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. 2026 Sep 10;17:1887849. doi: 10.3389/fphar.2026.1887849

Zolbetuximab-associated adverse event reporting signals in gastric cancer: a FAERS disproportionality analysis

Jingshun Zhang 1,†, Zhuo Zhen 1,†, Zhijun Li 1, Peng Zhu 1,*
PMCID: PMC13601259  PMID: 42787158

Abstract

Background

Zolbetuximab has an established upper gastrointestinal tolerability profile, but the broader post-marketing spectrum of gastric mucosal events and findings related to albumin, protein loss, and fluid balance remains incompletely characterized.

Methods

We conducted an indication-restricted, report-level US Food and Drug Administration Adverse Event Reporting System (FAERS) analysis from 2024 Q1 through 2026 Q1, comparing 597 zolbetuximab reports with 1,231 pooled nivolumab/pembrolizumab reports. Reporting odds ratios (RORs) were used for primary screening, with five contextual reporting backgrounds, adjusted Firth models, and chemotherapy-, drug-role-, geographic-, calendar-time-, and submission-channel analyses. Time to onset and co-reporting were summarized descriptively.

Results

Among 1,041 screened preferred terms, 58 met the ROR criterion and 48 were clinically retained. The findings clustered into three groups: upper gastrointestinal and intake-related findings, gastric mucosal findings, and findings related to albumin, protein loss, and fluid balance. The eight post hoc focus preferred terms (PTs) retained support across all five backgrounds and the principal adjusted analyses. Gastritis was reported in 22 zolbetuximab versus 1 pooled PD-1 report (ROR 32.07, 95% CI 6.12–167.97), hypoalbuminemia in 72 versus 3 (ROR 48.43, 95% CI: 16.49–142.24), and protein-losing gastroenteropathy (PLE) in 10 versus 2 (ROR 8.79, 95% CI: 2.21–35.04). Japan accounted for 83.8% of zolbetuximab reports, with limited support outside Japan.

Conclusion

The analysis reinforced established upper gastrointestinal findings. Gastritis and findings related to albumin, protein loss, and fluid balance require clinical confirmation, while protein-losing gastroenteropathy was reported sparsely. Overall, the results characterize reporting disproportionality in an early, Japan-dominant setting, not incidence or comparative clinical risk.

Keywords: CLDN18.2, FAERS, gastric cancer, PD-1 inhibitors, pharmacovigilance, zolbetuximab

1. Introduction

Gastric cancer remains a substantial global health burden, with an estimated 968,350 new cases and 659,853 deaths in 2022 (Bray et al., 2024). For unresectable or metastatic adenocarcinoma, fluoropyrimidine–platinum (FP + Pt) chemotherapy remains a core systemic backbone, while treatment selection is increasingly biomarker-informed. HER2 status guides HER2-directed therapy, PD-L1 expression helps contextualize immune-checkpoint strategies, and claudin 18 isoform 2 (CLDN18.2) has emerged as an additional actionable target (Smyth et al., 2020; Ajani et al., 2025; Miyajima and Kawakami, 2025). Zolbetuximab, a CLDN18.2-directed monoclonal antibody, is approved with fluoropyrimidine- and platinum-containing chemotherapy for first-line treatment of adults with CLDN18.2-positive, HER2-negative, locally advanced unresectable or metastatic gastric or gastroesophageal-junction adenocarcinoma (U.S. Food and Drug Administration, 2025). Its introduction creates a need for early post-marketing evaluation as clinical exposure and spontaneous reporting practices evolve.

CLDN18.2 is a gastric-lineage tight-junction protein expressed in differentiated gastric mucosal epithelium. In normal tissue, its location within tight junctions limits zolbetuximab access to the target, whereas malignant transformation and loss of epithelial polarity can expose CLDN18.2 on the tumor-cell surface (Nakayama et al., 2024; Zeng et al., 2024). Zolbetuximab binds CLDN18.2 and promotes antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. The randomized phase II FAST study and the multicohort phase II ILUSTRO study supported clinical development, followed by the phase III SPOTLIGHT and GLOW trials, which added zolbetuximab to mFOLFOX6 or CAPOX, respectively (Sahin et al., 2021; Klempner et al., 2023; Shitara et al., 2023; Shah et al., 2023). Across the pivotal program and current product information, nausea, vomiting, and decreased appetite were prominent tolerability findings. These well-characterized upper gastrointestinal events frame the remaining post-marketing questions.

Nausea and vomiting are well characterized, but the broader post-marketing spectrum remains less complete. Gastritis has been described in limited endoscopic and case-based evidence, while selected reports of protein-losing gastroenteropathy (PLE), alongside separate protein or albumin abnormalities, suggest additional clinically relevant phenomena that remain incompletely characterized (Yamamoto et al., 2025; Yanagimoto et al., 2025; Mitsui et al., 2025). This evidence is dispersed across studies with different designs and ascertainment methods and cannot define the complete post-marketing reporting spectrum. A systematic spontaneous-reporting analysis can map disproportionate reporting and organize these observations, although it cannot estimate incidence or comparative clinical risk or establish causality (Cutroneo et al., 2024; Fusaroli et al., 2024).

To address this gap, we conducted an indication-restricted US Food and Drug Administration Adverse Event Reporting System (FAERS) analysis to characterize zolbetuximab reporting disproportionality in gastric cancer and position the principal patterns alongside external clinical evidence. Pooled nivolumab and pembrolizumab reports served as the principal preferred term screening background to provide a relevant contemporary treatment context rather than a direct clinical comparison. Assessments by the National Institute for Health and Care Excellence and Canada's Drug Agency likewise considered PD-1 inhibitor-based chemotherapy in the contemporary treatment pathway (National Institute for Health and Care Excellence, 2025; Canada’s Drug Agency, 2025). Four additional contextual reporting backgrounds, together with adjusted and restricted analyses, were used to assess the dependence of findings on reporting context. FAERS date-field-derived time to onset and co-reporting were summarized descriptively.

