Claudin 18.2 expression in gastroesophageal adenocarcinoma: biomarker overlap and association with clinical outcomes in a European cohort

E Terán; R Pazo; L Caritá; M Alsina; C Hierro; C Blanco; M Reboredo; S Landolfi; A Zucchiatti; L Visa; A Calvo; A López; R Vidal-Tocino; C Agra; I Alés; S Foti; B García-Paredes; V Genovesi; L Fornaro; T Sauri; I Macías; E Martínez; J Martínez; C Buges; P Ribera; JM Herranz; D Acosta; A Vivancos; J Tabernero; E Élez; TV Tian; T Macarulla

doi:10.1016/j.esmoop.2025.106053

. 2026 Jan 27;11(2):106053. doi: 10.1016/j.esmoop.2025.106053

Claudin 18.2 expression in gastroesophageal adenocarcinoma: biomarker overlap and association with clinical outcomes in a European cohort

E Terán ^1,^∗, R Pazo ², L Caritá ³, M Alsina ⁴, C Hierro ⁵, C Blanco ², M Reboredo ⁶, S Landolfi ⁷, A Zucchiatti ⁷, L Visa ⁸, A Calvo ⁹, A López ¹⁰, R Vidal-Tocino ¹¹, C Agra ⁴, I Alés ¹², S Foti ¹³, B García-Paredes ¹⁴, V Genovesi ¹⁵, L Fornaro ¹⁵, T Sauri ^16,¹⁷, I Macías ^16,¹⁷, E Martínez ¹⁸, J Martínez ¹⁹, C Buges ⁵, P Ribera ²⁰, JM Herranz ²¹, D Acosta ¹, A Vivancos ²², J Tabernero ¹, E Élez ¹, TV Tian ^17,^21,^∗, T Macarulla ^16,^17,^21,^∗

¹Medical Oncology Department, Gastrointestinal Cancer Unit, Vall d’Hebron University Hospital, Barcelona, Spain

²Medical Oncology Department, Miguel Servet University Hospital, Zaragoza, Spain

³Statistics Unit, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain

⁴Medical Oncology Department, Hospital Universitario de Navarra (HUN), Navarrabiomed-IdiSNA, Pamplona, Spain

⁵Medical Oncology Department, Catalan Institute of Oncology (ICO)-Badalona, Badalona-Applied Group in Oncology (B-ARGO), Badalona, Barcelona, Spain

⁶Medical Oncology Department, A Coruña University Hospital, Galicia, Spain

⁷Pathology Department, Vall d’Hebron University Hospital, Barcelona, Spain

⁸Medical Oncology Department, Hospital del Mar Research Institute, Barcelona, Spain

⁹Medical Oncology Department, Gregorio Marañón University Hospital, Madrid, Spain

¹⁰Medical Oncology Department, Burgos University Hospital, Burgos, Spain

¹¹Medical Oncology Department, C.A. Universitario de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain

¹²Medical Oncology Department, Málaga Regional University Hospital, Málaga, Spain

¹³Medical Oncology Department, San Raffaele Scientific Institute, Milán, Italy

¹⁴Medical Oncology Department, Clínico San Carlos Hospital, Madrid, Spain

¹⁵U.O Oncologia, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy

¹⁶Medical Oncology Department, Hospital Clínic de Barcelona, Barcelona, Spain

¹⁷Translational Oncology in Upper Gastrointestinal Cancer Group, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain

¹⁸Medical Oncology Department, Marqués de Valdecilla University Hospital, Instituto de Investigación Valdecilla (IDIVAL), Santander, Spain

¹⁹Medical Oncology Department, Virgen de las Nieves University Hospital, Granada, Spain

²⁰Medical Oncology Department, Parc Taulí University Hospital, Badalona, Spain

²¹Upper Gastrointestinal and Endocrine Tumor Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain

²²Cancer Genomics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain

^∗

Correspondence to: Dr Eduardo Terán, Medical Oncology Department, Gastrointestinal Cancer Unit, Vall d’Hebron University Hospital, Passeig de la Vall d’Hebron, 119, Horta-Guinardó, 08035 Barcelona, Spain. Tel: +34-934-89-30-00 eduardoteran@vhio.net

^∗

Dr Tian Tian, Upper Gastrointestinal and Endocrine Tumor Group, Medical Oncology Department, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron University Hospital, Centro Cellex, Carrer de Natzaret, 117, Horta-Guinardó, 08035 Barcelona, Spain. Tel: +34-932-54-34-50 tiantian@vhio.net

^∗

Dr Teresa Macarulla, Medical Oncology Department, Hospital Clínic de Barcelona, Barcelona, Spain; Translational Oncology in Upper Gastrointestinal Cancer Group, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Carrer de Villarroel, 170, L’Eixample, 08036 Barcelona, Spain. Tel: +34-932-27-54-00 macarulla@clinic.cat

PMCID: PMC12865641 PMID: 41604819

Abstract

Background

Claudin 18.2 (CLDN18.2) is highly expressed in up to 40% of gastroesophageal adenocarcinomas (GEA) and represents an emerging therapeutic target for these tumors. However, its distribution across molecular subtypes and its prognostic and predictive roles remain insufficiently studied.

Methods

This ambispective, multicenter study included 563 patients with GEA diagnosed between 2019 and 2025 across 17 European institutions. Tumor samples were analyzed for CLDN18.2, human epidermal growth factor receptor 2 (HER2), mismatch repair, Epstein–Barr virus (EBV), and programmed death-ligand 1 [PD-L1; combined positive score (CPS)] using immunohistochemistry and/or in situ hybridization. Molecular alterations were characterized using next-generation sequencing. Associations between molecular features and clinical outcomes, such as overall response rate (ORR), median progression-free survival (mPFS), and median overall survival (mOS), were evaluated.

Results

High CLDN18.2 expression was observed in 48.3% of tumors, correlating with diffuse-type histology and peritoneal involvement (P < 0.01). Its prevalence varied across molecular subtypes: 33.9% in deficient mismatch repair, 62.5% in EBV-positive, 41.9% in HER2-positive tumors, and 47.2% in tumors with PD-L1 CPS ≥5. Among patients treated with first-line chemotherapy, CLDN18.2 status did not affect mPFS [hazard ratio (HR) 0.90; P = 0.50] or mOS (HR 1.06; P = 0.80). However, among HER2-positive patients, CLDN18.2-high tumors were associated with improved outcomes with HER2-targeted therapy (mPFS 17.0 versus 8.9 months, HR 0.42; P = 0.03; mOS 43.0 versus 23.0 months, HR 0.40; P = 0.07). By contrast, in patients with CLDN18.2-high tumors receiving an immunotherapy-based regimen (IO), there was a trend toward lower ORR (51% versus 64%; P = 0.15), shorter mPFS (8.9 versus 14.0 months; HR 1.47; P = 0.14), and reduced mOS (16.0 versus 43.0 months; HR 2.04; P = 0.052). Combined analyses of CLDN18.2 and PD-L1 showed poorer survival outcomes in CLDN18.2-high tumors across PD-L1 thresholds.

