Zolbetuximab combined with chemotherapy improves progression-free survival and overall survival in CLDN18.2-expressing gastric cancersNew drug shows promise for advanced stomach and esophageal cancer

IntroductionAdvanced gastric and gastroesophageal junction (G/GEJ) adenocarcinomas are characterized by an aggressive course and a very poor prognosis. Due to the limited benefit of immunotherapy in patients with HER2-negative tumors, new therapeutic targets are sought. Zolbetuximab is a chimeric monoclonal antibody targeting the CLDN18.2 protein, which is overexpressed in 50–80% of gastric cancers.Materials and methodsThis review is based on phase I–III clinical trials, including the pivotal SPOTLIGHT, GLOW, FAST, and ILUSTRO trials. The efficacy and safety of zolbetuximab in combination with chemotherapy were assessed as first-line treatment for adults with locally advanced or metastatic G/GEJ adenocarcinoma, HER2-negative, and highly CLDN18.2-expressing.ResultsEarly phase studies confirmed the clinical activity and tolerability of zolbetuximab. A Japanese phase I study demonstrated the safety and pharmacokinetic profile of zolbetuximab as monotherapy, establishing the recommended dose in subsequent studies. The phase II FAST study demonstrated that the addition of zolbetuximab to EOX chemotherapy significantly improved both PFS (HR 0.44; p=0.0005) and OS (HR 0.55; p=0.0001). The phase II ILUSTRO study demonstrated activity of zolbetuximab both as monotherapy (ORR 9%) and in combination with mFOLFOX6 (ORR 39%), supporting its advancement to phase III. These results were confirmed in two pivotal randomized phase III studies. In the SPOTLIGHT study, the addition of zolbetuximab to mFOLFOX6 reduced the risk of death by 25% (median OS 18.23 vs. 15.54 months), and in the GLOW study, the addition of zolbetuximab to CAPOX reduced the risk of death by almost 23% (median OS 14.39 vs. 12.16 months). The most common adverse events were nausea and vomiting, occurring primarily in the first treatment cycle.ConclusionsZolbetuximab represents a significant advancement in the treatment of patients with advanced G/GEJ adenocarcinoma overexpressing CLDN18.2, addressing an important unmet clinical need. However, optimizing the stringent threshold for CLDN18.2 positivity (requiring staining in ≥75% of cells) and establishing a treatment regimen for patients with concurrent CLDN18.2 and PD-L1 expression remains a significant challenge. The review protocol was prospectively registered in the PROSPERO database (International Prospective Register of Systematic Reviews) under registration number CRD420261383764.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD420261383764.