Zolbetuximab or Immunotherapy as the Initial Targeted Therapy in CLDN18.2-Positive, HER2-Negative Advanced Gastric Cancer: Weighing the Options

Advanced gastric/gastroesophageal junction (G/GEJ) adenocarcinoma remains a common and deadly form of cancer. Advances in G/GEJ cancer treatment have improved survival outcomes with the claudin-18.2 (CLDN18.2)-targeted agent, zolbetuximab, and immune checkpoint inhibitors (ICIs) targeting the PD-1 receptor. This article offers an evidence-informed opinion on considerations when selecting between these first-line treatments for G/GEJ adenocarcinoma in patients with HER2-negative disease that expresses CLDN18.2 and/or PD-L1, including the reliability of biomarker scoring and interpretation, overall survival (OS) rates, toxicity profiles, and logistical practicalities. Evidence from Phase III trials for zolbetuximab and ICIs suggest similar OS benefits of 14-18 months compared to chemotherapy alone, but there appears to be a gradient of benefit for ICIs with increasing PD-L1 combined positive score (CPS). There is high inter-observer variability in CPS scoring, particularly at lower thresholds. Zolbetuximab is associated with high rates of nausea and vomiting during the initial infusion, whereas ICIs are associated with risk of later-onset immune-related toxicities that can be fatal in rare cases. In considering the available evidence, our opinion is that zolbetuximab is a reasonable option for initial targeted treatment in HER2-/CLDN18.2-positive advanced G/GEJ when PD-L1 CPS score is <10 based on the reliability of biomarker testing, comparable OS, and avoidance of potentially irreversible ICI-induced immune toxicity.