According to the REGATTA trial [1], continued chemotherapy is the standard approach for patients with unresectable advanced gastric cancer. The ToGA trial [2] established trastuzumab as a 1st-line treatment for HER2-positive gastric cancer. Subsequently, the ATTRACTION-2 trial [3] led to the approval of nivolumab as a 3rd-line therapy. More recently, the CheckMate 649 [4] and ATTRACTION-4 [5] trials have expanded the role of nivolumab to a 1st-line treatment for HER2-negative gastric cancer. Despite these advancements, the range of 1st-line options has remained relatively limited. The SPOTLIGHT [6] and GLOW [7] trials have positioned zolbetuximab as a promising 1st-line agent for HER2-negative gastric cancer expressing CLDN 18.2. Similarly, the KEYNOTE-811 [8] trial has demonstrated the efficacy of combining trastuzumab and pembrolizumab as the 1st-line treatment for HER2-positive gastric cancer, marking a notable advancement. These developments mark significant progress but also add complexity to treatment selection, and thereby increasing the reliance on companion diagnostics and biomarker-driven strategies. The potential for serious irAEs further underscores the need for expertise in managing these therapies. As treatment options continue to expand, identifying patients with oligo-metastasis who may benefit from surgery, and ensuring appropriate management of recurrence, remains a clinical priority.

We describe a case of PLE that emerged during zolbetuximab treatment, initially suspected due to incidental finding of gallbladder edema. Zolbetuximab is used as a 1st-line treatment for unresectable advanced or recurrent gastric cancer. Zolbetuximab targets CLDN 18.2, a tight junction protein critical for maintaining the gastric mucosal barrier [9, 10]. Its mechanism of action involves binding to CLDN18.2, thereby inducing antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), which exert antitumor effects. Among the AEs, nausea and vomiting are well recognized; however, with its clinical use, a variety of additional AEs have been identified [6, 7]. These include hypoalbuminemia and gastritis. To date, reports of PLE during zolbetuximab therapy are extremely limited [11, 12]. Since CLDN 18.2 is also expressed in normal gastric mucosa, binding to these sites is thought to increase mucosal permeability, allowing the passage of protons and various other molecules [13]. This may lead to protein leakage resulting in hypoalbuminemia, while proton infiltration into the submucosal layer is considered to cause gastritis. Furthermore, according to the Human Protein Atlas portal (https://www.proteinatlas.org/), CLDN 18 protein expression is not limited to the stomach and lungs but is also observed in the gall bladder (Fig. 4A and B). To our knowledge, this is the first report to highlight gallbladder edema as a potential early diagnostic clue. Although scintigraphy did not show protein leakage from the gallbladder, the overall clinical course and findings strongly suggest an association between zolbetuximab and the observed PLE as the patient exhibited diffuse gallbladder wall edema rather than localized changes suggestive of peritoneal dissemination, and no findings indicative of cholecystitis were observed. The mechanism of gallbladder edema is often attributed to venous congestion associated with conditions such as hepatic failure or cardiac failure; however, no such signs were observed in this case. Instead, it is possible that decreased intravascular oncotic pressure secondary to hypoalbuminemia contributed to its development. According to the Human Protein Atlas, CLDN 18 expression in the gallbladder is observed at low levels. On the other hand, a previous report [14] has shown that the expression rate of CLDN 18 in gallbladder cancer exceeds 60% although it frequently exhibits heterogeneity. We considered that gallbladder edema may have preceded gastric edema. One possible explanation is that, within the context of intratumoral heterogeneity, certain regions might have shown relatively high expression levels. Notably, even when the gallbladder edema improved over time, gastric edema persisted, which may support the assumption that gallbladder edema developed earlier than gastric edema.

CLDN expression profile according to the Human Protein Atlas. A List of organs expressing CLDN. https://www.proteinatlas.org/ENSG00000066405-CLDN18/tissue. B Immunohistochemical staining of the gallbladder showing CLDN expression. https://www.proteinatlas.org/ENSG00000066405-CLDN18/tissue/gallbladder

In the present case, curative surgery was performed following NAC for StageIV gastric cancer with oligo-metastatic PAN. Although the patient developed an irAE during the preoperative course, timely intervention enabled successful surgical resection. As surgical indications for oligo-metastatic gastric cancer are expected to increase, prompt and appropriate management of preoperative AEs, including irAEs, will be essential for optimizing outcomes. Moreover, patients may undergo adjuvant chemotherapy or systemic therapy upon recurrence, necessitating careful selection of agents and vigilant monitoring and management of associated toxicities. In this case, the patient developed gallbladder edema accompanied by right upper abdominal pain during treatment with zolbetuximab. Without accurate diagnosis, such a presentation could potentially be mistaken for cholecystitis, possibly leading to unnecessary interventions, including surgery. Thorough evaluation led to a diagnosis of PLE and allowed for the exclusion of cholecystitis, enabling continued administration of zolbetuximab. This highlights the importance of precise assessment in managing novel treatment-related toxicities to avoid premature discontinuation of effective therapies. PLE and the associated gallbladder edema observed in this case may emerge with increasing frequency as the use of zolbetuximab become more widespread.

In conclusion, as treatment strategies for advanced gastric cancer continue to grow more complex, achieving maximum therapeutic benefit requires not only appropriate drug selection but also timely recognition and management of AEs. This report underscores the importance of recognizing such potential toxicities and highlights the need to consider PLE and gallbladder edema as relevant AEs in the context of zolbetuximab therapy.