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553 DKN-01 and tislelizumab as a second-line (2L) investigational therapy in advanced DKK1 high gastroesophageal adenocarcinoma (GEA): DisTinGuish Trial
  1. Samuel Klempner1,
  2. Jaffer Ajani2,
  3. Joseph Chao3,
  4. Hope Uronis4,
  5. Cynthia Sirard5,
  6. Michael Kagey5,
  7. Jason Baum5,
  8. Lilin Zhang6,
  9. In-Ho Kim7,
  10. Do-Youn Oh8,
  11. Byoung Yong Shim7,
  12. Sun Jin Sym9,
  13. Mohamad Sonbol10,
  14. Mohamedtaki Tejani11,
  15. Zev Wainberg12,
  16. Devalingam Mahalingam13 and
  17. Keun-Wook Lee14
  1. 1Massachusetts General Hospital, Boston, MA, United States
  2. 2MD Anderson, Houston, TX, United States
  3. 3City of Hope, Duarte, CA, United States
  4. 4Duke University Medical Center, Durham, NC, United States
  5. 5Leap Therapeutics, Inc., Cambridge, MA, United States
  6. 6BeiGene, Beijing, China
  7. 7The Catholic University of Korea, Seoul, Korea, Republic of
  8. 8Seoul National University Hospital, Seoul, Korea, Republic of
  9. 9Gachon University Gil Medical Center, Incheon, Korea, Republic of
  10. 10Mayo Clinic Hospital, Phoenix, AZ, United States
  11. 11AdventHealth Cancer Institute, Orlando, FL, United States
  12. 12University of California Los Angeles, Los Angeles, CA, United States
  13. 13Northwestern University, Chicago, IL, United States
  14. 14Seoul National University Bundang Hospit, Seoul, Korea, Republic of


Background Elevated tumoral DKK1 expression is seen in approximately one third of previously treated GEA and has been associated with more aggressive disease and shorter overall survival. DKN-01 (D) is a targeted anti-DKK1 mAb which has demonstrated improved clinical outcomes in previously treated GEA pts with elevated tumoral DKK1 expression when used in combination with an anti-PD1 antibody.

Methods DisTinGuish (NCT04363801) is a Phase 2a single arm 2-part trial; Part A is reported separately; Part B investigated two dosing cohorts of D (300 mg and 600 mg) + tislelizumab (TS) as 2L therapy for DKK1-high GEA pts. Primary objective was to examine safety and tolerability and secondary objectives evaluated multiple efficacy endpoints including overall response rate (ORR) and disease control rate (DCR) in a modified intent to treat (mITT) population (>1 dose D).

Results 52 pts enrolled between 27 Oct 2020 and 7 Jun 2022; (D-300 mg, 24 pts; D-600 mg 28 pts). Median age was 63 (29, 76); 41 males (79%). 18 pts (35%) had gastroesophageal junction (GEJ) adenocarcinoma; 34 pts (65%) had gastric cancer (GC). 22 pts from US, 30 pts from Republic of Korea. 49 pts have PD-L1 visually-estimated combined positive score (vCPS) results: <1 n=13 (27%); 1-<10 n=22 (45%); ≥10 n=14 (29%). 38 pts with genomic profiling: Wnt activating mutations in 12 pts, no MSI-H. 4 pts were IO experienced. Median number of cycles 2 (1, 19). 12 pts remain on therapy. 19 pts (37%) experienced D-related adverse events (AE); 74% were G1/2. Most common regimen related AEs: fatigue, nausea, AST increased. 3 pts (6%) had serious D-related AEs [vomiting, fatigue, dehydration]. No G5 TRAEs. No D-related AE led to D-dose reduction or discontinuation. Preliminary ORR in response evaluable IO naive mITT (n=36) was 25% and DCR 44%. mITT ORR by vCPS (figure 1): <1: [n=11; PR-3 (27%), SD-1, PD-7]; 1-<10: [n=12; PR-1 (8%), SD-3, PD-8 (1 PD pt -> irPR)]; ≥10: [n=11; PR-5 (45%), SD-3, PD-3]. 6 of 9 responders remain on therapy, median DoR not reached. Median PFS: 1.4 mos (vCPS <1: 1.4 mos, 1-<10: 1.4 mos, ≥10: 2.9 mos).

Conclusions The combination of D + TS represents a well-tolerated, active chemotherapy-free combination in previously treated DKK1-high IO naïve GEA pts. Encouraging durable activity was observed particularly in DKK1 high/vCPS≥10 cohort: ORR 45%, DCR 73%. Updated ORR, DoR, PFS and additional correlative biomarker evaluation will be reported.

Acknowledgements Diane Piper and Mathis Thoma, Leap Therapeutics, Inc. biometrics support

Trial Registration NCT04363801

Abstract 553 Figure 1

Waterfall Plot by vCPS: IO naive mITT Population

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