A case of zolbetuximab-induced protein-losing gastroenteropathy in a patient with advanced gastric cancer

Abstract

Zolbetuximab is a monoclonal antibody targeting Claudin 18.2 that has been approved for the treatment of advanced gastric cancer in Japan. Zolbetuximab has its anticancer effects through a variety of mechanisms, including antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Previous studies have identified edema and hypoalbuminemia as adverse events associated with zolbetuximab treatment although the mechanisms underlying these effects remain unclear. In this report, we present a case of zolbetuximab-inducing protein-losing gastroenteropathy in a patient with advanced gastric cancer. This case demonstrated protein leakage from the upper gastrointestinal tract, confirmed through protein leakage scintigraphy. This finding could provide the mechanisms of zolbetuximab-induced edema and hypoalbuminemia.

Introduction

The treatment of advanced gastric cancer remains challenging, and chemotherapy is the mainstay for patients with advanced disease. Several biomarkers have been identified, including HER2 and PD-L1, leading to the development of targeted therapies for advanced gastric cancer. Zolbetuximab is a monoclonal antibody targeting Claudin 18.2, a tight junction protein that is a therapeutic target in several cancers [1]. Pivotal phase III trials in gastric cancer have demonstrated that combining zolbetuximab with chemotherapy significantly improves overall survival compared with chemotherapy alone [2, 3]. Consequently, zolbetuximab has been approved as a standard treatment for Claudin 18.2-positive gastric cancer in Japan.

While zolbetuximab has shown considerable efficacy, it is associated with certain characteristic side effects. Nausea and vomiting are more frequently observed with zolbetuximab compared with conventional therapies [2, 3], which is thought to be due to the effects on normal gastric mucosa expressing Claudin 18.2 [4]. Additionally, increased edema and hypoalbuminemia have been reported following zolbetuximab treatment [2, 3] although the underlying mechanisms of these adverse events remain unclear. We present a case of prolonged hypoalbuminemia following treatment with zolbetuximab in patients with advanced gastric cancer. This case is notable for their characteristic findings on protein leakage scintigraphy.

Case report

The patient is a 64-year-old man. He was referred to our hospital after a gastric tumor was identified during an endoscopy conducted at another institution. Our endoscopic examination confirmed gastric cancer and computed tomography scan revealed multiple liver metastases. Owing to worsening liver function secondary to the liver metastasis, an initial treatment regimen of S-1 combined with oxaliplatin was started while awaiting biomarker results. The subsequent biomarker analysis revealed that the tumor exhibited proficient mismatch repair, was negative for HER2, had a PD-L1 combined positive score (28–8) greater than 5, and was positive for Claudin 18.2. Based on these findings, prompting the addition of zolbetuximab to S-1 and oxaliplatin started from the second cycle.

The patient did not experience severe emesis but did develop thrombocytopenia at the beginning of the third cycle, prompting a treatment delay of one week. The dose of oxaliplatin was subsequently reduced, and treatment continued. An endoscopic examination after two cycles of treatment revealed tumor shrinkage. However, erythema of the normal gastric mucosa was observed (Fig. 1). At the start of the fourth cycle, the patient observed leg edema. Blood tests ruled out renal dysfunction and abnormal thyroid function as causes. Despite a significant improvement in dietary intake since the start of chemotherapy, serum albumin levels remained low throughout treatment, measuring 2.9 mg/dL at the start of the fourth cycle (Table 1), raising suspicion of zolbetuximab-induced edema. The fourth cycle of treatment was delayed by two weeks, and therapy was continued with S-1 plus oxaliplatin alone. A protein-leak scintigraphy was performed after the discontinuation of zolbetuximab. A protein leak from the upper gastrointestinal tract was visualized, confirming the diagnosis of protein-losing gastroenteropathy (Fig. 2). Following the discontinuation of zolbetuximab, the patient’s edema and hypoalbuminemia improved (Fig. 3). Additionally, an endoscopic examination conducted before the fifth cycle revealed that the erythema of the normal gastric mucosa had resolved (Fig. 4). Considering that the half-life of zolbetuximab is several weeks, these improvements suggested recovery, zolbetuximab was reintroduced at the fifth cycle.

Fig. 1.

Upper gastrointestinal endoscopy revealed erythema of normal gastric mucosa

Table 1.

Laboratory findings at the start of 4 cycle

Total protein (g/dL)	5.3	Urine protein (ng/mL)	–
Albumin (g/dL)	2.9	Spot protein–creatinine ratio (g/g Cr)	0.1
Creatinine (mg/dL)	1.10
CRP (g/dL)	0.39
IgA (mg/dL)	168
IgG (mg/dL)	562
IgM (mg/dL)	2.2

CRP c-reactive protein, IgA immunoglobulin A, IgG immunoglobulin G, IgM immunoglobulin M

Fig. 2.

a Protein-leak scintigraphy revealed accumulation at 2 h, primarily in the upper gastrointestinal tract (White arrow). b By 24 h, this accumulation had migrated to the colon, consistent with protein leakage from the gastrointestinal tract (Black arrow)

Fig. 3.

Hypoalbuminemia did not improve during treatment with zolbetuximab rather it worsened. However, an improvement was observed following its discontinuation

Fig. 4.

