Published online Aug 15, 2026. doi: 10.4251/wjgo.v18.i8.121158
Revised: April 20, 2026
Accepted: May 13, 2026
Published online: August 15, 2026
Processing time: 142 Days and 19.9 Hours
Ramucirumab plus paclitaxel remains the standard second-line treatment for advanced gastric cancer (AGC), despite evolving frontline therapies. However, the prognostic and predictive significance of claudin 18.2 (CLDN18.2) expression in this setting remains unclear.
To evaluate the prognostic and predictive significance of CLDN18.2 expression in patients with AGC treated with ramucirumab plus paclitaxel.
This retrospective study included patients with AGC who underwent treatment with ramucirumab plus paclitaxel as second-line therapy between January 2023 and October 2025, and had available CLDN18.2 data. CLDN18.2 positivity was defined as membranous staining in ≥ 75% of tumor cells. Survival outcomes were analyzed using Kaplan-Meier estimates and Cox models, with restricted mean survival time applied when proportional hazards assumptions were not met.
Among 103 patients, 42 (40.8%) and 61 (59.2%) were CLDN18.2-positive and CLDN18.2-negative, respectively. Baseline clinical and molecular characteristics did not differ significantly between the two groups. CLDN18.2 expression status was not associated with overall survival (hazard ratio = 1.12; 95%CI: 0.67-1.86; P = 0.666). Restricted mean survival time analysis also showed comparable survival between the two groups (12.7 months vs 13.3 months; P = 0.753). Progression-free survival did not differ significantly according to CLDN18.2 expression status (hazard ratio = 1.14; 95%CI: 0.70-1.85; P = 0.595), and objective response rate did not differ significantly between the two groups (30.6% vs 35.1%; P = 0.822).
CLDN18.2 expression is not associated with outcomes of ramucirumab plus paclitaxel second-line therapy and may have limited utility for treatment selection in AGC.
Core Tip: Claudin expression is an established biomarker for targeted therapy in gastric cancer; however, its clinical relevance remains uncertain. In this retrospective study, claudin expression was not associated with survival or treatment response in patients with advanced gastric cancer who were treated with ramucirumab plus paclitaxel. These findings highlight a key distinction between intrinsic tumor biomarkers and therapies targeting the tumor microenvironment. Claudin expression should not be used to guide second-line anti-angiogenic treatments, emphasizing the need for mechanism-based biomarker selection in precision oncology.
- Citation: Han MR, Shin JE, Lim SH, Lee J, Kim ST. Association of claudin 18.2 expression with outcomes of ramucirumab plus paclitaxel as second-line therapy in advanced gastric cancer. World J Gastrointest Oncol 2026; 18(8): 121158
- URL: https://www.wjgnet.com/1948-5204/full/v18/i8/121158.htm
- DOI: https://dx.doi.org/10.4251/wjgo.v18.i8.121158
Gastric cancer remains a major global health burden, accounting for substantial cancer-related morbidity and mortality worldwide, with particularly high incidence rates in Eastern Asia and Eastern Europe[1].
Historically, patients treated with conventional cytotoxic chemotherapy alone had a median overall survival (OS) of approximately 11 months[2]. However, the therapeutic landscape has evolved with the introduction of molecularly targeted agents, including human epidermal growth factor receptor 2 (HER2)-directed therapies and immune checkpoint inhibitors that target the programmed cell death protein 1/programmed death ligand 1 axis, resulting in improved clinical outcomes in selected patient populations[2,3]. Recently, claudin 18.2 (CLDN18.2) has emerged as a novel therapeutic target and a clinically relevant biomarker that guides treatment selection in advanced gastric cancer (AGC)[4].
Despite these advances, ramucirumab, a monoclonal antibody targeting vascular endothelial growth factor receptor 2, in combination with paclitaxel, remains the standard treatment, as supported by phase III evidence from the RAINBOW trial, which demonstrated a significant OS benefit compared to paclitaxel alone[5,6]. As ramucirumab plus paclitaxel continues to be administered irrespective of their molecular characteristics, the identification of predictive biomarkers for this regimen represents an important unmet clinical need.