Conclusions

CLDN18.2-high GEA was more prevalent than previously reported in pivotal trials and showed substantial overlap across molecular subtypes. It was associated with a greater benefit from HER2-targeted therapy but a trend toward poorer outcomes with IO, underscoring the need for biomarker-guided therapeutic strategies in GEA.

Key words: gastroesophageal adenocarcinoma, Claudin 18.2, HER2, PD-L1, overlapping biomarkers, targeted therapies, immunotherapy

Highlights

•
A high prevalence of CLDN18.2-high GEA was observed in a European cohort, with substantial overlap across biomarkers.
•
Patients with concurrent HER2 positivity and high CLDN18.2 expression showed better outcomes with HER2-targeted therapies.
•
CLDN18.2-high patients treated with IO-based regimens experienced a trend toward poorer clinical outcomes.
•
These findings highlight the need for tailored therapeutic strategies in populations with overlapping biomarkers.

Background

Gastroesophageal tumors rank as the fifth most commonly diagnosed cancer worldwide, with ∼1.5 million new cases reported in 2022, and constitute the fourth leading cause of cancer-related mortality globally.¹ In advanced-stage disease, the prognosis remains poor,² and combination chemotherapy with platinum agents and fluoropyrimidines constitutes the cornerstone of systemic treatment.3, 4, 5 A key advance in understanding these tumors came with their comprehensive molecular characterization, particularly through the classification proposed by The Cancer Genome Atlas in 2014.⁶ This framework has provided valuable insights into the biological complexity and heterogeneity of the disease. Currently, the therapeutic landscape of gastroesophageal tumors is rapidly evolving.⁷ Several validated biomarkers in advanced gastroesophageal adenocarcinoma (GEA), including human epidermal growth factor receptor 2 (HER2), programmed death-ligand 1 (PD-L1), mismatch repair (MMR) proteins, and, more recently, Claudin 18.2 (CLDN18.2), play a crucial role in guiding treatment decisions.⁸ In HER2-positive advanced GEA, which represents ∼15%-20% of cases, the ToGA clinical trial⁹ demonstrated the benefit of combining trastuzumab with chemotherapy, establishing a new standard of care and marking a pivotal milestone in the development of biomarker-driven clinical trials. A PD-L1 combined positive score (CPS) ≥1 has been reported in ∼30%-60% of GEA.¹⁰ In this context, the addition of anti-programmed cell death protein 1 (anti-PD-1) therapies to chemotherapy, in both HER2-negative and HER2-positive disease, has significantly improved median overall survival (mOS) in patients with PD-L1 CPS ≥1 and/or high microsatellite instability (MSI-H).⁸^,¹¹^,¹²

By contrast, CLDN18.2, a member of the claudin family, is specifically expressed in epithelial cells of the normal gastric mucosa, where it functions as a key component of intercellular tight junctions. During oncogenic transformation, CLDN18.2 becomes exposed on the cell surface, making it a promising therapeutic target.¹³^,¹⁴ In this context, zolbetuximab, a chimeric monoclonal antibody targeting CLDN18.2, exerts its antitumor activity through antibody- and complement-dependent cytotoxicity.¹⁵ After showing preliminary efficacy as both monotherapy and combination therapy in phase II trials (MONO¹⁶ and FAST¹⁷ studies), the phase III SPOTLIGHT¹⁸ and GLOW¹⁹ trials evaluated zolbetuximab in combination with chemotherapy [modified FOLFOX6 or capecitabine and oxaliplatin (CAPOX)] as the first-line treatment for advanced HER2-negative, CLDN18.2-positive GEA. Furthermore, in a pooled analysis of both phase III studies, the addition of zolbetuximab to chemotherapy significantly improved mOS; [16.4 versus 13.7 months; hazard ratio (HR) 0.77; P < 0.001], establishing a new first-line treatment option for patients with CLDN18.2-positive advanced GEA.²⁰

CLDN18.2 positivity, defined as moderate-to-strong (2+/3+) membranous expression in ≥75% of tumor cells, as assessed by the VENTANA CLDN18 (43-14A) RxDx Assay (Roche Diagnostics Solutions, Tucson, AZ), has been reported in ∼24.0%-33.4% of cases.²¹^,²² This positivity appears to be evenly distributed across the different molecular subtypes, with a prevalence of 20.8% in tumors with microsatellite instability (MSI-H)/deficient mismatch repair (dMMR) and 26.7% in both Epstein–Barr virus (EBV)-positive and HER2-positive subgroups.¹⁴ Coexpression of PD-L1 and CLDN18.2 has also been reported in up to 20%-40% of cases.²¹^,²³

Given the substantial overlap between CLDN18.2 and other biomarkers and considering that zolbetuximab has emerged as a first-line therapeutic option for CLDN18.2-positive disease, the optimal selection between chemoimmunotherapy or chemotherapy plus zolbetuximab in the HER2-negative population remains uncertain, due to limited comparative evidence. This clinical dilemma is further complicated by retrospective data indicating that CLDN18.2-positive GEA may have worse mOS when treated with immune checkpoint inhibitors (ICIs), a finding linked to a distinct and complex immune microenvironment.²⁴

Therefore, our study aims to comprehensively characterize the clinicopathological and molecular features associated with CLDN18.2 expression in a large, multicenter cohort of GEA patients, evaluate the coexpression patterns between CLDN18.2 and other key biomarkers (e.g. MMR, HER2, EBV, and PD-L1 CPS), and assess the impact of CLDN18.2 expression on survival outcomes following standard first-line treatment, including chemotherapy, anti-PD-1 agents, and HER2-based targeted therapies.²⁵

Methods

Patient selection

We conducted an ambispective, multicenter study (across 17 centers in Spain and Italy) to analyze the clinicopathological and molecular features of patients whose tumors were assessed for CLDN18.2 expression. Its correlation was evaluated with the four TCGA molecular subtypes of GEA, HER2-positive, MSI-H/dMMR, EBV-positive, and all-negative, and with the PD-L1 CPS and other genomic alterations assessed by next-generation sequencing (NGS).

