Claudin 18.2 (CLDN18.2), a tight junction protein selectively expressed in normal gastric epithelium and widely retained during carcinogenesis, has emerged as a promising therapeutic target for advanced gastric cancer (AGC). SPOTLIGHT and GLOW trials evaluated the anti-CLDN18.2 monoclonal antibody (mAb) zolbetuximab in combination with first-line chemotherapy, and established CLDN18.2 as a therapeutic target, initiating a paradigm shift toward a biomarker-driven treatment approach in AGC. In addition, from zolbetuximab to a diverse pipeline of promising high-affinity mAbs, bispecific antibodies, antibody-drug conjugates and chimeric antigen receptor T cells, this target has established a new and highly effective therapeutic avenue for CLDN18.2-expressing AGC. Therefore, as research progresses, CLDN18.2-targeted therapy is poised to become a cornerstone of treatment across multiple disease stages and cancer types. This review describes the biological role of CLDN18.2 in normal gastric epithelium and gastric carcinogenesis and summarizes the current therapeutic landscape and future perspectives targeting CLDN18.2 in AGC.

Purpose: Determination of optimal treatment strategies for HER2-positive advanced gastric cancer (AGC) in randomized trials is necessary despite difficulties in direct comparison between trastuzumab deruxtecan (T-DXd) and nivolumab as third or later-line treatments. Materials and Methods: This single-institution, retrospective study aimed to describe the real-world efficacy and safety of T-DXd and nivolumab as ≥ third line treatments for HER2-positive AGC between March 2016 and May 2022. Overall, 58 patients (median age, 64 years;69% male) were eligible for the study (T-DXd group, n=20; nivolumab group, n=38). Results: Most patients exhibited a HER2 3+ status (72%) and presented metastatic disease at diagnosis (66%). The response rates of 41 patients with measurable lesions in the T-DXd and nivolumab groups were 50% and 15%, respectively. The T-DXd and nivolumab groups had a median progression-free survival of 4.8 months (95% confidence interval [CI], 3.3, 7.0) and 2.3 months (95% CI, 1.5, 3.5), median overall survival (OS) of 10.8 months (95% CI, 6.9, 23.8) and 11.7 months (95% CI, 7.6, 17.1), and grade 3 or greater adverse event rates of 50% and 2%, respectively. Overall, 64% patients received subsequent treatment. Among 23 patients who received both regimens, the T-DXd–nivolumab and nivolumab–T-DXd groups had a median OS of 14.0 months (95% CI, 5.0, not reached) and 19.3 months (95% CI, 9.5, 25.1), respectively. Conclusions T-DXd and nivolumab showed distinct efficacy and toxicity profiles as ≥ third line treatments for HER2-positive AGC. Considering the distinct features of each regimen, they may help clinicians personalize optimal treatment approaches for these patients.