2. Materials and methods

2.1. Data source and study design

We conducted a retrospective, report-level disproportionality study using individual FAERS case safety reports from 2024 Q1 through 2026 Q1. Quarterly ASCII files from demographic (DEMO), drug information (DRUG), indications (INDI), adverse reactions (REAC), patient outcomes (OUTC), report sources (RPSR), and therapy dates (THER) were analyzed together with the corresponding DELETE files. The quarterly extracts are raw, non-cumulative relational files, and source-file structure and field definitions were interpreted using the FDA quarterly data documentation (U.S. Food and Drug Administration, 2026). The analytical unit was one retained report. Each MedDRA preferred term (PT) was represented by its presence or absence at the report level, and repeated occurrences of the same PT within a report were counted once.

2.2. Report preprocessing and relational linkage

Reports associated with case identifiers (CASEIDs) in the FDA DELETE files were removed before selecting the case version. For each remaining CASEID, the latest version was selected deterministically using date received (FDA_DT), highest case version number (CASEVERSION), the numeric primary identifier (PRIMARYID), and source-quarter order, after which retained PRIMARYIDs were propagated to the related quarterly tables. DRUG rows were linked to INDI and THER rows within PRIMARYID by the corresponding drug sequence fields. The complete linkage rules and source fields are provided in Supplementary Table S1. Potential duplicates across different CASEIDs were examined conservatively using manufacturer identifiers and report signatures. Signature similarity alone was not used to remove a report.

2.3. Gastric cancer eligibility and cohort assignment

Disease eligibility was based on an author-defined normalized nine-term dictionary applied to INDI.INDI_PT. The qualifying indication had to be linked by PRIMARYID and drug sequence to the primary suspect (PS) row for the assigned study drug. Eligible concepts included gastric cancer and gastric adenocarcinoma, including stage, recurrent, metastatic, and HER2-positive gastric cancer terms. Gastroesophageal-junction or gastroesophageal indications, esophageal primary disease, metastasis to the stomach, gastric neuroendocrine or carcinoid disease, and conflicts with an additional non-gastric primary malignancy were outside the study scope. Exact included and out-of-scope normalized terms are listed in Supplementary Table S1.

Study drugs were identified from standardized drug-name information in DRUG using prespecified aliases, and their roles were obtained from DRUG.ROLE_COD. The principal index arm comprised reports with zolbetuximab coded as PS; the reference arm comprised reports with nivolumab and/or pembrolizumab coded as PS. A report containing both nivolumab and pembrolizumab contributed once to the pooled PD-1 reference arm. Reports with zolbetuximab and a pooled PD-1 study drug in PS or secondary suspect (SS) roles were excluded from the principal comparison. Study drugs recorded only as concomitant (C) or interacting (I) did not determine arm assignment. Chemotherapy, other targeted treatments, and supportive treatments were not exclusion criteria unless they created a cross-arm conflict regarding the assigned PS/SS designation of the study drug. Tislelizumab reports were analyzed separately in an exploratory comparison.

2.4. Reporting backgrounds and chemotherapy context

Pooled nivolumab/pembrolizumab reports formed the reference for the principal PT screen. Clinically retained PTs were subsequently presented in parallel across five reporting backgrounds: pooled PD-1, all gastric cancer reports without zolbetuximab in a valid role, non-PD-1 gastric cancer reports, FP + Pt-compatible reports, and chemotherapy-dominant reports. Each report contributed at most once within a background.

FP + Pt compatibility was assessed using drugs recorded in PS, SS, C, or I roles. Reports were classified as compatible when they contained both a fluoropyrimidine and oxaliplatin or cisplatin, or a recognized complete fluoropyrimidine–platinum (FP) regimen name; this represented report-level regimen compatibility rather than confirmed concurrent administration. Chemotherapy-dominant reports additionally excluded any prespecified immune-checkpoint inhibitor or targeted-treatment family recorded in these roles, while other co-reported treatments were permitted. The full fluoropyrimidine, platinum, regimen, immune-checkpoint, and targeted-treatment dictionaries are provided in Supplementary Table S1.

2.5. Adverse event mapping, PT screening, and clinical review

Reaction labels were obtained from REAC. PTs were harmonized to MedDRA version 29.0. Exact current PT matches were retained, and remaining exact authorized lower-level terms were assigned to their corresponding current PTs. Unmatched reaction strings were excluded from PT-level analyses without removing the associated reports or their other mapped reactions.

All PTs present in the principal comparison were screened, and every PT meeting the principal reporting odds ratio (ROR) criterion underwent clinical classification. One gastrointestinal surgeon performed the initial classification, and two additional gastrointestinal surgeons reviewed the classifications sequentially. Disagreements were resolved through discussion and consensus. Reviewers were not blinded to PT identity or the screening summaries. Because review was sequential rather than independent, inter-rater agreement could not be estimated. PTs were retained when they represented an adverse event or clinically relevant investigation finding; exclusions comprised disease-status or outcome terms, indication-related terms, and administration, dosing, or product-use terms.

A post hoc focus set of eight PTs was selected for concise main-text interpretation based on clinical relevance, representation of the principal reporting patterns, consistency across contextual and adjusted analyses, and external evidence positioning. All clinically retained PTs remained available in Figure 1 and Supplementary Table S2.