A total of 563 patients with available tumor samples from primary tumor or metastatic sites and complete clinical information were reviewed. The clinicopathological parameters collected included sex, age at diagnosis, primary tumor location, histological type, ethnicity, stage at diagnosis, metastatic sites, site of biomarker assessment, and molecular testing (as described below).

Clinical outcomes with standard first-line chemotherapy, HER2-based targeted therapy, immunotherapy (IO) using ICIs, and anti-CLDN18.2-based treatments were evaluated according to CLDN18.2 expression.

The eligibility criteria were as follows: (i) locally advanced unresectable or advanced/metastatic GEA; (ii) diagnosis between 2019 and 2025; and (iii) availability of an archival tumor tissue to evaluate CLDN18.2, HER2, MMR, EBV, and PD-L1 CPS status. All patients provided written informed consent at each participating center for biomarker analyses and the use of their clinical data. This study was approved by the Ethics Committee and conducted in accordance with the principles of the Declaration of Helsinki.

Molecular evaluation

Pathological biomarker assessment for CLDN18.2, MMR, EBV, HER2, and PD-L1 (CPS) was conducted locally at each participating center. Analyses were carried out on formalin-fixed, paraffin-embedded tissue specimens obtained from either primary tumors or metastatic lesions. CLDN18.2 expression was evaluated by immunohistochemistry (IHC) using the CLDN18 antibody (clone 43-14A; Roche Ventana, Oro Valley, AZ). In tumor cells, CLDN18.2 positivity was defined by the presence of membranous staining with an intensity of 2+ or 3+ in 1%-100% of tumor cells. CLDN18.2-high expression was classified as moderate to strong staining in ≥75% of tumor cells, whereas CLDN18.2-low expression corresponded to staining in <75% of tumor cells.

IHC and in situ hybridization for PD-L1, HER2, EBV, and MMR were carried out according to established guidelines,² and the detailed protocols are provided in Supplementary Table S1, available at https://doi.org/10.1016/j.esmoop.2025.106053.

In addition, DNA- and RNA-based NGS panels, including both in-house (VHIO-300) and commercial platforms;Illumina (Illumina, Inc, San Diego, CA), Ion Torrent (Thermo Fisher Scientific Inc, Waltham, MA), CARIS (Caris Life Sciences, Inc, Irving, TX) and FoundationOne CDx (Foundation Medicine, Inc, Boston, MA), were retrospectively carried out centrally to detect clinically relevant genomic alterations. The International Organization for Standardization (ISO) 15189-accredited VHIO-300 panel²⁶ enables the analysis of >450 genes, detecting single-nucleotide variants, insertions/deletions, copy number alterations, fusions, and tumor mutational burden. The CLDN18–ARHGAP26/6 fusion was specifically assessed by RNA sequencing and quantitative PCR in patients with sufficient archival tissue.

Biomarker assessment and clinical data were retrospectively extracted from patients’ electronic medical records.

Statistical analysis and oncological outcomes

Descriptive and comparative analyses were carried out using the Wilcoxon test, Fisher’s exact test, and Pearson’s chi-square test, as appropriate.

According to RECIST version 1.1 criteria, the overall response rate (ORR) was defined as the sum of complete responses and partial responses, while the disease control rate was defined as the sum of complete responses, partial responses, and stable disease. Efficacy analyses included Kaplan–Meier estimates of mOS and median progression-free survival (mPFS). Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression models.

Univariate and multivariate analyses were conducted using Cox proportional hazards models. All tests were two-sided, and P values <0.05 were considered statistically significant. All statistical analyses were conducted using R version 4.5.1 (R Foundation, Vienna, Austria).

Results

Clinicopathological and molecular features

A total of 563 patients were enrolled between June 2019 and May 2025. The median age was 66 years (range 18-95 years), and the cohort included 212 females (37.7%) and 351 males (62.3%). Specimens were locally evaluated using archival tissues obtained either from the primary tumor (n = 517, 91.8%) or from metastatic sites (n = 46, 8.2%). Comprehensive molecular profiling included the assessment of HER2 expression (n = 559, 99.3%), MMR status (n = 520, 92.4%), EBV status (n = 202, 35.9%), and PD-L1 CPS (n = 387, 68.7%). NGS analysis was carried out centrally in 123 patients (21.8%), as shown in Figure 1.

**Molecular analysis of CLDN18.2, HER2, MMR, and EBV status, together with PD-L1 CPS and NGS profiling, in our global cohort of gastroesophageal adenocarcinoma.** CLDN18.2, Claudin 18.2; CNA, copy number alteration; CPS, combined positive score; EBV, Epstein–Barr virus; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; MMR-D, mismatch repair deficient; MMR-P, mismatch repair proficient; NGS, next-generation sequencing; PD-L1, programmed death-ligand 1; TMB, tumor mutational burden.

Among patients with quantifiable CLDN18.2 expression (n = 482), 77.6% showed any positivity with IHC 2+/3+ (≥1% of tumor cells), with 62.9% and 56.4% meeting the ≥25% and ≥50% expression thresholds, respectively. CLDN18.2-high expression was observed in 48.3% of the overall cohort (272/563).

As summarized in Table 1, there were no significant differences in sex (P = 0.3) or ethnicity (P = 0.5) between patients with CLDN18.2-high and those with CLDN18.2-low expression. By contrast, CLDN18.2-high levels were significantly associated with a higher prevalence of diffuse-type histology (37.5% versus 25.5%; P = 0.003), presence of signet-ring cells (36.0% versus 26.1%; P = 0.01), and peritoneal involvement (53.7% versus 34.4%; P < 0.001), compared with CLDN18.2-low tumors. Similarly, no significant differences in CLDN18.2 expression were observed by sample site (primary versus metastatic, P = 0.39) or sample age (≥2 versus <2 years, P = 0.17).

Table 1.

Clinicopathological and molecular features according to CLDN18.2 expression.

