Introduction
Based on positive results from the phase III SPOTLIGHT and GLOW trials, zolbetuximab, a monoclonal antibody targeting CLDN18.2, combined with chemotherapy, has become the standard first-line treatment for human epidermal growth factor receptor 2 (HER2)-negative, CLDN18.2-positive unresectable advanced gastric cancer.1, 2, 3 Nausea, vomiting, and anorexia are the most common zolbetuximab-related toxicities and can lead to early discontinuation. In ferrets, gastritis characterized by edema, redness, and erosion was observed macroscopically immediately after zolbetuximab administration.4 Histologically, inflammatory cell infiltration extended into deeper layers, progressing with vomiting. However, such gastritis was not reported in pivotal trials. Here, we report a case of gastritis following zolbetuximab administration.
Case report
A 58-year-old male patient with HER2-negative and CLDN18.2-positive metastatic gastric cancer received zolbetuximab (800 mg/m2) in combination with FOLFOX (a regimen consisting of levofolinate, fluorouracil, and oxaliplatin) as first-line therapy. Rabeprazole (20 mg) was administered for gastric acid suppression. During the first cycle, the patient developed grade 2 nausea and vomiting, leading to a temporary interruption of the infusion. Prochlorperazine was administered to alleviate symptoms. The infusion was subsequently resumed and completed without further incident. Due to grade 2 anorexia, olanzapine (2.5 mg) was initiated on day 5, followed by intravenous nutritional support starting on day 9. Grade 2 anorexia persisted through day 12 of the first cycle. At the initiation of the second cycle, the symptom had abated; grade 1 anorexia persisted, however. During the infusion of zolbetuximab (400 mg/m2), no new grade ≥1 gastrointestinal (GI) symptoms, including nausea, vomiting, or abdominal pain, were observed, and the full dose was administered without interruption.
Upper GI endoscopy carried out on day 4 of the second cycle demonstrated diffuse redness and erosions in the non-neoplastic gastric mucosa, extending from the cardia to the antrum, findings consistent with grade 2 gastritis (Figure 1). Histopathological analysis revealed superficial mucosal erosion, infiltration of inflammatory cells from the superficial to deep layers of the mucosa, focal fibrosis, and submucosal edema (Figure 1). Laboratory evaluation showed a decline in serum albumin levels (3.8 to 2.7 g/dl).
Figure 1.
Clinical course with endoscopic findings. The top panel illustrates the treatment regimen, including chemotherapy, PPI, and antiemetic use over time. A line graph below shows the changes in serum albumin levels, accompanied by the timing of gastrointestinal toxicities. Representative upper gastrointestinal endoscopic images at three time points—pretreatment, during treatment 1 (cycle 2), and during treatment 2 (cycle 4)—are shown from left to right. At each time point, images from the cardia, angular region, and antrum are presented. Left: normal mucosal appearance without significant inflammation. Middle: diffuse mucosal redness, edema, and erosions consistent with grade 2 gastritis. Right: improvement in gastric mucosal findings. Magnified histological images of gastric mucosal biopsies stained with hematoxylin–eosin are included for the two on-treatment time points, showing histopathological improvement over time. C, cycle; mFOLFOX6, modified FOLFOX6; PPI, proton pump inhibitor; Zolbe, zolbetuximab.
A follow-up endoscopy was carried out on day 15 of the fourth cycle, demonstrating the improvement in gastric inflammation, with no evidence of redness or edema throughout the stomach. In addition, a reduction in the size of the primary lesion was observed. At that time, the serum albumin level had recovered to 3.9 g/dl. Treatment was continued without recurrence of GI toxicities. At the 16th cycle, endoscopy showed no evidence of tumor progression at the primary site.
Discussion
Consistent with recently published case reports, zolbetuximab may induce gastritis. Notably, this is the first report to demonstrate recovery without discontinuation of zolbetuximab.5,6 Zolbetuximab-induced gastritis may represent on-target off-tumor toxicity against CLDN18.2-expressing normal gastric epithelium or may be triggered by zolbetuximab-induced immune responses.7
Conclusions
Zolbetuximab may induce inflammation in normal gastric mucosa, as seen in animal studies. Notably, the findings were transient, reversible, and did not require treatment interruption. A deeper understanding of these inflammatory changes could inform more effective management strategies and potentially prevent early treatment discontinuation.
Acknowledgements
We thank the patient for granting permission to publish this information. We gratefully acknowledge the contributions of Naoya Sakamoto, Amane Jubashi, and Kazumasa Yamamoto whose collaboration and insights were essential to the completion of this study.
Funding
None declared.
Disclosure
IN: research funding from Astellas, Ono Pharmaceutical Co., Ltd., Merck Sharp & Dohme (MSD), Daiichi Sankyo, Boehringer Ingelheim, and Chugai Pharmaceutical Co., Ltd; honoraria from Astellas, Ono Pharmaceutical Co., Ltd., Bristol Myers Squibb (BMS), MSD, Daiichi Sankyo, and Chugai Pharmaceutical Co., Ltd. KS: advisory roles (personal fees) from BMS, Takeda, Ono Pharmaceutical, Novartis, Daiichi Sankyo, Amgen, Boehringer Ingelheim, Merck Pharmaceutical, Astellas, Guardant Health Japan, Janssen, AstraZeneca, Zymeworks Biopharmaceuticals, ALX Oncology Inc., Bayer, GlaxoSmithKline K.K., Healios K.K., Moderna Inc, and Arcus Biosciences Inc; honoraria (lecture fees) from BMS, Ono Pharmaceutical, Janssen, Eli Lilly, Astellas, and AstraZeneca; and research funding (all to institution) from Astellas, Ono Pharmaceutical, Daiichi Sankyo, Taiho Pharmaceutical, Chugai, Merck Pharmaceutical, Amgen, Eisai, PRA Health Sciences, Syneos Health, AstraZeneca, PPD-SNBL K.K., and Toray. MI has declared no conflicts of interest.
Declaration of Generative AI and AI-Assisted Technologies in The Writing Process
During the preparation of this work, the authors used ChatGPT (https://chat.openai.com) to assist with language refinement during the drafting process. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.
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