Background: Advanced G/GEJ cancer is a major cause of cancer-related mortality requiring novel therapies. DKN-01 is a humanized mAb that binds and neutralizes DKK1. DKK1 plays a major role in WNT-pathway regulation and is overexpressed in multiple cancers. DKK1 expression is associated with poor prognosis, an immunosuppressive tumor microenvironment, and resistance to chemotherapy in G/GEJ cancer. The non-randomized Part A of DisTinGuish demonstrated durable clinical benefit in patients with G/GEJ adenocarcinoma. Higher response rates were observed in patients with high tumoral DKK1 expression, when DKN-01 was administered in combination with an anti-PD1 mAb, tislelizumab, and chemotherapy^1,2. Furthermore, in Part B, durable responses were seen in 2L patients with DKK1-high G/GEJ cancers treated with a chemotherapy-free doublet regimen, DKN-01 plus tislelizumab¹. Part C will evaluate the efficacy of this chemoimmunotherapy combination in a randomized fashion in treatment-naïve G/GEJ adenocarcinoma patients. Methods: Part C is an ongoing, global, randomized phase 2 open-label study evaluating DKN-01 in combination with tislelizumab + chemotherapy (CAPOX or mFOLFOX6) vs tislelizumab + chemotherapy in patients with advanced G/GEJ adenocarcinoma. Patients are randomized 1:1 and stratified by DKK1 and PD-L1 expression. Approximately 160 patients will be enrolled from 5 different countries. Key inclusion criteria include patients with HER2 negative, G/GEJ adenocarcinoma who have received no prior systemic treatment in the unresectable locally advanced/metastatic setting and can provide tumor tissue to document PD-L1 CPS and DKK1 expression, as performed at a central lab. Key exclusion criteria include prior treatment with anti-PD1/L1/L2. The primary endpoint is PFS according to RECIST v1.1 as assessed by the investigator in patients with DKK1-high tumors. Key secondary and exploratory end points include PFS, OS, ORR, DoR in patients with tumors with any level of DKK1 expression, as assessed by both investigator and by blinded, central review. Recruitment is ongoing. Clinical trial information: NCT04363801. References SJ Klempner, et al. DKN-01 and tislelizumab ± chemotherapy as a first-line (1L) and second-line (2L) investigational therapy in advanced gastroesophageal adenocarcinoma (GEA): DisTinGuish Trial. JCO 40, no. 4_suppl, 2022, 292-292.  SJ Klempner, et al. DKN-01 and Tislelizumab + Chemotherapy as First-line (1L) Investigational Therapy in Advanced Gastroesophageal Adenocarcinoma (GEA): DisTinGuish Trial. ESMO Annual Meeting September 2022. Clinical trial information: NCT04363801.