Clinicopathological features		Overall population (n = 563)	CLDN18.2-high (n = 272, 48.3%)	CLDN18.2-low (n = 291, 51.7%)	P-value
Age (years)	Median (range)	66 (18-95)	65 (18-94)	66 (18-95)	0.5
	<50	90 (15.9)	42 (15.4)	48 (16.5)	0.7
	≥50	473 (84.1)	230 (84.6)	243 (83.5)	0.7
Sex, n (%)	Male	351 (62.3)	163 (59.9)	188 (64.6)	0.3
Sex, n (%)	Female	212 (37.7)	109 (40.1)	103 (35.4)	0.3
Ethnicity, n (%)	European	528 (93.8)	255 (93.8)	273 (93.8)	>0.9
Ethnicity, n (%)	Other	35 (6.2)	17 (6.2)	18 (6.2)	>0.9
Primary site, n (%)	Esophageal	42 (7.5)	16 (5.9)	26 (8.9)	0.2
	EGJ	127 (22.6)	58 (21.3)	69 (23.7)	0.2
	Gastric	392 (69.6)	198 (72.8)	194 (66.7)
Histological type, n (%)	Intestinal	252 (44.8)	107 (39.3)	145 (49.8)	0.002
	Diffuse	176 (31.3)	102 (37.5)	74 (25.4)	0.002
	Missing	135 (23.9)	63 (23.2)	72 (24.7)
Signet ring cells, n (%)	No	341 (60.6)	153 (56.3)	188 (64.6)	0.014
	Yes	174 (30.9)	98 (36)	76 (26.1)	0.014
	Missing	48 (8.5)	21 (7.7)	27 (9.3)
Stage at diagnosis, n (%)	Localized	201 (35.7)	94 (34.6)	107 (36.8)	0.6
Stage at diagnosis, n (%)	Metastatic	362 (64.3)	178 (65.4)	184 (63.2)	0.6
Surgery of primary tumor, n (%)	No	368 (65.4)	177 (65.1)	191 (65.6)	0.9
Surgery of primary tumor, n (%)	Yes	195 (34.6)	95 (34.9)	100 (34.4)	0.9
Liver metastasis, n (%)	No	334 (59.3)	185 (68.0)	149 (51.2)	<0.001
	Yes	162 (28.8)	63 (23.2)	99 (34.0)	<0.001
	Missing	67 (11.9)	24 (8.8)	43 (14.8)
Peritoneal metastasis, n (%)	No	250 (44.4)	102 (37.5)	148 (50.9)	<0.001
	Yes	246 (43.7)	146 (53.7)	100 (34.4)	<0.001
	Missing	67 (11.9)	24 (8.8)	43 (14.8)
Ganglionar metastasis, n (%)	No	297 (52.8)	158 (58.1)	139 (47.8)	0.082
	Yes	199 (35.3)	90 (33.1)	109 (37.5)	0.082
	Missing	67 (11.9)	24 (8.8)	43 (14.8)
Lung/pleural metastasis, n (%)	No	428 (76.0)	217 (79.8)	211 (72.5)	0.4
	Yes	68 (12.1)	31 (11.4)	37 (12.7)	0.4
	Missing	67 (11.9)	24 (8.8)	43 (14.8)
Number metastatic sites, n (%)	<2 sites	277 (49.2)	141 (51.8)	136 (46.7)	0.7
	≥2 sites	219 (38.9)	107 (39.3)	112 (38.5)	0.7
	Missing	67 (11.9)	24 (8.8)	43 (14.8)
CLDN18.2 site determination, n (%)	Metastasis	46 (8.2)	25 (9.2)	21 (7.2)	0.39
CLDN18.2 site determination, n (%)	Primary tumor	517 (91.8)	247 (90.8)	270 (92.8)	0.39
Sample antiquity	Median (range)	71 (0-8325)	69 (0-8325)	71 (0-4095)	0.6
	≥2 years	89 (15.8)	49 (18.0)	40 (13.7)	0.17
	<2 years	474 (84.2)	223 (82.0)	251 (86.3)	0.17
MMR status, n (%)	dMMR	53 (9.4)	18 (6.6)	35 (12.0)	0.03
	pMMR	467 (82.9)	232 (85.3)	235 (80.8)	0.03
	Missing	43 (7.6)	22 (8.1)	21 (7.2)
EBV status, n (%)	Positive	8 (1.4)	5 (1.8)	3 (1.0)	0.3
	Negative	194 (34.5)	84 (30.9)	110 (37.8)	0.3
	Missing	361 (64.1)	183 (67.3)	178 (61.2)
HER2 status, n (%)	Positive (3+/2+ISH+)	74 (13.1)	31 (11.4)	43 (14.8)	0.2
	Negative (0+/1+/2+ISH−)	485 (86.1)	239 (87.9)	246 (84.5)	0.2
	Missing	4 (0.7)	2 (0.7)	2 (0.7)
HER2, n (%)	3+	55 (9.8)	23 (8.5)	32 (10.9)	0.6
	2+ISH+	24 (4.3)	11 (4.0)	13 (4.5)
	2+ISH−	76 (13.5)	39 (14.3)	37 (12.7)
	1+	88 (15.6)	88 (32.4)	49 (16.8)
	0+	293 (52.0)	147 (54.0)	146 (50.2)
	Missing	27 (4.8)	13 (4.8)	14 (4.8)
PD-L1, n (%)	CPS ≥1	276 (49.0)	126 (46.3)	150 (51.4)	0.3
	CPS <1	111 (19.7)	57 (20.9)	54 (18.6)	0.3
	CPS ≥5	176 (31.3)	83 (30.5)	93 (31.9)	>0.9
	CPS <5	211 (37.5)	100 (36.8)	111 (38.1)	>0.9
	CPS ≥10	113 (20.1)	52 (19.1)	61 (20.9)	0.7
	CPS <10	274 (48.7)	131 (48.2)	143 (49.1)	0.7
	Missing	176 (31.3)	89 (32.7)	87 (29.9)

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Data are presented as n (%) unless indicated otherwise.

CLDN18.2, Claudin 18.2, CPS, combined positive score; dMMR, mismatch repair deficient; EBV, Epstein–Barr virus; EGJ, esophagogastric junction; HER2, human epidermal growth factor receptor 2; ISH, in situ hybridization; MMR, mismatch repair proteins; PD-L1, programmed death-ligand 1; pMMR, mismatch repair proficient.

CLDN18.2 biomarker overlap

CLDN18.2-high expression was detected across molecular subtypes, including 18 of 53 patients (33.9%) with dMMR, 5 of 8 (62.5%) with EBV-positive tumors, and 31 of 74 (41.9%) with HER2-positive tumors. Among patients with positive PD-L1 expression, CLDN18.2-high status was identified in 126 of 276 (45.7%) patients with CPS ≥1 and in 83 of 176 (47.2%) patients with CPS ≥5. PD-L1 expression showed no significant difference between CLDN18.2-high and CLDN18.2-low tumors (CPS ≥1: 46.3% versus 51.4%, P = 0.3; CPS ≥5: 30.5% versus 31.9%, P > 0.9). Additional molecular data are summarized in Table 1.