Although CLDN18.2 is an established predictive biomarker for CLDN18.2-targeted therapies, its clinical relevance beyond target-directed treatments remains uncertain. In particular, whether CLDN18.2 expression influences clinical outcomes the vascular endothelial growth factor (VEGF) pathway, on clinical outcomes has not been clearly defined. Therefore, we aimed to investigate the prognostic and predictive significance of CLDN18.2 expression status in patients with AGC treated with ramucirumab plus paclitaxel as second-line therapy.
This analysis included patients with AGC who received ramucirumab plus paclitaxel as second-line therapy between January 2023 and October 2025 and had available data on CLDN18.2 expression. The study was approved by the Institutional Review Board of Samsung Medical Center, and the requirement for informed consent was waived owing to its retrospective design.
Immunohistochemical staining for CLDN18.2 was performed on formalin-fixed, paraffin-embedded tumor samples using a commercially available anti-CLDN18.2 antibody in the pathology laboratory according to standard protocols. Staining was performed using an automated platform. CLDN18.2 expression was evaluated based on the membranous staining of tumor cells. Tumors were considered CLDN18.2-positive when ≥ 75% of tumor cells showed membranous staining of any intensity. All slides were independently reviewed by two experienced pathologists who were blinded to clinical outcomes. In cases of discrepancies, a consensus was reached through a joint review.
Patients were followed up until December 31, 2025, or death from any cause, whichever occurred first. Baseline demographic and clinicopathological characteristics were extracted from electronic medical records. The collected variables included age, sex, Eastern Cooperative Oncology Group (ECOG) performance status, HER2 status, Epstein-Barr virus status, MutL homolog 1 expression, tumor mutational burden category, and microsatellite instability (MSI) status.
The objective response rate (ORR) was evaluated according to the Response Evaluation Criteria in Solid Tumors, version 1.1, and compared between groups using Fisher’s exact test.
OS was defined as the time from initiation of ramucirumab plus paclitaxel treatment to death from any cause. Progression-free survival (PFS) was defined as the time from treatment initiation to radiological disease progression or death from any cause, whichever occurred first.
Survival curves were estimated using the Kaplan-Meier method and compared using the log-rank test. Univariable Cox proportional hazards (PH) models were used to evaluate the association between the CLDN18.2 status and survival outcomes. Multivariable Cox PH models were constructed to adjust for clinically relevant covariates, including age, ECOG performance status, HER2 positivity (defined as immunohistochemistry 3+ or immunohistochemistry 2+ with in situ hybridization positivity), and the presence of liver and peritoneal metastases. The number of outcome events met the recommended thresholds to ensure model stability and minimize the risk of overfitting.
The PH assumption was evaluated using the Schoenfeld residuals. When a violation of the PH assumption was detected. Restricted mean survival time (RMST) analysis was performed as an alternative approach. RMST was calculated up to a predefined truncation time (τ), defined as the maximum time point at which survival estimates remained reliable and an adequate number of patients remained at risk in both groups.
A total of 103 patients were included in the analysis, of whom 61 (59.2%) were CLDN18.2-negative and 42 (40.8%) were CLDN18.2-positive (Table 1). The median follow-up duration was 21.9 months (95%CI: 13.2-28.6). The mean age at treatment initiation was 60.6 years in the overall population and did not differ between the two groups (61.1 years vs 59.9 years, P = 0.616). Sex distribution was comparable between the two groups (female, 52.5% vs 47.6%, P = 0.778). Most patients had an ECOG performance status of 0-1, with no significant between-group differences (98.4% vs 92.9%, P = 0.367).