FIGURE 1.

Bubble chart showing preferred-term reporting patterns for zolbetuximab across three reporting backgrounds. Bubble size reflects the number of zolbetuximab reports, while color intensity indicates log2(ROR).

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Unadjusted reporting odds ratios for the 48 clinically retained preferred terms across pooled PD-1, non-PD-1, and chemotherapy-dominant reporting backgrounds. Terms are ordered by descending pooled PD-1 ROR. The first and second denominators in each column header are the zolbetuximab and reference totals, respectively. Bubble area represents the number of zolbetuximab reports; colored bubbles indicate a lower 95% CI above 1, with fill intensity representing log2 (ROR), and hollow gray bubbles indicate a lower 95% CI of 1 or less. CI, confidence interval; PD-1, programmed cell death protein 1; PT, preferred term; ROR, reporting odds ratio.

2.6. Disproportionality analysis

For each PT and reporting background, a report-level 2 × 2 table was constructed. The ROR was the principal screening metric; a PT met the screen when it occurred in at least three zolbetuximab reports, and the lower limit of its 95% confidence interval exceeded 1. A 0.5 continuity correction was applied to all four cells. The proportional reporting ratio (PRR) and information component (IC) were supportive metrics. PRR support required at least three zolbetuximab reports, PRR ≥2, and Pearson chi-square ≥4. IC was calculated as log2 [(a +0.5)/(E + 0.5)], where E = N_index (a + c)/(N_index + N_reference); IC support required at least three zolbetuximab reports and IC025 > 0. Two-sided Fisher exact p-values and Benjamini–Hochberg q-values were exploratory descriptors calculated across the complete screened PT universe in each background.

2.7. Adjusted and sensitivity analyses

For each clinically retained PT, Firth logistic regression (Firth, 1993) modeled report-level PT presence with study drug (zolbetuximab versus pooled PD-1) as the exposure. Covariates were age quintile, sex, reporting period, reporter region, and reporter category. Unknown levels were retained where applicable. The reporting period was derived from FAERS source-quarter metadata. Adjusted odds ratios (ORs) and profile-likelihood 95% confidence intervals were reported. Variable categories, reference levels, and model evaluability and convergence information are provided in Supplementary Table S3.

Three adjusted Firth sensitivities were performed: complete case analysis, restriction to FP + Pt-compatible reports, and inclusion of reports in which the assigned study drug was coded as PS or SS.

Restricted disproportionality analyses considered Japan, outside Japan, Japan reports submitted by healthcare professionals (Japan-HCP), and the common complete quarters from 2025 Q1 through 2026 Q1. Country was defined from OCCR_COUNTRY when available and REPORTER_COUNTRY otherwise. Japan-HCP was defined using reporter occupation codes detailed in Supplementary Table S3. The sole-PS analysis retained principal-cohort reports in which the assigned study drug was the only distinct drug concept coded PS; drugs in SS, C, or I roles did not affect this classification. Report-submission channel was derived from DEMO.REPT_COD, with expedited/periodic (EXP/PER) classified as manufacturer-submitted and DIR as direct-to-FDA. Restricted ROR, PRR, and IC estimates were calculated only when both study arms were evaluable.

Two exploratory Firth comparisons evaluated zolbetuximab against tislelizumab, first retaining missing reporter category as an explicit level and then omitting reporter category. A disease-definition sensitivity omitted the HER2-positive gastric cancer indication term while retaining all other cohort and analysis rules.

2.8. Time to onset, co-reporting, and external evidence assessment

Time to onset (TTO) was calculated as DEMO.EVENT_DT minus THER.START_DT for the assigned study drug. THER rows were linked by PRIMARYID and the study-drug sequence. Only complete dates were parsed; partial dates were not imputed, and the earliest complete eligible start date was used when more than one was available. Negative intervals were excluded from valid summaries. Zero-day intervals were retained as a separate descriptive category and excluded from positive-interval medians and interquartile ranges.

Within zolbetuximab reports, PT co-reporting was summarized at PRIMARYID level by shared-report counts, Jaccard indices, and overlap coefficients. Clinically prioritized PTs were contextualized using current regulatory labeling, the SPOTLIGHT and GLOW phase III trials, and selected primary post-marketing evidence to distinguish established, emerging, supportive but non-specific, and sparse hypothesis-generating findings.

2.9. Software

Analyses were performed in R version 4.5.3. Data processing and IC calculations used the data.table package version 1.18.4; Firth regression used logistf version 1.26.1; and figures were prepared with ggplot2 version 4.0.3 and patchwork version 1.3.2. Reaction terms were harmonized to MedDRA version 29.0.

3. Results

3.1. Cohort construction and PT classification

The gastric cancer indication screen identified 5,349 eligible reports, of which 1,837 had a qualifying gastric cancer indication linked to a principal study drug coded PS. Cross-arm study-drug conflicts excluded eight reports from the zolbetuximab side and one from the pooled PD-1 side, leaving 597 zolbetuximab and 1,231 pooled nivolumab/pembrolizumab reports (1,828 reports overall). The conservative cross-CASEID audit identified no manufacturer-identifier-supported duplicate cluster, and no report was removed solely on the basis of a signature match (Figure 2; Supplementary Table S1).

FIGURE 2.

Flowchart showing the FAERS data processing pipeline for gastric cancer analysis from 2024 Q1 to 2026 Q1, detailing steps of preprocessing, deduplication, selection of drug-specific cohorts, PT-level screening, exclusion criteria, and analytical methods employed.

