Efficacy and safety of anti-CLDN18.2 therapies in advanced or metastatic gastric, gastro-oesophageal junction, and oesophageal carcinomas with CLDN18.2 positivity: a systematic review and meta-analysis

The optimal treatment strategy for advanced or metastatic gastric, gastro-esophageal junction or esophageal carcinomas expressing Claudin-18 isoform 2 (CLDN18.2) remains inadequately defined and requires further investigation.
A systematic search was conducted to identify randomized controlled trials and single-arm studies.
Four randomized controlled trials comprising five cohorts compared anti-CLDN18.2–based therapies with chemotherapy or physician’s choice. Anti-CLDN18.2 therapy, primarily consisting of first-line zolbetuximab combined with chemotherapy, significantly improved progression-free survival (PFS) (hazard ratios [HR] 0.564; 95% confidence interval [CI]: 0.417–0.711) and overall survival (OS) (HR 0.716; 95% CI: 0.631–0.802), along with enhanced 1- and 2-year survival rates. However, higher rates of nausea, neutropenia, and vomiting were observed in patients treated with zolbetuximab-based regimens. A single-arm meta-analysis, which included ten cohorts from seven trials, demonstrated that antibody-drug conjugates (ADCs) exhibited greater antitumor activity compared to zolbetuximab-based regimens.
Anti-CLDN18.2 therapies, particularly first-line zolbetuximab plus chemotherapy, significantly improve PFS and OS in advanced gastric, gastro-esophageal junction, or esophageal carcinoma compared to standard treatments. ADCs have shown promising antitumor activity in single-arm studies, suggesting the need for confirmatory randomized trials. Standardized definitions for CLDN18.2 positivity and high expression are urgently needed.
www.crd.york.ac.uk/prospero identifier is CRD420251123719.
What is this article about?This article reviews new treatments for advanced cancers of the stomach and esophagus. These cancers are hard to treat, especially when spread. We focused on cancers with a specific surface protein called Claudin-18 isoform 2 (CLDN18.2), found on many cancer cells but few healthy cells, making it a good treatment target.
What did we do?We combined data from 11 clinical studies involving over 1,900 patients, including four randomized controlled trials (the strongest evidence). We evaluated the overall effectiveness and side effects of CLDN18.2-targeting treatments.
What did we find?A medicine called zolbetuximab, given with chemotherapy as first treatment, helps patients live longer and keeps cancer from growing longer than chemotherapy alone. This benefit was consistent across large trials.
Newer treatments called antibody-drug conjugates (ADCs) also showed promise in early studies. These act as “smart bombs” delivering chemotherapy directly to cancer cells. Larger trials are now needed.
Common side effects of zolbetuximab included nausea, vomiting, and low white blood cell counts. These were manageable.
Why is this important?Our findings support zolbetuximab plus chemotherapy as a new standard. However, studies used different definitions of “CLDN18.2-positive.” A single, clear definition is urgently needed so the right patients receive the right treatment.