DKN-01 and tislelizumab as second-line therapy in DKK1-high gastroesophageal adenocarcinoma: DisTinGuish trial part B
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-...
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Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-61420-x |
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| author | Keun-Wook Lee Devalingam Mahalingam Byoung Yong Shim In-Ho Kim Do-Youn Oh Hope Uronis Sun Jin Sym Mohamad Sonbol Khaldoun Almhanna Mohamedtaki A. Tejani Beodeul Kang Michael H. Kagey Melissa Stilian Calvin Jia Cynthia A. Sirard Jaffer A. Ajani Samuel J. Klempner |
| author_facet | Keun-Wook Lee Devalingam Mahalingam Byoung Yong Shim In-Ho Kim Do-Youn Oh Hope Uronis Sun Jin Sym Mohamad Sonbol Khaldoun Almhanna Mohamedtaki A. Tejani Beodeul Kang Michael H. Kagey Melissa Stilian Calvin Jia Cynthia A. Sirard Jaffer A. Ajani Samuel J. Klempner |
| author_sort | Keun-Wook Lee |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-a3107a89b0f644a3af46eb96469aaa7c |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-a3107a89b0f644a3af46eb96469aaa7c2025-08-20T04:02:56ZengNature PortfolioNature Communications2041-17232025-07-011611810.1038/s41467-025-61420-xDKN-01 and tislelizumab as second-line therapy in DKK1-high gastroesophageal adenocarcinoma: DisTinGuish trial part BKeun-Wook Lee0Devalingam Mahalingam1Byoung Yong Shim2In-Ho Kim3Do-Youn Oh4Hope Uronis5Sun Jin Sym6Mohamad Sonbol7Khaldoun Almhanna8Mohamedtaki A. Tejani9Beodeul Kang10Michael H. Kagey11Melissa Stilian12Calvin Jia13Cynthia A. Sirard14Jaffer A. Ajani15Samuel J. Klempner16Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of MedicineRobert H. Lurie Comprehensive Cancer Center, Northwestern UniversityThe Catholic University of Korea St. Vincent’s HospitalSeoul St. Mary’s Hospital, The Catholic University of KoreaSeoul National University Hospital, Cancer Research Institute, Seoul National University College of MedicineDuke University Medical CenterGachon University Gil Medical CenterMayo Clinic HospitalRhode Island Hospital, Brown University Medical CenterAdvent Health Cancer InstituteCHA Bundang Medical CenterLeap TherapeuticsLeap TherapeuticsLeap TherapeuticsLeap TherapeuticsMD Anderson Cancer CenterDepartment of Medicine, Division of Hematology-Oncology, Massachusetts General HospitalAbstract 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.https://doi.org/10.1038/s41467-025-61420-x |
| spellingShingle | Keun-Wook Lee Devalingam Mahalingam Byoung Yong Shim In-Ho Kim Do-Youn Oh Hope Uronis Sun Jin Sym Mohamad Sonbol Khaldoun Almhanna Mohamedtaki A. Tejani Beodeul Kang Michael H. Kagey Melissa Stilian Calvin Jia Cynthia A. Sirard Jaffer A. Ajani Samuel J. Klempner DKN-01 and tislelizumab as second-line therapy in DKK1-high gastroesophageal adenocarcinoma: DisTinGuish trial part B Nature Communications |
| title | DKN-01 and tislelizumab as second-line therapy in DKK1-high gastroesophageal adenocarcinoma: DisTinGuish trial part B |
| title_full | DKN-01 and tislelizumab as second-line therapy in DKK1-high gastroesophageal adenocarcinoma: DisTinGuish trial part B |
| title_fullStr | DKN-01 and tislelizumab as second-line therapy in DKK1-high gastroesophageal adenocarcinoma: DisTinGuish trial part B |
| title_full_unstemmed | DKN-01 and tislelizumab as second-line therapy in DKK1-high gastroesophageal adenocarcinoma: DisTinGuish trial part B |
| title_short | DKN-01 and tislelizumab as second-line therapy in DKK1-high gastroesophageal adenocarcinoma: DisTinGuish trial part B |
| title_sort | dkn 01 and tislelizumab as second line therapy in dkk1 high gastroesophageal adenocarcinoma distinguish trial part b |
| url | https://doi.org/10.1038/s41467-025-61420-x |
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