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Cohort construction and analytical flow. FAERS, FDA Adverse Event Reporting System; PS, primary suspect; PD-1, programmed cell death protein 1; PT, preferred term; ROR, reporting odds ratio; PRR, proportional reporting ratio; IC, information component; FP + Pt, fluoropyrimidine plus platinum; TTO, time to onset. The diagram highlights DEMO, DRUG, INDI, and REAC as the core cohort construction files; OUTC, RPSR, and THER were also linked, and DELETE files were used during preprocessing. Detailed disease-scope exclusion flags were overlapping rather than sequential and are reported in Supplementary Table S1. Cross-arm exclusion indicates reports containing both zolbetuximab and a pooled PD-1 study drug in PS or SS roles.

The principal comparison contained 1,041 mapped PTs. Fifty-eight met the ROR screening criterion and underwent clinical classification; 48 were retained as AE-related PTs and 10 were excluded, comprising five disease-status or outcome terms, one indication-related term, and four administration, dosing, or product-use terms.

3.2. Reporting characteristics

Zolbetuximab reports first appeared in 2024 Q4, and 572 of 597 (95.8%) occurred during the common 2025 Q1–2026 Q1 interval, compared with 719 of 1,231 (58.4%) pooled PD-1 reports. In 2026 Q1, 140 zolbetuximab reports (23.5%) and 169 pooled PD-1 reports (13.7%) were recorded. Among zolbetuximab reports, the largest age group was 80–100 years (161/597, 27.0%), followed by 70–74 years (127/597, 21.3%); age was unknown in 48/597 (8.0%), compared with 217/1,231 (17.6%) pooled PD-1 reports. Men accounted for 355/597 (59.5%) and 729/1,231 (59.2%) reports, respectively. Most reports originated from Japan (500/597, 83.8%; 871/1,231, 70.8%) and were submitted by HCPs (486/597, 81.4%; 986/1,231, 80.1%). The most frequently recorded outcomes were other serious outcome (423/597, 70.9%; 1,041/1,231, 84.6%), hospitalization (217/597, 36.3%; 486/1,231, 39.5%), and death (85/597, 14.2%; 289/1,231, 23.5%); outcome categories were not mutually exclusive. Weight was the most frequently missing characteristic (486/597, 81.4%; 974/1,231, 79.1%). These values describe FAERS reports rather than patient-level incidence or comparative clinical severity (Figure 3).

FIGURE 3.

Composite figure with three panels comparing reporting characteristics of pooled PD-1 and zolbetuximab reports. Panel A shows within-group reporting proportions over FAERS quarters from 2024 Q1 to 2026 Q1. Panel B shows within-group proportions by age, sex, reporter region, and reporter category. Panel C shows reported outcomes and the proportions of unknown or unreported demographic and reporting characteristics.

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Reporting characteristics. (A) Within-group quarterly distribution of reports. (B) Within-group distributions of age group, sex, reporter region, and reporter category. (C) Within-group distributions of reported outcomes and missingness; outcome categories were not mutually exclusive. HCP, healthcare professional; PD-1, programmed cell death protein 1.

3.3. PT reporting patterns and focus PTs

Figure 1 presents unadjusted report-level RORs for all 48 retained PTs; adjusted Firth estimates are reported separately in Figure 4. Upper gastrointestinal and intake-related findings included nausea (231 zolbetuximab versus 18 pooled PD-1 reports; ROR: 41.43, 95% CI: 25.44–67.48), vomiting (93 versus 13; ROR: 16.73, 95% CI: 9.37–29.88), retching (7 versus 0; ROR: 31.28, 95% CI: 1.78–548.68), decreased appetite (114 versus 47; ROR: 5.91, 95% CI: 4.14–8.42), and feeding disorder. Gastric and abdominal findings included gastritis (22 versus 1; ROR: 32.07, 95% CI: 6.12–167.97), upper abdominal pain, and abdominal discomfort. Nutritional and hydration-related findings included nutritional condition abnormal, weight decreased, and dehydration. Albumin, protein-balance, and fluid-related findings included hypoalbuminemia (72 versus 3; ROR: 48.43, 95% CI: 16.49–142.24), blood albumin decreased (45 versus 5; ROR: 18.36, 95% CI: 7.54–44.74), protein-losing gastroenteropathy (10 versus 2; ROR: 8.79, 95% CI: 2.21–35.04), Oedema peripheral (30 versus 9; ROR: 6.92, 95% CI: 3.32–14.42), edema, and ascites.

FIGURE 4.

Two-panel figure summarizing adjusted and restricted reporting analyses for eight focus preferred terms. Panel A shows a forest plot of adjusted reporting associations comparing zolbetuximab with pooled PD-1 reports. Panel B shows the consistency of findings across multiple sensitivity and restricted analyses.

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Adjusted and restricted analyses for the eight focus preferred terms. Panel A shows principal adjusted Firth odds ratios with profile-likelihood 95% CIs. Panel B shows complete case, FP + Pt-compatible, and PS-or-SS adjusted Firth sensitivities, followed by restricted RORs for Japan-HCP, outside Japan, and the complete 2025 Q1–2026 Q1 interval. Complete case required non-missing model covariates; Japan-HCP denotes Japan reports submitted by HCPs. Filled points indicate a lower 95% CI above 1; hollow points indicate that the 95% CI includes 1. CI, confidence interval; FP + Pt, fluoropyrimidine plus platinum; HCP, healthcare professional; OR, odds ratio; PS, primary suspect; PT, preferred term; ROR, reporting odds ratio; SS, secondary suspect.