Overall, overlap between CLDN18.2-high expression and at least one of the following biomarkers (MMR deficiency, EBV positivity, PD-L1 CPS ≥5, or HER2 positivity) was identified in 121 (21.5%) patients (Figure 2). Coexpression of three biomarkers was observed in 17 patients, including CLDN18.2/PD-L1/EBV (n = 1), CLDN18.2/PD-L1/HER2 (n = 10), and CLDN18.2/PD-L1/dMMR (n = 6). In addition, CLDN18.2-high tumors were particularly enriched in the triple-negative (non-dMMR/EBV/HER2) subgroup.

**Biomarker overlap in gastroesophageal adenocarcinoma (GEA) stratified by PD-L1 CPS.** CLDN18.2, Claudin 18.2; CPS, combined positive score; dMMR, mismatch repair deficient; EBV, Epstein–Barr virus; HER2, human epidermal growth factor receptor 2; PD-L1, programmed death-ligand 1.

Next-generation sequencing results

Among the 563 patients included, genomic analysis using DNA- or RNA-based NGS was conducted on 123 patients. A significantly higher frequency of APC mutations was observed in CLDN18.2-low compared with CLDN18.2-high patients (10.7% versus 0%; P = 0.02). Upon exclusion of EBV-positive, MSI-H/dMMR, and HER2-positive cases (n = 97), NF1 mutations were found to be more prevalent in CLDN18.2-high than in CLDN18.2-low tumors (7.5% versus 0%; P = 0.04; Supplementary Table S2, available at https://doi.org/10.1016/j.esmoop.2025.106053). In addition, CDK6 gene amplification was significantly more frequent in CLDN18.2-low patients (10.6% versus 0%; P = 0.03). The CLDN18–ARHGAP26/6 fusion was identified in 2 of 123 patients (1.6%), both of whom presented with a diffuse histological subtype and peritoneal involvement.

Clinical outcomes of standard first-line therapy according to CLDN18.2 expression status

Of the 563 patients included, 483 received first-line treatment for advanced disease: 221 (45.8%) were treated with chemotherapy alone, 167 (34.6%) with IO-based regimens, 46 (9.5%) with HER2-targeted therapy, and 63 (13.0%) with anti-CLDN18.2 therapy.

Supplementary Table S3, available at https://doi.org/10.1016/j.esmoop.2025.106053, describes the treatment responses according to therapy type and CLDN18.2 expression. Regardless of treatment, patients with CLDN18.2-high expression showed longer mPFS (10.0 versus 7.3 months; HR 0.78, 95% CI 0.62-0.99; P = 0.043), with no significant difference in mOS (19.0 versus 18.0 months; HR 1.00, 95% CI 0.76-1.31; P > 0.9). In addition, CLDN18.2 expression at any cut-off was not associated with mOS in patients with GEA.

mPFS and mOS by first-line treatment and CLDN18.2 expression levels are summarized in Supplementary Table S4, available at https://doi.org/10.1016/j.esmoop.2025.106053.

First-line chemotherapy

A total of 221 patients received standard first-line chemotherapy with a fluoropyrimidine–platinum doublet. The ORR did not differ significantly between the CLDN18.2-high and CLDN18.2-low groups (44.7% versus 34.7%; P = 0.20; Supplementary Table S3, available at https://doi.org/10.1016/j.esmoop.2025.106053), nor after stratification by PD-L1 CPS (CPS ≥5 versus CPS <5; Supplementary Table S5, available at https://doi.org/10.1016/j.esmoop.2025.106053).

mPFS was 8.5 months in the CLDN18.2-high group and 6.4 months in the CLDN18.2-low subset (HR 0.90, 95% CI 0.65-1.23; P = 0.50). Similarly, mOS was 17.0 versus 15.0 months, with no significant difference between groups (HR 1.06, 95% CI 0.74-1.51; P = 0.80; Supplementary Figure S1, available at https://doi.org/10.1016/j.esmoop.2025.106053).

Stratification by PD-L1 expression (n = 136) using a CPS cut-off of 5 showed no significant differences in mPFS (HR 1.27; P = 0.40). A combined analysis of CLDN18.2 status and CPS revealed no significant associations: CPS ≥5/CLDN18.2-high versus CPS ≥5/CLDN18.2-low (HR 0.50; P = 0.20) and CPS <5/CLDN18.2-high versus CPS <5/CLDN18.2-low (HR 0.78; P = 0.40). A mOS analysis showed no differences by CPS expression (≥5 versus <5; HR 1.36; P = 0.40) or when CLDN18.2 status was combined with CPS: CPS ≥5/CLDN18.2-high versus CPS ≥5/CLDN18.2-low (HR 0.47; P = 0.20) and CPS <5/CLDN18.2-high versus CPS <5/CLDN18.2-low (HR 0.85; P = 0.60), as shown in Supplementary Figure S2, available at https://doi.org/10.1016/j.esmoop.2025.106053.

In both univariate and multivariate analyses, CLDN18.2 expression was not associated with mOS. The remaining analyses and variables are summarized in Supplementary Figure S3, available at https://doi.org/10.1016/j.esmoop.2025.106053.

First-line targeted HER2-based targeted therapy

Among the 46 patients who received first-line chemotherapy plus HER2-targeted therapy, the ORR was numerically higher in the CLDN18.2-high group (83.3% versus 68.4%) but did not reach statistical significance (P = 0.40; Supplementary Table S3, available at https://doi.org/10.1016/j.esmoop.2025.106053), and no differences were observed after stratification by PD-L1 expression (P >0.9; Supplementary Table S6, available at https://doi.org/10.1016/j.esmoop.2025.106053). In addition, CLDN18.2-high expression was associated with significantly longer mPFS compared with CLDN18.2-low expression (17.0 versus 8.9 months; HR 0.42, 95% CI 0.18-0.97; P = 0.03), and numerically longer mOS (43.0 versus 23.0 months; HR 0.40, 95% CI 0.15-1.11; P = 0.07), as shown in Supplementary Figure S4 and Table S4, available at https://doi.org/10.1016/j.esmoop.2025.106053.

