Impact of claudin 18.2 expression on the efficacy of trastuzumab deruxtecan in patients with HER2-positive gastric or gastroesophageal junction cancer

Background: Human epidermal growth factor receptor 2 (HER2) and claudin 18.2 (CLDN18.2) are key therapeutic targets in metastatic gastric and gastroesophageal junction cancer (mGC/GEJC).Trastuzumab deruxtecan (T-DXd) is standard care for previously treated HER2-positive mGC/GEJC, but the prognostic impact of CLDN18.2 remains unclear.Patients and methods: We retrospectively reviewed patients with HER2-positive mGC/GEJC treated with T-DXd at National Cancer Center Hospital East until February 2025.T-DXd outcomes were compared between CLDN18.2positive(2+ in 75% of tumor cells) and -negative patients in two cohorts: those with HER2 positivity before first-line therapy (overall cohort) and those maintaining HER2 positivity immediately before T-DXd (remaining HER2 cohort).CLDN18.2expression was evaluated at any time before T-DXd administration.Results: Eighty-seven patients were included in the overall cohort and 30 in the remaining HER2 cohort.In the overall cohort, progression-free survival (PFS) was shorter in CLDN18.2-positivepatients [3.9 versus 5.3 months; hazard ratio (HR) 1.87, 95% confidence interval (CI) 1.04-3.34,P = 0.036], with an adjusted HR of 1.82 (95% CI 1.02-3.28,P = 0.047).Overall survival (OS) showed a shorter trend (8.6 versus 11.2 months, HR 1.36, 95% CI 0.76-2.45,P = 0.30).In the remaining HER2 cohort, CLDN18.2-positivepatients had shorter PFS (3.2 versus 8.0 months, HR 3.40, 95% CI 1.38-8.40,P = 0.008) and OS (7.1 versus 12.9 months, HR 2.44, 95% CI 1.04-5.74,P = 0.041).Conclusions: CLDN18.2 positivity may attenuate the efficacy of T-DXd in HER2-positive mGC/GEJC, supporting the rationale for dual blockade of CLDN18.2 and HER2.