| Variable | Level | Overall (n = 103) | Negative (n = 61) | Positive (n = 42) | P value |
| Age [mean (SD)] | 60.57 (11.55) | 61.05 (10.56) | 59.88 (12.96) | 0.616 | |
| Sex | Female | 52 (50.5) | 32 (52.5) | 20 (47.6) | 0.778 |
| Male | 51 (49.5) | 29 (47.5) | 22 (52.4) | ||
| Eastern Cooperative Oncology Group | 0-1 | 99 (96.1) | 60 (98.4) | 39 (92.9) | 0.367 |
| ≥ 2 | 4 (3.9) | 1 (1.6) | 3 (7.1) | ||
| Human epidermal growth factor receptor 2 | 0 | 62 (60.2) | 38 (62.3) | 24 (57.1) | 0.476 |
| 1+ | 30 (29.1) | 17 (27.9) | 13 (31.0) | ||
| 2+, SISH- | 5 (4.9) | 3 (4.9) | 2 (4.8) | ||
| 2+, SISH+ | 2 (1.9) | 2 (3.3) | 0 (0.0) | ||
| 3+ | 4 (3.9) | 1 (1.6) | 3 (7.1) | ||
| Epstein-Barr virus | 0 | 84 (81.6) | 52 (85.2) | 32 (76.2) | 0.180 |
| 1 | 2 (1.9) | 0 (0.0) | 2 (4.8) | ||
| NE | 17 (16.5) | 9 (14.8) | 8 (19.0) | ||
| MutL homolog 1 | 0 | 87 (84.5) | 52 (85.2) | 35 (83.3) | 0.633 |
| 1 | 1 (1.0) | 1 (1.6) | 0 (0.0) | ||
| NE | 15 (14.6) | 8 (13.1) | 7 (16.7) | ||
| Tumor mutational burden | High | 11 (10.7) | 6 (9.8) | 5 (11.9) | 0.653 |
| Low | 73 (70.9) | 42 (68.9) | 31 (73.8) | ||
| NE | 19 (18.4) | 13 (21.3) | 6 (14.3) | ||
| Microsatellite instability status | MSS | 0 (0.0) | 0 (0.0) | 0 (0.0) | Not available |
| non-MSS | 103 (100.0) | 61 (100.0) | 42 (100.0) | ||
| Metastasis | No | 4 (3.9) | 2 (3.3) | 2 (4.8) | 1.000 |
| Yes | 99 (96.1) | 59 (96.7) | 40 (95.2) | ||
| Liver | No | 81 (78.6) | 49 (80.3) | 32 (76.2) | 0.796 |
| Yes | 22 (21.4) | 12 (19.7) | 10 (23.8) | ||
| Peritoneal | No | 43 (41.7) | 27 (44.3) | 16 (38.1) | 0.674 |
| Yes | 60 (58.3) | 34 (55.7) | 26 (61.9) | ||
| Bone | No | 99 (96.1) | 60 (98.4) | 39 (92.9) | 0.367 |
| Yes | 4 (3.9) | 1 (1.6) | 3 (7.1) |
Overall, 96.1% of the patients had metastatic disease at treatment initiation. The metastatic patterns, including the frequencies of liver (21.4%), peritoneal (58.3%), and bone (3.9%) metastases, were similar between the two groups (all P > 0.3).
Molecular characteristics, including HER2 status (P = 0.476), Epstein-Barr virus status (P = 0.180), MutL homolog 1 expression (P = 0.633), and tumor mutational burden category (P = 0.653), did not differ significantly according to CLDN18.2 status. All patients were microsatellite stable, precluding analysis based on MSI status.
The median OS was 11.4 months (95%CI: 9.4-15.5) in the CLDN18.2-negative group and 10.4 months (95%CI: 5.8-16.7) in the CLDN18.2-positive group (Figure 1A). In the univariable Cox analysis, CLDN18.2 positivity was not associated with OS [hazard ratio (HR) = 1.12; 95%CI: 0.67-1.86; P = 0.666].