Immunotherapy outcomes (first- and second-line treatments)

In the cohort of 167 patients treated with IO, a trend toward a lower ORR was observed in the CLDN18.2-high group compared with the CLDN18.2-low group (51.0% versus 64.0%; P = 0.15). After excluding dMMR, HER2-positive, and EBV-positive cases, the ORR remained lower in the CLDN18.2-high population (42.5% versus 60.8%; P = 0.08; Supplementary Table S3, available at https://doi.org/10.1016/j.esmoop.2025.106053). Similarly, after stratification by PD-L1 expression (CPS ≥1 and CPS ≥5), ORR was ∼10%-15% lower in CLDN18.2-high patients (Supplementary Table S7, available at https://doi.org/10.1016/j.esmoop.2025.106053).

Patients with CLDN18.2-high expression showed a tendency toward shorter mPFS (8.9 versus 14.0 months; HR 1.47, 95% CI 0.88-2.44; P = 0.14) and mOS (16.0 versus 43.0 months; HR 2.04, 95% CI 0.98-4.24; P = 0.052) compared with those with low expression (Figure 3). This trend remained consistent after excluding dMMR/MSI-H cases (Supplementary Figure S5, available at https://doi.org/10.1016/j.esmoop.2025.106053).

**(A) Progression-free survival (PFS) and (B) overall survival (OS) of immunotherapy-based treatment in first- and second-line settings according to CLDN18.2 expression.** CI, confidence interval; CLDN18.2, Claudin 18.2; HR, hazard ratio; NR, not reached.

Higher CLDN18.2 expression levels were associated with numerically poorer outcomes, affecting both mPFS (HR 0.94; P = 0.80 for ≥1% versus HR 1.47; P = 0.14 for ≥75%) and mOS (HR 1.06; P > 0.90 for ≥1% versus HR 2.04; P = 0.052 for ≥75%) (Supplementary Table S4, available at https://doi.org/10.1016/j.esmoop.2025.106053).

A combined analysis of CLDN18.2 status and PD-L1 showed a consistent trend toward poorer mPFS in patients with CLDN18.2-high tumors across PD-L1 cut-offs: CPS ≥1/CLDN-high versus CPS ≥1/CLDN-low (HR 1.26; P = 0.40), CPS ≥5/CLDN-high versus CPS ≥5/CLDN-low (HR 1.39; P = 0.30), and CPS ≥10/CLDN-high versus CPS ≥10/CLDN-low (HR 1.51; P = 0.30). Similarly, mOS was numerically shorter in the CLDN18.2-high subgroup according to CPS and CLDN18.2 expression: CPS ≥1/CLDN-high versus CPS ≥1/CLDN-low (HR 2.42; P = 0.058), CPS ≥5/CLDN-high versus CPS ≥5/CLDN-low (HR 2.25; P = 0.082), and CPS ≥10/CLDN-high versus CPS ≥10/CLDN-low (HR 2.92; P = 0.073; Figure 4).

**Progression-free survival (PFS) and overall survival (OS) in patients receiving immunotherapy in first- or second-line settings.** Combined analysis of CLDN18.2 expression (high versus low) and PD-L1 CPS [CPS ≥1 (A, D), CPS ≥5 (B, E), and CPS ≥10 (C, F)]. CI, confidence interval; CLDN18.2, Claudin 18.2; CPS, combined positive score; HR, hazard ratio; NR, not reached; PD-L1, programmed death-ligand 1.

In univariate analysis, dMMR/MSI-H status was associated with improved mOS, while in multivariate analysis, CLDN18.2-high status tended to correlate with worse mOS (Supplementary Figure S6, available at https://doi.org/10.1016/j.esmoop.2025.106053).

In the comparative analysis of chemotherapy versus chemoimmunotherapy in patients with PD-L1-positive tumors (CPS ≥5), stratified by CLDN18.2 status (high versus low), the addition of IO conferred a significantly greater benefit in the CLDN18.2-low subgroup, with improved mPFS (12.0 versus 3.4 months; HR 5.05; P < 0.001) and mOS (43.0 versus 3.4 months; HR 11.0; P < 0.001), but not in patients with CLDN18.2-high tumors (Supplementary Figure S7, available at https://doi.org/10.1016/j.esmoop.2025.106053).

Discussion

We conducted an ambispective study to analyze the pathological and molecular features, and the clinical outcomes, in a European cohort of 563 patients with advanced GEA who received chemotherapy, HER2-targeted therapy, and an IO-based regimen, using different expression cut-offs for CLDN18.2 and PD-L1.

Recent studies have evaluated the clinicopathological features and biomarker overlap in GEA, as well as the potential predictive and prognostic value of CLDN18.2 status in patients receiving chemotherapy, mainly in Asian cohorts.²⁷^,²⁸ However, inconsistencies have been reported across studies due to differences in antibodies, geographic variations, and evolving criteria for defining CLDN18.2-positive GEA. In our cohort, 48.3% of patients exhibited CLDN18.2 expression ≥75%, ∼10% higher than previously reported,²¹^,²⁷^,²⁸ whereas 62.9% showed ≥25% expression, indicating a substantial targetable population and supporting the potential relevance of antibody–drug conjugates (ADCs), which are active at lower expression levels.

As reported in other studies, in our cohort, CLDN18.2-high expression was significantly associated with diffuse-type histology,²⁹^,³⁰ peritoneal involvement, and a lower incidence of liver metastases.⁷ Indeed, while Hong et al.²⁹ and Waters et al.³¹ reported an association between CLDN18.2 expression and diffuse-type GEA, a recent meta-analysis found no significant correlation with Lauren classification.³²

Compared with the study by Malla et al.,³³ our cohort also showed a significantly lower proportion of APC mutations in CLDN18.2-low tumors. However, we did not identify a higher incidence of KRAS alterations in the CLDN18.2-high population, as reported in other series.²⁸^,³³

As shown by Kubota et al.,²⁸ we found that CLDN18.2-high tumors were described across all four molecular subtypes identified in GEA TCGA, including dMMR, EBV-positive, and HER2-positive tumors, suggesting that CLDN18.2 could be a broadly targetable molecular marker. Particularly, we identified a significant association between mismatch repair proficient (pMMR) tumors and CLDN18.2-high expression. In addition, although it was not statistically significant and limited by the small EBV-tested subgroup, CLDN18.2-high expression appeared more frequent in EBV-positive tumors, consistent with prior reports indicating an 80%-85% prevalence in this subtype.⁷^,³² While studies by Qi et al.³⁴ and Kadono et al.³⁵ reported ∼10% lower PD-L1 expression in patients with CLDN18.2-high tumors, we did not observe differences in the proportion of PD-L1 positivity (CPS cut-off of 1, 5, or 10) based on CLDN18.2 expression⁷^,²⁸ in our cohort.

