations in the wnt signaling pathway. Dickkopf-1 (DKK1) is a key regulator of wnt signaling and implicated in disease progression, metastasis and angiogenesis. Circulating levels of DKK1 are higher in CRC patients (pts) than healthy controls and are associated with shorter survival. Sirexatamab (sirexa) is an IgG4 antibody that potently inhibits DKK1.
Methods
DeFianCe (NCT05480306) is a phase 2 randomized, global, open-label study to evaluate efficacy and safety of sirexa plus FOLFIRI/FOLFOX + bevacizumab (experimental [exp]) vs FOLFIRI/FOLFOX + bevacizumab (control [con]) as 2L treatment of advanced MSS, BRAF wildtype CRC. Primary objective is investigator assessed PFS in ITT population. A key prespecified exploratory endpoint is baseline plasma DKK1 levels, assessed by the SomaScan platform (SomaLogic, Boulder CO). DKK1-high was defined as the upper median. Other secondary endpoints include tolerability, ORR and OS.
Results
188 pts enrolled between Aug 2023-Sept 2024 (94 pts per arm); 88 pts DKK1-high (50 exp, 38 con). 84% received FOLFIRI on study. For both arms, TEAE profile was similar, 63% had ≥grade 3 adverse events (59% exp, 67% con), 20% had SAEs (20% exp, 19% con), 17% discontinued due to an AE (15% exp, 19% con), 40% required dose reductions (37% exp, 43% con), no related deaths. Median study duration: 11.1 months (mo). In ITT population, all clinical outcomes favored the exp arm: median PFS (9.2 vs 8.3 mo; p=0.1712; HR (95% CI): 0.838 (0.583, 1.207), ORR (35% vs 27%) and median DoR (11.1 vs 7.6 mo). Greater advantage for sirexa in DKK1-high; median PFS (9.0 vs 7.1 mo [HR:0.61, (95% CI: 0.37, 1.0) p=0.0255]; ORR (38% vs 24%); median DoR (11.1 vs 7.4 mo) and OS (NR vs 14.4 mo (HR:0.42, 95% CI: 0.19, 0.91; p=0.0118). Increasing DKK1 above upper median further improved PFS, OS and ORR for the sirexa arm.
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 trial identification
NCT05480306.
Legal entity responsible for the study
Leap Therapeutics, Inc.
Funding
Leap Therapeutics, Inc.
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