Visual inspection of the Kaplan-Meier curves suggested crossing hazards, and formal testing confirmed the violation of the proportional hazard assumption (Schoenfeld test, P = 0.043). Therefore, OS was also evaluated using RMST analysis. With a truncation time (τ) of 29 months, the RMST was 13.3 months in the CLDN18.2-negative group and 12.7 months in the CLDN18.2-positive group (difference, -0.69 months; 95%CI: -4.94 to 3.57; P = 0.753).
In the multivariable analysis adjusting for age, ECOG performance status, HER2 positivity, and liver and peritoneal metastases, CLDN18.2 status remained not independently associated with OS (adjusted HR = 1.00; 95%CI: 0.59-1.69; P = 0.997) (Figure 1B). The results of the global Schoenfeld test for the multivariable model were not statistically significant (P = 0.082).
None of the remaining covariates, including age (adjusted HR per year increase = 1.00; 95%CI: 0.98-1.03; P = 0.801), ECOG performance status (adjusted HR = 0.38; 95%CI: 0.11-1.26; P = 0.114), HER2 positivity (adjusted HR = 1.61; 95%CI: 0.56-4.65; P = 0.379), or liver metastasis (adjusted HR = 0.74; 95%CI: 0.35-1.55; P = 0.423), were significantly associated with OS. Peritoneal metastasis showed a borderline association with inferior survival (adjusted HR = 1.86; 95%CI: 0.97-3.55; P = 0.061).
The median PFS was 5.6 months (95%CI: 4.17-7.33) in the CLDN18.2-negative group and 5.3 months (95%CI: 4.01-7.36) in the CLDN18.2-positive group (Figure 2A). The status of CLDN18.2 expression was not associated with PFS in the univariable analysis (HR = 1.14; 95%CI: 0.70-1.85; P = 0.595), and the PH assumption was satisfied (Schoenfeld global test, P = 0.67).
In the multivariable analysis, CLDN18.2 status remained not independently associated with PFS (adjusted HR = 1.21; 95%CI: 0.74-1.98; P = 0.452; Figure 2B). None of the remaining covariates – including age (adjusted HR per year increase = 0.99; 95%CI: 0.96-1.01; P = 0.271), ECOG performance status (adjusted HR = 0.47; 95%CI: 0.13-1.68; P = 0.247), HER2 positivity (adjusted HR = 1.49; 95%CI: 0.45-4.98; P = 0.516), liver metastasis (adjusted HR = 1.03; 95%CI: 0.53-2.02; P = 0.921), or peritoneal metastasis (adjusted HR = 1.12; 95%CI: 0.62-2.04; P = 0.705) – were significantly associated with PFS.
Among the patients evaluable for response, the ORR was 35.1% (20/57) in the CLDN18.2-negative group and 30.6% (11/36) in the CLDN18.2-positive group, with no significant difference between the groups (Fisher’s exact test, P = 0.8216; odd ratio = 1.23; 95%CI: 0.46–3.36). No significant differences in survival outcomes or response rates were observed according to CLDN18.2 status.
Our findings demonstrated that the CLDN18.2 expression status did not influence the clinical outcomes of ramucirumab plus paclitaxel as a second-line therapy for patients with AGC. Importantly, the lack of association was consistent across survival endpoints, response outcomes, and multivariable analyses, reinforcing the robustness of our findings. Although the PH assumption was marginally violated in the univariable analysis (P = 0.043), it was not in the multivariable analysis (P = 0.082). This discrepancy may be explained by the adjustment for potential confounders, which can stabilize time-dependent effects. Therefore, the HRs derived from the multivariable Cox model were considered valid and interpretable.
These results suggest that CLDN18.2 expression should not be considered a biomarker to guide second-line treatment selection with ramucirumab plus paclitaxel in patients with AGC.
CLDN18.2, a tight-junction protein normally restricted to the gastric epithelial mucosa, is largely preserved during gastric carcinogenesis[7-9]. Loss of epithelial polarity during malignant transformation leads to surface exposure to CLDN18.2, which enables recognition by monoclonal antibodies[9]. This biological feature provides a clear mechanistic rationale for the predictive role of CLDN18.2 in zolbetuximab-based therapy, in which antitumor activity depends on direct antigen binding and immune-mediated cytotoxicity[10].
