Making Zolbetuximab deliverable in practice: multidisciplinary management of nausea, vomiting, gastritis, and hypoalbuminemia in first-line CLDN18.2-positive, HER2-negative gastric/GEJ adenocarcinoma.

Zolbetuximab plus platinum-fluoropyrimidine chemotherapy has emerged as an approved first-line treatment option for patients with CLDN18.2-positive, HER2-negative gastric or gastroesophageal junction adenocarcinoma. However, its implementation in routine practice is frequently challenged by early gastrointestinal toxicities, particularly nausea and vomiting during the first infusion. A clinically important observation from the combined Japanese subgroup analysis of the phase III SPOTLIGHT and GLOW trials is that Japanese patients achieved a greater progression-free survival benefit (median 20.53 months; hazard ratio [HR] 0.482) than the overall trial populations (HR 0.69-0.75), alongside higher relative dose intensity (> 80% in 98.2% versus 88.9% of non-Japanese patients) and greater cumulative drug exposure. Notably, no Japanese patient discontinued zolbetuximab permanently due to nausea or vomiting. These observations are hypothesis-generating and suggest that systematic, proactive toxicity management and maintained drug delivery may contribute to clinical benefit, while alternative biological, clinical, and population-level explanations should also be considered. Accumulating real-world evidence suggests that zolbetuximab-related adverse events should not be viewed in isolation. Endoscopy-based data have shown early-onset gastritis in 89.7% of evaluated patients, with diffuse gastritis associated with more frequent anorexia and greater serum albumin decline. Pragmatic institutional protocols, real-world safety frameworks, and Delphi-based consensus guidance indicate that high-emetic-risk antiemetic prophylaxis, stepwise infusion-rate escalation, temporary interruption, rescue antiemetics, intravenous hydration, and education of patients and clinic staff can improve tolerability and reduce treatment interruption in subsequent cycles. Formal pharmacokinetic analyses further demonstrate an association between higher average zolbetuximab concentration throughout treatment (Cave) and longer progression-free and overall survival. These findings provide a plausible mechanistic link between dose delivery and clinical benefit, but they do not by themselves establish causality. This review proposes an integrated clinical framework in which nausea, vomiting, gastritis, anorexia, and hypoalbuminemia are understood as potentially interconnected on-target/off-tumor gastric toxicities requiring multidisciplinary management by physicians, nurses, and pharmacists. Throughout the review, we distinguish established evidence from hypotheses generated by clinical, endoscopic, real-world, and pharmacokinetic observations. Proactive toxicity management may preserve treatment continuity and effective drug exposure, thereby maximizing the likelihood of clinical benefit; however, prospective studies are required to determine whether supportive-care interventions directly improve efficacy outcomes.

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