Eight PTs were selected post hoc for focused main-text interpretation: nausea, vomiting, decreased appetite, gastritis, hypoalbuminemia, blood albumin decreased, Oedema peripheral, and protein-losing gastroenteropathy. Each met the ROR, PRR, and IC support criteria in all five reporting backgrounds (Table 1). All 48 clinically retained PTs are reported in Figure 1 and Supplementary Table S2.

TABLE 1.

Reporting patterns for the eight focus preferred terms across five reporting backgrounds.

PT Pooled PD-1 All non-zolbetuximab gastric cancer Non-PD-1 FP + Pt-compatible Chemotherapy-dominant
Nausea 231/597 vs. 18/1,231; ROR 41.43 (25.44–67.48); R+/P+/I+ 231/597 vs. 241/4,695; ROR 11.65 (9.45–14.36); R+/P+/I+ 231/597 vs. 151/2,431; ROR 9.51 (7.53–12.00); R+/P+/I+ 165/364 vs. 135/2,441; ROR 14.12 (10.79–18.48); R+/P+/I+ 163/352 vs. 61/1,132; ROR 15.03 (10.79–20.94); R+/P+/I+
Vomiting 93/597 vs. 13/1,231; ROR 16.73 (9.37–29.88); R+/P+/I+ 93/597 vs. 172/4,695; ROR 4.86 (3.72–6.35); R+/P+/I+ 93/597 vs. 110/2,431; ROR 3.89 (2.91–5.21); R+/P+/I+ 68/364 vs. 96/2,441; ROR 5.62 (4.03–7.83); R+/P+/I+ 66/352 vs. 34/1,132; ROR 7.39 (4.80–11.38); R+/P+/I+
Decreased appetite 114/597 vs. 47/1,231; ROR 5.91 (4.14–8.42); R+/P+/I+ 114/597 vs. 172/4,695; ROR 6.21 (4.82–8.01); R+/P+/I+ 114/597 vs. 78/2,431; ROR 7.10 (5.24–9.62); R+/P+/I+ 95/364 vs. 103/2,441; ROR 8.01 (5.90–10.87); R+/P+/I+ 92/352 vs. 42/1,132; ROR 9.11 (6.18–13.42); R+/P+/I+
Gastritis 22/597 vs. 1/1,231; ROR 32.07 (6.12–167.97); R+/P+/I+ 22/597 vs. 2/4,695; ROR 73.40 (19.81–271.90); R+/P+/I+ 22/597 vs. 1/2,431; ROR 63.35 (12.10–331.62); R+/P+/I+ 11/364 vs. 2/2,441; ROR 31.74 (8.05–125.21); R+/P+/I+ 11/352 vs. 1/1,132; ROR 25.40 (4.61–139.86); R+/P+/I+
Hypoalbuminemia 72/597 vs. 3/1,231; ROR 48.43 (16.49–142.24); R+/P+/I+ 72/597 vs. 11/4,695; ROR 56.20 (29.97–105.38); R+/P+/I+ 72/597 vs. 6/2,431; ROR 51.48 (22.95–115.50); R+/P+/I+ 58/364 vs. 5/2,441; ROR 84.55 (34.99–204.29); R+/P+/I+ 55/352 vs. 2/1,132; ROR 84.36 (23.60–301.49); R+/P+/I+
Blood albumin decreased 45/597 vs. 5/1,231; ROR 18.36 (7.54–44.74); R+/P+/I+ 45/597 vs. 12/4,695; ROR 30.86 (16.40–58.06); R+/P+/I+ 45/597 vs. 7/2,431; ROR 26.62 (12.23–57.96); R+/P+/I+ 28/364 vs. 5/2,441; ROR 37.52 (14.95–94.14); R+/P+/I+ 28/352 vs. 2/1,132; ROR 39.72 (10.84–145.54); R+/P+/I+
Oedema peripheral 30/597 vs. 9/1,231; ROR 6.92 (3.32–14.42); R+/P+/I+ 30/597 vs. 32/4,695; ROR 7.71 (4.67–12.74); R+/P+/I+ 30/597 vs. 11/2,431; ROR 11.31 (5.71–22.43); R+/P+/I+ 20/364 vs. 21/2,441; ROR 6.70 (3.62–12.40); R+/P+/I+ 20/352 vs. 2/1,132; ROR 27.88 (7.46–104.23); R+/P+/I+
Protein-losing gastroenteropathy 10/597 vs. 2/1,231; ROR 8.79 (2.21–35.04); R+/P+/I+ 10/597 vs. 2/4,695; ROR 33.55 (8.42–133.64); R+/P+/I+ 10/597 vs. 0/2,431; ROR 86.91 (5.09–1485.38); R+/P+/I+ 8/364 vs. 2/2,441; ROR 23.27 (5.65–95.73); R+/P+/I+ 8/352 vs. 0/1,132; ROR 55.89 (3.22–970.75); R+/P+/I+
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Values are zolbetuximab n/N versus reference n/N, followed by ROR (95% CI). R+ indicates at least three zolbetuximab reports and a lower ROR (95% CI above 1); P+ indicates at least three zolbetuximab reports, PRR ≥2, and chi-square ≥4; I+ indicates at least three zolbetuximab reports and IC025 >0.

CI, confidence interval; IC, information component; PRR, proportional reporting ratio; PT, preferred term; ROR, reporting odds ratio.