Consistent with our findings, recent studies have shown that CLDN18.2 status does not impact survival in either localized disease (as reported by Ungureanu et al.³⁶) or metastatic settings.²⁵^,³⁰^,³²^,³⁷ Specifically, Kubota et al.²⁸ found no differences in mPFS or mOS of patients receiving chemotherapy, and Cox analyses by Kayikcioglu et al.³⁸ showed no association between CLDN18.2 and mOS.

To date, research and development of CLDN18.2-targeted therapies have primarily focused on the HER2-negative population,³⁹ and the impact of CLDN18.2 status on the efficacy of anti-HER2 treatment remains unknown. In our cohort, patients with CLDN18.2-low expression who received HER2-targeted therapy consistently showed poorer mPFS and mOS. However, interpretation is limited by the small sample size of this subgroup and the lack of supporting evidence in the literature. These findings suggest a potential predictive and prognostic role of CLDN18.2 status in this context, warranting further investigation.

IO-based strategies constitute the first-line treatment for advanced GEA, and a significant proportion of patients present with PD-L1 CPS ≥5 (30%-60%).¹¹^,³⁹ A meaningful mOS benefit has been demonstrated with the addition of IO to chemotherapy in metastatic HER2-negative, PD-L1-positive GEA, as shown in the phase III trials CheckMate-649,⁴⁰ KEYNOTE-859,⁴¹ and RATIONALE-305.⁴² However, the efficacy of IO according to CLDN18.2 status remains poorly defined. Although not statistically significant, our cohort showed worse outcomes in the CLDN18.2-high group, and there was a trend toward poorer results with increasing CLDN18.2 expression cut-off values. The predictive and prognostic significance of CLDN18.2 positivity requires further investigation, particularly in the light of different cut-off definitions and the growing use of ICIs. In previous studies focused on Asian populations,²⁸^,34, 35, 36 no significant differences in IO efficacy were observed according to CLDN18.2 status in first-line or refractory settings.⁴³^,⁴⁴ By contrast, Qi et al.³⁴ reported worse ORR and mPFS among 83 patients treated with IO in the first- or second-line setting, with no evidence of a synergistic antitumor effect by adding IO to chemotherapy in the CLDN18.2-high population. They also found that PD-L1 expression was not associated with IO outcomes, consistent with our findings. Similarly, Malla et al.³³ observed worse mPFS with pembrolizumab in CLDN18.2-high versus CLDN18.2-low patients. Conversely, CLDN18.2-positive GEA exhibits higher proportions of CD8+ T cells lacking PD-1, lymphocyte-activation gene 3 (LAG3), and T-cell immunoglobulin and mucin domain-containing-3 (TIM3) expression and reduced natural killer cell infiltration, as reported by Jia et al.,²⁴ a profile associated with poor prognosis.⁴⁵ In CLDN18.2-positive patients, poorer outcomes with IO (mOS 10.0 versus 20.1 months; P = 0.04) were reported. In addition, CD68 levels, reflecting tumor-associated macrophages, are increased in CLDN18.2-positive tumors.²⁸ These cells contribute to angiogenesis and modulation of the immune microenvironment,⁴⁶^,⁴⁷ promoting an immunoresistant state through immunosuppressive mechanisms and tumor microenvironment remodeling.

In the current therapeutic landscape, marked by biomarker overlap and heterogeneity, as well as multiple treatment options for advanced GEA, our data support biomarker-driven patient stratification to guide personalized treatment strategies. Notably, the ∼40% coexpression of CLDN18.2 and PD-L1 defines a substantial subgroup in which the current first-line therapeutic dilemma, chemoimmunotherapy versus CLDN18.2-targeted therapy, both approved options, is most pressing.⁴⁸^,⁴⁹

We suggest that CLDN18.2-high tumors harbor distinct clinicopathological and molecular characteristics and have poorer outcomes with IO-based strategies, potentially supporting the use of anti-CLDN18.2 therapy over IO, regardless of the PD-L1 threshold. This hypothesis requires prospective validation and further translational research to confirm its clinical relevance. Furthermore, the spatial and temporal heterogeneity of GEA, reflected by dynamic biomarker changes, including the ∼20% variation in CLDN18.2 expression during chemoimmunotherapy (Lim et al.⁵⁰), underscores the need for more adaptive therapeutic strategies.

This context strongly supports combination strategies,⁵¹ in which safety is as pivotal as efficacy, and warrants prospective validation. Ongoing trials include the phase II ILUSTRO⁵² study and the phase III LUCERNA trial (NCT06901531),⁵³ evaluating combinations of chemotherapy, pembrolizumab, and zolbetuximab. Currently, patients with CLDN18.2 expression <75% represent a distinct therapeutic niche, supporting the development of emerging modalities such as ADCs, bispecific antibodies, and chimeric antigen receptor T-cells, active at lower expression levels.¹⁵ Notably, the CLDN18.2-targeted ADC AZD0901 is under advanced evaluation in the CLARITY-Gastric 01⁵⁴ (monotherapy) and GEMINI-Gastric⁵⁵ (combination with IO) trials.

Our study has several strengths, including a large multicenter European cohort that enhances the applicability of the findings, the standardized CLDN18.2 assessment aligned with pivotal phase III trials, and a comprehensive molecular profiling by NGS in a substantial subset of patients. However, the retrospective design introduces potential selection bias; the local determination of biomarkers and the incomplete biomarker testing across the cohort may limit the interpretation of the findings. A major limitation is the lack of EBV status in 64.1% of cases, as EBV is not a guideline-recommended biomarker and is therefore not routinely assessed in many hospitals. Likewise, PD-L1 CPS data were missing in 31.3% of patients, introducing additional bias and potentially affecting the accuracy of biomarker-overlap prevalence estimates in these subgroups. In addition, spatial heterogeneity must be considered, as most analyses were carried out on primary tumor samples, which may not fully capture the biomarker profile of metastatic lesions.

Overall, the critical next step is to generate robust prospective evidence to optimize these tailored approaches for each molecular subgroup, integrating clinicopathological features, toxicity profiles, and individual preferences to maximize clinical benefit for our patients.