In contrast, ramucirumab acts via a fundamentally different mechanism. As a monoclonal antibody targeting vascular endothelial growth factor receptor 2, it blocks VEGF-mediated signaling and inhibits angiogenesis. VEGF regulates vascular permeability and endothelial cell survival, and its overexpression is associated with tumor progression and poor prognosis[11,12]. Accordingly, inhibition of the VEGF–VEGFR signaling axis suppresses tumor angiogenesis and modulates the tumor microenvironment rather than directly targeting tumor epithelial cells[12,13]. In combination with paclitaxel, this strategy has demonstrated survival benefits and has been established as the standard second-line treatment for AGC[13].
Given this distinct therapeutic mechanism, a biological association between CLDN18.2 expression and the efficacy of ramucirumab-based therapy was not expected. Therefore, the findings of this analysis are biologically consistent with the mechanism of action of the VEGF pathway inhibition.
More broadly, our findings underscore the important conceptual distinction between tumor cell-intrinsic biomarkers and microenvironment-directed therapeutic strategies[14]. While CLDN18.2 is an effective predictive biomarker for therapies that directly exploit its expression, it appears to be insufficient for predicting the response to anti-angiogenic treatment. Instead, the activity of ramucirumab-based therapy is more likely to be influenced by immune and vascular remodeling within the tumor microenvironment than by tumor epithelial markers alone[13].
Emerging evidence further supports this distinction, demonstrating that antitumor immunity is shaped by the immune context of the tumor microenvironment, including CD8 + T-cell infiltration, programmed death ligand 1 expression, and the balance between effector and regulatory T-cell populations[15]. VEGF contributes to immune suppression by limiting T-cell proliferation and tumor infiltration, which may be reversed by inhibiting the VEGF pathway. Accordingly, ramucirumab-containing therapies have been associated with enhanced CD8 + T cell infiltration and reduced regulatory T cell activity, thereby shifting the tumor microenvironment toward a more immunoreactive state[16]. These observations provide a mechanistic rationale for prioritizing microenvironment-based biomarkers over epithelial surface markers when predicting responses to anti-angiogenic therapy[1].
This study had several limitations. First, its retrospective design may have introduced selection bias. Secondly, the sample size was modest, potentially limiting the statistical power to detect small differences. Given the observed HRs close to unity (HR = 1.12-1.14) and the limited sample size, the study was likely underpowered to detect small effect sizes, and therefore, modest but clinically meaningful differences cannot be definitively excluded. Third, CLDN18.2 expression was assessed using a predefined cutoff, and alternative thresholds were not explored. Additionally, all patients in this study had microsatellite stable tumors. Given the distinct biological and immunological characteristics of MSI-high gastric cancer, the applicability of our findings to this subgroup may be limited. Finally, translational correlations of the tumor microenvironment were not available, precluding mechanistic validation. External validation in independent cohorts would further strengthen these findings.
Moreover, future studies should explore alternative biomarkers that may better reflect the mechanism of action of anti-angiogenic therapies. Particularly, angiogenesis-related markers, such as VEGF-A and VEGFR2 expression, as well as immune microenvironmental features, including CD8+ T cell infiltration, may provide further insights into the treatment response to ramucirumab. Integrating these markers may help refine patient selection and improve the precision of therapeutic strategies.
As CLDN18.2 testing becomes increasingly integrated into clinical practice, there is a potential risk of overgeneralizing its predictive value across different treatment settings[16]. Our findings emphasize that biomarker applications must align with the therapeutic mechanisms. Precision oncology requires not only the identification of molecular targets but also mechanistic clarity regarding how those targets are therapeutically engaged. Based on our results, CLDN18.2 expression should not be considered as a biomarker to guide second-line treatment selection with ramucirumab plus paclitaxel in AGC.
The authors would like to thank all patients and clinical staff who contributed to this study.
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