3.4. Adjusted and sensitivity analyses

In contrast to the unadjusted RORs in Figure 1, Figure 4A shows covariate-adjusted Firth ORs. All eight focus PTs had 95% confidence intervals above 1 in the principal model. Representative estimates were 45.77 (95% CI: 26.23–85.94) for nausea, 23.35 (11.73–51.04) for vomiting, 5.06 (3.38–7.71) for decreased appetite, 33.30 (6.92–378.27) for gastritis, 51.01 (17.92–201.40) for hypoalbuminemia, and 7.52 (1.82–52.25) for protein-losing gastroenteropathy. Across all 48 retained PTs, 38 had a principal adjusted lower confidence limit above 1.

The focus findings were supported in the complete case, FP + Pt-compatible, and PS-or-SS Firth sensitivities. All 597 zolbetuximab reports and all 1,231 pooled PD-1 reports met the sole-PS definition; none contained another distinct PS drug concept. Consequently, the sole-PS ROR estimates reproduced the principal estimates, and all eight focus PTs retained support. The Japan-only and Japan-HCP restrictions supported all eight focus PTs; the Japan-HCP restriction included 425 zolbetuximab and 824 pooled PD-1 reports. All eight focus PTs also met the ROR criterion in the 2025 Q1–2026 Q1 common-quarter analysis, whereas three did so outside Japan. The manufacturer-submitted channel was evaluable for all eight focus PTs using 597 zolbetuximab and 1,226 pooled PD-1 reports, with all eight retaining ROR support. The direct-to-FDA channel included no zolbetuximab reports and five pooled PD-1 reports and was therefore not evaluable.

The exploratory tislelizumab comparisons included 597 zolbetuximab and 420 tislelizumab reports; sparse events produced imprecise estimates in both reporter category specifications. Omitting the HER2-positive gastric cancer indication term as an eligibility route left the zolbetuximab cohort at 597 reports and reduced the pooled PD-1 cohort from 1,231 to 1,205; all eight focus PTs retained support.

3.5. External evidence and clinical positioning

Table 2 summarizes the regulatory, phase III, and primary post-marketing evidence used to position the eight focus PTs by evidence tier.

TABLE 2.

External evidence and clinical positioning of the eight post hoc focus preferred terms across current US FDA labeling, phase III trials, and primary post-marketing studies.

Preferred term Evidence tier Current US FDA label Phase III context Primary post-marketing evidence Key caveat
Nausea Established Listed Prominent with zolbetuximab Management study (Narita et al., 2025) Known event; chemotherapy background and stimulated reporting
Vomiting Established Listed Prominent with zolbetuximab Management study (Narita et al., 2025) Known event; chemotherapy background and stimulated reporting
Decreased appetite Established Listed More frequent with zolbetuximab Observational and management studies (Yamamoto et al., 2025; Narita et al., 2025) Non-specific in advanced gastric cancer and chemotherapy
Gastritis Emerging Not listed as a named reaction Not prominent as a named trial event Endoscopic cohort and case report (Yamamoto et al., 2025; Mitsui et al., 2025) Predominantly Japanese observational evidence; limited support outside Japan
Hypoalbuminemia Supportive but non-specific Not listed as a named reaction; related decreased albumin laboratory abnormality is listed Decreased albumin laboratory abnormality reported Hypoalbuminemia cohort and albumin-kinetic cohort (Shimozaki et al., 2025; Ushimaru et al., 2026) Multiple competing causes
Blood albumin decreased Supportive but non-specific Decreased albumin laboratory abnormality listed Reported in laboratory safety data Albumin-kinetic cohort (Ushimaru et al., 2026) Overlaps clinically with hypoalbuminemia; not independent confirmation
Oedema peripheral Supportive but non-specific Reported Reported; clinically non-specific No distinct primary study identified Multiple alternative causes of fluid imbalance
Protein-losing gastroenteropathy Sparse, hypothesis-generating Not listed Not a named trial event Case series and case report (Yanagimoto et al., 2025; Mitsui et al., 2025) Very sparse evidence; case-level confirmation required
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Evidence tiers were assigned post hoc for descriptive clinical interpretation and do not represent validated causal or confirmatory signal classifications.

3.6. Time to onset and co-reporting

Complete event and linked study-drug start dates were available for 408/597 zolbetuximab reports; 373 had nonnegative TTO, including 201 0-day and 172 positive intervals. Among focus PTs, positive-interval medians were 11 days for vomiting (IQR: 4–21; n = 13), 11.5 days for nausea (IQR: 2–21; n = 32), 13.5 days for decreased appetite (IQR: 4.5–22.5; n = 36), 14 days for Oedema peripheral (IQR: 7–49; n = 9), 20 days for blood albumin decreased (IQR: 14–68; n = 15), 21 days for hypoalbuminemia (IQR: 6–50; n = 19), and 30 days for gastritis (IQR: 7–55; n = 9). Protein-losing gastroenteropathy had a median of 68 days (IQR: 39–97), based on only two positive intervals.

Across all 1,128 unique unordered pairs among the 48 retained PTs, nausea and vomiting were co-reported in 72 reports (Jaccard 0.286; overlap coefficient 0.774), and nausea and decreased appetite were co-reported in 69 (0.250; 0.605). Hypoalbuminemia appeared with decreased appetite in 32 reports (0.208; 0.444), with Oedema peripheral in 16 (0.186; 0.533), and with protein-losing gastroenteropathy (PLE) in 6 (0.079; 0.600). The relatively high overlap coefficient involving PLE should be interpreted cautiously because PLE was reported infrequently. These metrics describe shared reporting and do not establish temporal sequence.

