Nat Commun. 2025;16(1):6393.

DKN-01 and tislelizumab as second-line therapy in DKK1-high gastroesophageal adenocarcinoma: DisTinGuish trial part B.

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제1저자 이근욱 · 교신저자 이근욱, Samuel J. Klempner

PMID 40640119 PMC12246393 DOI 10.1038/s41467-025-61420-x IF 18.1 혈액종양내과

소속 (14)

Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea. imdoctor@snu.ac.kr.
Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA.
The Catholic University of Korea St. Vincent's Hospital, Suwon, Korea.
Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea.
Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
Duke University Medical Center, Durham, NC, USA.
Gachon University Gil Medical Center, Incheon, Korea.
Mayo Clinic Hospital, Phoenix, AZ, USA.
Rhode Island Hospital, Brown University Medical Center, Providence, RI, USA.
Advent Health Cancer Institute, Orlando, FL, USA.
CHA Bundang Medical Center, Seongnam, Korea.
Leap Therapeutics, Cambridge, MA, USA.
MD Anderson Cancer Center, Houston, TX, USA.
Department of Medicine, Division of Hematology-Oncology, Massachusetts General Hospital, Boston, MA, USA. sklempner@mgb.org.

Abstract

Biomarker-enriched, chemotherapy-free treatments for patients with advanced gastric and gastroesophageal junction cancer have not been widely explored. In this multicenter, phase 2 trial (NCT04363801), we evaluated the efficacy and safety of second-line doublet immunotherapy, combining DKN-01, an immunomodulating antibody targeting Dickkopf-related protein 1 (DKK1), with the anti-programmed cell death-1 (PD1) antibody, tislelizumab in patients with advanced gastric/gastroesophageal junction cancer and elevated tumor DKK1 expression, a putative predictive biomarker for DKN-01. Here we report part B (second line cohort) of the larger DisTinGuish trial. The primary endpoint was safety and tolerability, with secondary endpoints including objective response rate (ORR), overall survival (OS), progression free survival (PFS), and disease control rate (DCR). 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. 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.

Figures

**Fig. 1** Tumor response in the modified intent-to-treat population. Waterfall plot for best percent change in sum of diameters per RECIST (v1.1) by Dose (A) and PD-L1 (B) in the overall modified intent-to-treat (mITT) population; C Spider plot for percent change in sum of diameters by PD-L1 in the overall mITT population. Source data is provided in the source Data file.

**Fig. 2** Survival outcomes with tislelizumab and DKN-01. Kaplan-Meier curves for progression-free survival by Overall (A), Dose (B) and by PD-L1 (C) in the overall modified intent-to-treat population; Kaplan-Meier curves for overall survival by Overall (D), Dose (E) and by PD-L1 (F) in the overall population. Source data is provided in the source Data file.

그림 출처: PubMed Central 공개 논문 (PMC12246393)

Comment · 정정

Erratum in Nat Commun. 2026 Feb 6;17(1):1437. doi: 10.1038/s41467-026-69394-0.

Conflict of interest statement

Competing interests: K.W.L. reports research funding to his institution for conducting clinical trials from Leap Therapeutics in relation to this manuscript. He also reported research funding to his institution for conducting clinical trials from MSD, AstraZeneca, Ono Pharmaceutical, Roche, Merck KGaA, BeiGene, Astellas Pharma, Amgen, Daiichi Sankyo, ALX Oncology, GlaxoSmithKline, Macrogenics, Taiho Pharmaceutical, Seagen, Y-BIOLOGICS, Bolt Biotherapeutics, Trishula Therapeutics, InventisBio, MedPacto, Ildong Pharmaceutical, Genome & Company, Arcus Biosciences, Elevar Therapeutics, Jazz Pharmaceuticals, TRIO Oncology, Exelixis, IgM Biosciences, Panolos Bioscience, Metafines, Wellmarker Bio, Medicenna, and Erasca; consulting fees from Daiichi Sankyo, MSD, Astellas Pharma, AbbVie, and Metafines; honoraria for lectures or presentations from Sanofi/Aventis, Astellas Pharma, Bayer, Daiichi Sankyo, and Merck KGaA. D.M. has received research funding from Amgen, Merck, Oncolytics and Rafael; scientific advisory board for Actuate, Qurient, and an advisory/speaker bureau for Amgen, BMS, Eisai, and Exelixis; has received funding paid to their institution from Acepodia, Actuate Therapeutics, ADC Therapeutics, Amgen, AVEO, Bayer, Blueprint Medicines, BMS, BioNTech, Dialectic Therapeutics, Epizyme, Fujifilm, ImmuneSensor, Immune-Onc Therapeutics, Leap Therapeutics, Lycera Corp, Merck, Millennium, MiNA Alpha, NGM Biopharmaceuticals, Novartis, Oncolytics, Orano Med, Puma, Qurient, Rafael, Repare Therapeutics, Triumvira Immunologics, Vigeo Therapeutics, Warewolf Therapeutics. H.J.C. has received honoraria from Eisai, Roche, ONO, MSD, Bristol Myers Squibb, BeiGene, Sanofi, Servier, AstraZeneca, Aptamer Science, and Boryung; served on advisory boards for Eisai, Roche, ONO, MSD, Bristol Myers Squibb, BeiGene, Servier, AstraZeneca, Boryung, IMBDx, and Aptamer Science; and received research grants from Roche, BeiGene, IMBDx, Dong-A ST, and Boryung Pharmaceuticals. M.H.K., M.S., C.J., and C.A.S. are employees of Leap Therapeutics and report stock ownership in Leap Therapeutics. S.J.K. has served a consultant/advisory role for Bristol Myers Squibb, Merck, Roche, Astellas, Daiichi-Sankyo, Pieris, Natera, Novartis, AstraZeneca, Mersana, Sanofi-Aventis, I-Mab, Taiho Oncology, Eisai, Gilead, BeiGene, and Elevation Oncology, Boehringer-Ingelheim. S.J.K. reports research support (institutional) from Arcus Biosciences, I-Mab, AstraZeneca, Parabilis, Debbie’s Dream Foundation, Degregorio Foundation, StandUp2Cancer, AACR, NIH/NCI, Gastric Cancer Foundation, and the Korean Ministry of Health. The remaining authors declare no competing interests.

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