sirexatamab + tislelizumab + chemotherapy

Sirexatamab + tislelizumab + chemotherapy is a combination regimen investigated as a first-line treatment for patients with inoperable, locally advanced or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma. The regimen consists of **sirexatamab** (DKN-01), a humanized monoclonal antibody targeting Dickkopf-1 (DKK1); **tislelizumab**, an anti-PD-1 immune checkpoint inhibitor; and standard-of-care **chemotherapy** (typically CAPOX or mFOLFOX6). DKK1 is a secreted protein that inhibits the Wnt signaling pathway and is associated with an immunosuppressive tumor microenvironment and poor prognosis in gastric cancer. By inhibiting DKK1, sirexatamab aims to restore Wnt signaling and enhance immune cell infiltration, while tislelizumab blocks the PD-1/PD-L1 axis to reactivate T-cell antitumor responses. In the Phase 2 DisTinGuish study (NCT04363801), the combination demonstrated improved response rates in specific biomarker populations, such as DKK1-high and PD-L1 negative patients. However, the study did not meet its primary progression-free survival (PFS) endpoints, leading Leap Therapeutics to discontinue development of this specific triplet for gastric cancer in favor of other indications like colorectal cancer.

Other names

DKN-01 + tislelizumab + chemotherapy