4. Discussion

This study organized zolbetuximab reporting in gastric cancer into three broad patterns: upper gastrointestinal and intake-related findings, gastric mucosal findings, and findings related to albumin, protein loss, and fluid balance. Nausea, vomiting, and decreased appetite were positioned as established because they are supported by pivotal trials, current product information, and management literature. Gastritis was positioned as emerging on the basis of informative but still limited post-marketing endoscopic evidence. Hypoalbuminemia, blood albumin decreased, and Oedema peripheral were considered supportive but non-specific because several competing explanations are common in advanced gastric cancer. Protein-losing gastroenteropathy (PLE) remained sparse and hypothesis-generating, with evidence derived mainly from selected cases (Shitara et al., 2023; Shah et al., 2023; Yamamoto et al., 2025; Ushimaru et al., 2026; Yanagimoto et al., 2025; Mitsui et al., 2025). Table 2 integrates these reporting patterns with regulatory, phase III, and primary post-marketing evidence.

The upper gastrointestinal findings were consistent with the established tolerability profile of zolbetuximab. Nausea, vomiting, and decreased appetite remained supported across contextual reporting backgrounds and adjusted analyses, in keeping with SPOTLIGHT, GLOW, and the current FDA label (Shitara et al., 2023; Shah et al., 2023; U.S. Food and Drug Administration, 2025). Clinical guidance and early practice reports emphasize anticipatory antiemetic prophylaxis around initial infusions, infusion-rate adjustment, prompt symptom reassessment, hydration, and support of oral intake so that chemotherapy and zolbetuximab can continue when clinically appropriate (Klempner et al., 2025; Narita et al., 2025; Shitara et al., 2026). Future cohorts should evaluate whether gastrectomy and residual-stomach status modify clinical presentation or management. Because 0-day records and incomplete dates were common, the timing summaries were interpreted descriptively.

Gastritis was reported in 22 zolbetuximab reports versus 1 pooled PD-1 report, with support across all 5 reporting backgrounds and adjusted analyses but limited support outside Japan. This finding adds a gastric mucosal component distinct from the established nausea and vomiting profile, although sparse reference events and the Japan-dominant reporting environment constrain interpretation. Because upper gastrointestinal symptoms alone cannot establish gastritis, direct mucosal assessment is important for distinguishing this finding from the established emesis profile. A Japanese cohort documented endoscopically confirmed inflammatory and erosive gastric changes during zolbetuximab-containing treatment (Yamamoto et al., 2025). Preclinical work supports the biological plausibility of gastric injury but cannot establish its human frequency or severity (Kinugasa et al., 2024). A reported case in which gastritis co-occurred with PLE suggests that gastric mucosal and protein loss findings may overlap in selected patients, without establishing a common sequence or mechanism (Mitsui et al., 2025). Prospective studies incorporating baseline and symptom-triggered endoscopy are needed to define the clinical spectrum and evaluate gastric-protective management strategies in routine care.

Findings related to albumin, protein loss, and fluid balance formed a recurring but clinically non-specific reporting pattern, while PLE may explain only a small subset of clinically confirmed cases. Hypoalbuminemia was reported in 72 zolbetuximab reports versus 3 pooled PD-1 reports and PLE in 10 versus 2; blood albumin decreased and edema peripheral also remained supported. Hypoalbuminemia and blood albumin decreased are clinically related coding concepts and therefore do not provide independent confirmation. Current product information identifies decreased albumin and peripheral edema as relevant findings, whereas PLE is not a named reaction (U.S. Food and Drug Administration, 2025). In a single-center retrospective exploratory cohort, Ushimaru et al. (2026) observed that serum albumin declined early during zolbetuximab-based treatment, without establishing PLE. A single-center cohort documented an early albumin decline and identified absence of prior total gastrectomy, capecitabine and oxaliplatin (CAPOX), higher body mass index, and nausea or vomiting during zolbetuximab introduction as factors associated with severe hypoalbuminemia, without establishing PLE (Shimozaki et al., 2025). Yanagimoto et al. (2025) reported two clinically documented cases of PLE during zolbetuximab treatment, providing evidence that PLE may occur in selected patients but not explaining the broader albumin- and fluid-related reporting pattern. PLE should therefore be considered only when supported by objective clinical evidence and should not be inferred from hypoalbuminemia or edema alone. Hypoalbuminemia and Oedema peripheral were shared in 16 reports (Jaccard 0.186); this metric indicates overlap within reports but establishes neither chronology nor a common mechanism. In advanced gastric cancer, reduced intake, vomiting, malnutrition, and cachexia complicate interpretation of albumin-related findings (Rosania et al., 2016). Tumor burden, organ dysfunction, and concomitant treatment may provide additional competing explanations. Prospective assessment should include serial albumin, body weight, dietary intake, nutritional evaluation, edema assessment, and objective testing for PLE to improve clinical attribution.

The five backgrounds: pooled PD-1, all non-zolbetuximab gastric cancer, non-PD-1, FP + Pt-compatible, and chemotherapy-dominant, showed how reporting context influenced effect magnitude. Nausea attenuated from an ROR of 41.43 against pooled PD-1 reports to approximately 9.5–15.0 across the other backgrounds, while vomiting showed a similar qualitative pattern. These analyses provided complementary reporting contexts. The FP + Pt-compatible and chemotherapy-dominant results, together with the complete case, PS/SS, sole-PS, and HER2-positive indication term sensitivities, did not materially alter the findings for the eight focus PTs. In contrast, interpretation of several non-focus PTs was more susceptible to disease- or treatment-related confounding. Ascites, diarrhea, neutrophil count decreased, malaise, and hypoesthesia were therefore not prioritized for focused interpretation; fluoropyrimidine–platinum exposure was a particular competing explanation for cytopenic, neurologic, and gastrointestinal findings (Cunningham et al., 2008; Yamada et al., 2015).