Endoscopic examination following the discontinuation of zolbetuximab demonstrated an improvement in gastric mucosal erythema

Discussions

We report a case of advanced gastric cancer with protein-losing gastroenteropathy induced by zolbetuximab. Previous studies have documented hypoalbuminemia and edema as adverse events associated with zolbetuximab administration [2, 3], but to our knowledge, no reports have described the specific mechanism behind these adverse events. In our case, patient exhibited erythema in a non-atrophic gastric area on endoscopy, and showed evidence of protein leakage on protein-leak scintigraphy. We hypothesize that protein leakage from the gastrointestinal tract, secondary to mucosal damage to the normal gastrointestinal tissue, may trigger hypoalbuminemia in some patients receiving zolbetuximab.

Drug-induced protein-losing gastroenteropathy has been reported in various conditions. Non-steroidal anti-inflammatory drugs (NSAIDs) are a known cause of this condition owing to their inhibition of prostaglandin synthesis, which reduces mucus production and blood flow to the intestinal mucosa, increasing the risk of gastrointestinal injury [5]. Mucosal damage from NSAIDs, including ulceration and erosion, can result in complications, such as bleeding, perforation, abdominal pain, and hypoalbuminemia. Anticancer drugs, including cytotoxic agents and certain molecularly targeted therapies, have also been reported to induce intestinal mucosal damage, resulting in secondary hypoalbuminemia. The common clinical manifestations associated with these drug-induced effects include abdominal pain and diarrhea [6]. Other drugs, such as proton pump inhibitors (PPIs), have also been reported to cause protein-losing gastroenteropathy through conditions such as collagenous colitis [7]. We propose that the mechanism of zolbetuximab-induced protein leakage is distinct from those previously described.

Zolbetuximab, a monoclonal antibody targeting Claudin 18.2, exerts its anticancer effects through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity [8]. Claudin 18.2, a key component of tight junctions located on gastric mucosal epithelial cells, plays an important role in the maintenance of cell polarity and barrier integrity [9]. Zolbetuximab disrupts these junctions, leading to increased mucosal permeability, leakage of acid and pepsin, and exacerbation of tissue damage. Histopathological evidence of mucosal erosions at sites of CLDN18.2 expression has been reported in preclinical models, which have suggested that zolbetuximab-induced nausea and vomiting may be linked to damage of normal gastric mucosa [4]. We hypothesize that zolbetuximab’s action on Claudin 18.2 in normal gastric mucosa could disrupt the integrity of tight junctions, thereby increasing gastrointestinal permeability and leading to protein-losing gastroenteropathy. The clinical findings in our cases, including erythema in a non-atrophic gastric area on endoscopy and protein leakage confirmed on scintigraphy, support this hypothesis.

The clinical course of this case suggests that protein leakage from the gastrointestinal tract induced by zolbetuximab is a reversible effect. In this case, hypoalbuminemia and gastric mucosal erythema were improved approximately six weeks after zolbetuximab discontinuation. The half-life of zolbetuximab is estimated to be several weeks [8], which coincides with the time of improvement in this case. Furthermore, the improvement of gastric mucosal changes and hypoalbuminemia following the discontinuation of zolbetuximab supports the hypothesis that hypoalbuminemia was induced by zolbetuximab-related gastric mucosal damage. Given the above considerations, when edema and hypoalbuminemia occur during zolbetuximab administration, it is essential to first exclude nephrotic syndrome and other possible triggers as a potential underlying cause. Subsequently, zolbetuximab should be temporarily discontinued, and the patient's condition should be reassessed after a few weeks before deciding on further treatment.

Protein leakage from the normal gastric mucosa induced by zolbetuximab may have broader implications beyond edema and hypoalbuminemia. Protein-losing gastroenteropathy can lead to loss of both albumin and immunoglobulins such as IgG. Albumin (66 kDa) is generally more likely to be lost than IgG (150 kDa) owing to its smaller molecular weight [10]. In case reported here, a marked decrease in IgG was observed. This suggests that zolbetuximab-induced disruption of tight junctions may allow the leakage of proteins with higher molecular weights. This is particularly significant information in cancer patients as low immunoglobulin levels may increase the risk of infection. On the other hand, while a decrease in IgM, a large protein, was observed, no significant reduction in IgA was detected. Although a definitive conclusion cannot be drawn, we hypothesized that IgA, which exists both in the bloodstream and as a secreted form, may be relatively preserved as protein loss in protein-losing gastroenteropathy primarily affects blood-derived proteins [10]. This suggests that the secretory function of the mucosa may remain at least partially intact, even in the presence of zolbetuximab-induced protein leakage. However, further research is necessary to substantiate this hypothesis.

In conclusion, we reported a case suggesting that zolbetuximab-induced gastrointestinal mucosal damage may cause protein leakage from the gastrointestinal tract. Several questions remain unanswered and require further investigation.

Data availability

This study is a case report, and no dataset was generated or analyzed. Due to ethical considerations and patient confidentiality, raw data cannot be shared.

Declarations

Conflict of interest

The authors declare that they have no financial considerations or relationships that may pose a conflict of interest.

Ethical approval

An approval is not required for case report in our institutional ethical committee.

Informed consent

Written informed consent was obtained from the patient to use medical information for clinical research and publication.