Gastric cancer (GC) remains a formidable global health challenge, ranking among the top-five causes of cancer-related deaths worldwide. The majority of patients face advanced stages at diagnosis, with a mere 6% five-year survival rate. First-line treatment for metastatic GC typically involves a fluoropyrimidine and platinum agent combination; yet, predictive molecular markers have proven elusive. This review navigates the evolving landscape of GC biomarkers, with a specific focus on Claudin 18.2 (CLDN18.2) as an emerging and promising target. Recent phase III trials have unveiled the efficacy of Zolbetuximab, a CLDN18.2-targeting antibody, in combination with oxaliplatin-based chemotherapy for CLDN18.2-positive metastatic GC. As this novel therapeutic avenue unfolds, understanding the nuanced decision making regarding the selection of anti-CLDN18.2 therapies over other targeted agents in metastatic GC becomes crucial. This manuscript reviews the evolving role of CLDN18.2 as a biomarker in GC and explores the current status of CLDN18.2-targeting agents in clinical development. The aim is to provide concise insights into the potential of CLDN18.2 as a therapeutic target and guide future clinical decisions in the management of metastatic GC.

Advanced cholangiocarcinoma harbors various genetic alterations, one of the most common being fibroblast growth factor receptor (FGFR) fusions. Although FGFR inhibitors have a good response rate, their median progression-free survival is about 6 – 9 months in most trials. The present manuscript is a non-systematic review that explores the mechanisms of resistance and the possible strategies to overcome this rapid resistance. From the findings, resistance to FGFR inhibition can be classified into either primary or secondary resistance. Primary resistance is less common, explained mostly by the presence of co-mutations. In contrast, secondary resistance mechanisms are similar to other tyrosine kinase inhibitors: On-target mutations alter the binding site of the FGFR protein (gatekeeper resistance); off-target mechanisms are multifactorial and involve the activation of related intracellular pathways and the loss of differentiation, leading to a mesenchymal phenotype. Various strategies are in development in order to maintain the efficacy of targeted therapy for patients by overcoming FGFR inhibition resistance, including the coinhibition of the related pathway, the use of pan-FGFR inhibitors, and the development of covalent or dual FGFR inhibitors.