Applicability is shaped by geography, launch timing, and reporting route. Geographically, Japan accounted for 83.8% of zolbetuximab reports, and only three of eight focus PTs met the ROR criterion outside Japan. Temporally, 95.8% of zolbetuximab reports occurred during 2025 Q1–2026 Q1, although the focus findings remained supported when both arms were restricted to those quarters. Reporting patterns may evolve as exposure, clinical familiarity, publicity, and reporting practices change after launch. Oncology drugs have not shown a uniform classical Weber pattern, and the present concentration should therefore not be labeled a Weber effect (Arora et al., 2017). By reporting route, the manufacturer-submitted analysis supported the focus findings, whereas the direct-to-FDA channel was not evaluable because it contained no zolbetuximab reports. Taken together, these results primarily describe an early, predominantly Japanese post-marketing environment rather than a globally generalizable clinical safety profile.

Strengths of this study include the indication-restricted cohort, exact drug–indication linkage, and the use of multiple reporting backgrounds, adjusted models, and restricted analyses to examine the same reporting patterns from complementary perspectives. However, FAERS has no exposure denominator and is subject to underreporting, selective or stimulated reporting, potential duplicate reports, and variable data quality; it cannot support incidence, comparative risk, or causal estimates. Clinical detail was incomplete for biomarker intensity, treatment line, gastrectomy and residual-stomach status, baseline nutrition and albumin, tumor burden, regimen details, dose modification, and endoscopic confirmation, which constrained case-level attribution. The concentration of zolbetuximab reports in Japan and the early post-launch period limits generalizability, while overlapping reporting backgrounds and sparse cells make some estimates context-dependent or imprecise. Finally, the focus set was selected post hoc, and clinical classification used non-blinded sequential review rather than independent parallel ratings, so inter-rater agreement was not estimable. Ambiguous or incomplete dates limit interpretation of TTO, and co-reporting cannot establish temporal order, mechanism, or a common clinical syndrome. These limitations are intrinsic to spontaneous-report analysis and require the findings to be interpreted as reporting disproportionality rather than estimates of frequency or treatment effect.

5. Conclusion

In this indication-restricted FAERS analysis, zolbetuximab reports showed disproportionate reporting of established upper gastrointestinal events, gastric mucosal findings, and findings related to albumin, protein loss, and fluid balance across multiple reporting backgrounds. Gastritis was the clearest emerging finding; albumin-related events require careful clinical attribution, and protein-losing gastroenteropathy was reported sparsely. Because early post-marketing reports from Japan dominated the data, broader validation is needed, particularly with endoscopic assessment and serial evaluation of albumin, nutrition, and fluid status.

Funding Statement

The author(s) declared that financial support was not received for this work and/or its publication.

Footnotes

Edited by: Qingmo Yang, The First Affiliated Hospital of Xiamen University, China

Reviewed by: Nemanja Maletin, Oncology Institute of Vojvodina, Serbia

Lisha Wu, Sun Yat-Sen Memorial Hospital, China

Data availability statement

Publicly available datasets were analyzed in this study. These data can be found at: Raw FAERS quarterly data: https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html. Reproducibility code, dictionaries, and aggregate outputs: https://github.com/Sjzz114514/zolbetuximab-faers-reproducibility. Archived release v1.1.0: https://zenodo.org/records/21548960. DOI: 10.5281/zenodo.21548960.

Ethics statement

Ethical approval was not required for the study involving humans in accordance with the local legislation and institutional requirements. Written informed consent to participate in this study was not required from the participants or the participants’ legal guardians/next of kin in accordance with the national legislation and the institutional requirements.

Author contributions

JZ: Conceptualization, Data curation, Formal Analysis, Methodology, Software, Writing – original draft. ZZ: Conceptualization, Methodology, Writing – original draft. ZL: Supervision, Validation, Visualization, Writing – review and editing. PZ: Project administration, Resources, Supervision, Writing – review and editing.

Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Generative AI statement

The author(s) declared that generative AI was used in the creation of this manuscript. The authors declare that OpenAI ChatGPT and Codex, using GPT-5-series models including GPT-5.5 and GPT-5.6 (OpenAI, San Francisco, CA, United States), were used to assist with English-language editing and with code drafting, debugging, and quality-assurance checks. The authors defined the study design, cohort and variable rules, preferred term clinical classification framework, and analytical specifications; executed and reviewed the analyses; and verified the numerical outputs, references, and final manuscript text. The tools did not independently determine report eligibility, classify preferred terms, select analyses, or make scientific interpretations. All authors reviewed and approved the final content and take full responsibility for the work.

Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fphar.2026.1887849/full#supplementary-material

Table2.xlsx (196.2KB, xlsx)
Table3.xlsx (61.5KB, xlsx)
Table4.xlsx (111.8KB, xlsx)
Table1.xlsx (33.2KB, xlsx)

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Table2.xlsx (196.2KB, xlsx)
Table3.xlsx (61.5KB, xlsx)
Table4.xlsx (111.8KB, xlsx)
Table1.xlsx (33.2KB, xlsx)

Data Availability Statement

Publicly available datasets were analyzed in this study. These data can be found at: Raw FAERS quarterly data: https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html. Reproducibility code, dictionaries, and aggregate outputs: https://github.com/Sjzz114514/zolbetuximab-faers-reproducibility. Archived release v1.1.0: https://zenodo.org/records/21548960. DOI: 10.5281/zenodo.21548960.

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