Acknowledgements

E. Terán gratefully acknowledges the grant received from the Spanish Society of Medical Oncology (SEOM) "SEOM Somos Futuro 2025". We also express our sincere gratitude to the patients, their families, and caregivers, as well as to all the participating centers, for their invaluable contributions to this study. We extend special recognition to MA and CH for their valuable support in the critical review and proofreading of the manuscript.

Funding

None declared.

Disclosure

ET reports speaking honoraria from BMS, MSD, Merck, Daiichi Sankyo, Jazz Pharmaceuticals, and AstraZeneca; and travel support and expenses from BMS, MSD, Lilly, Astellas, and Jazz Pharmaceuticals. RP reports speaking honoraria from Astellas, AstraZeneca, BMS, Eisai, Lilly, Roche, and Servier; and advisory board participation for Astellas, AstraZeneca, BMS, Ipsen, Roche, and Servier. MA reports speaking honoraria from Astellas, BeiGene, and Jazz Pharmaceuticals; and consulting and/or advisory board participation for Amgen, Astellas, AstraZeneca, BeiGene, Daiichi Sankyo, Dragonfly Therapeutics, Jazz Pharmaceuticals, BMS, Novartis, and MSD. CH reports speaking honoraria from AstraZeneca, BMS, Jazz Pharmaceuticals, Lilly, MSD, and Merck; and research funding to his institution from Merck. CB reports speaking honoraria from AstraZeneca, BMS, Roche, and Servier. SL reports speaking honoraria from Astellas. LV reports speaking honoraria from BMS, AstraZeneca, and Incyte; and travel support and expenses from BMS, AstraZeneca, and MSD. AL reports speaking honoraria from BMS, Amgen, AstraZeneca, Eisai, MSD, Roche, Servier, Astellas, Takeda, and BeOne; and advisory roles for Amgen, AstraZeneca, Eisai, and Roche. RVT reports honoraria as a speaker and/or advisory board member from Amgen, Merck, Servier, BMS, MSD, GSK, Roche, Pierre Fabre, and Astellas; and travel support and expenses from Amgen, Roche, Merck, Lilly, Bristol Myers Squibb, Pierre Fabre, MSD, and Servier. IA reports speaking honoraria from AstraZeneca, MSD, Lilly, Servier, and BMS; travel support and expenses from AstraZeneca, BMS, Roche, and Servier; and advisory board participation for AstraZeneca, MSD, Jazz Pharmaceuticals, and BMS. SF reports advisory board participation for BMS, Servier, Amgen, and Astellas. BGP reports honoraria as a speaker and/or advisory board member from Amgen, AAA, Servier, Roche Farma, Novartis, Eisai, MSD, BMS, GlaxoSmithKline, and AstraZeneca; and travel support and expenses from Servier, Novartis, Merck, Roche Farma, Ipsen, MSD, Amgen, BMS, and AstraZeneca. LF reports speaking honoraria from Incyte, Bristol Myers Squibb, and Lilly; institutional research funding from MSD, Bristol Myers Squibb, AstraZeneca, Incyte, BeiGene, Astellas, Daiichi Sankyo, and Roche; and advisory board participation for MSD, AstraZeneca, Incyte, Taiho, Servier, Daiichi Sankyo, Lilly, and Astellas. TS reports speaking honoraria from BMS, BeiGene, MSD, AstraZeneca, and Astellas; advisory board participation for BMS, Amgen, and Daiichi Sankyo; and travel support and expenses from BMS, MSD, and Daiichi Sankyo. IM reports speaking honoraria from Amgen, AstraZeneca, BeiGene, BMS, Daiichi Sankyo, MSD, Pierre Fabre, Roche, and Sanofi; advisory board participation for Amgen; and travel support and expenses from Ipsen, Jazz Pharmaceuticals, and Merck. JMH reports speaking honoraria from AstraZeneca; and advisory board participation for Astellas, AstraZeneca, and BMS. CBu reports speaking honoraria from BMS, Regeneron Pharmaceuticals, Astellas, and AstraZeneca. PR reports speaking honoraria from Merck, BMS, and AstraZeneca; and travel support and expenses from Merck, Amgen, and Takeda. DA reports speaking honoraria from BMS, MSD, Daiichi Sankyo, and AstraZeneca; and travel support and expenses from BMS, MSD, Lilly, and Jazz Pharmaceuticals. AV reports consulting or advisory board participation for Guardant Health, Merck, Roche, BMS, Incyte, and Bayer; and research funding from BMS, Roche, and Incyte. TVT reports speaking honoraria from AstraZeneca, Incyte, and Jazz Pharmaceuticals; and research funding to his institution from AstraZeneca, LOXO Oncology, Servier, Alentis, and Incyte. JT reports personal financial interests through scientific consultancy roles for Accent Therapeutics, Alentis Therapeutics, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Carina Biotech, Cartography Biosciences, Chugai, Daiichi Sankyo, F. Hoffmann La Roche, Genentech, Johnson & Johnson/Janssen, Lilly, Marengo Therapeutics, Menarini, Merus, MSD, Novartis, Ono Pharma USA, Peptomyc, Pfizer, Pierre Fabre, QUANTRO Therapeutics, Scandion Oncology, Scorpion Therapeutics, Servier, SOTIO Biotech, syntelios AG, Taiho, Takeda Oncology, and TOLREMO Therapeutics; and stock ownership in Alentis Therapeutics, ONIRIA Therapeutics, 1TRIALSP, and Pangaea Oncology. EE reports speaking honoraria from Organon and Novartis; personal advisory board honoraria from Amgen, Bayer, F. Hoffmann La Roche, Merck Serono, Sanofi, Pfizer, Pierre Fabre, MSD, and Servier; travel support and expenses from Amgen, Array Biopharma, Bristol Myers Squibb, Merck Serono, Pfizer, Roche, Sanofi, and Servier; and research funding from Amgen Inc., Array Biopharma Inc., AstraZeneca Pharmaceuticals LP, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Debiopharm International SA, F. Hoffmann La Roche Ltd., Genentech Inc., HalioDx SAS, Hutchison MediPharma International, Janssen-Cilag SA, MedImmune, Menarini, Merck Health KGaA, Merck Sharp & Dohme, Merus NV, Mirati, Novartis Farmacéutica SA, Pfizer, Pharma Mar, Sanofi Aventis Recherche & Développement, Servier, and Taiho Pharma USA Inc. TM reports advisory board participation for Amgen, Servier, Incyte, Sanofi, AstraZeneca, Taiho, Celgene, and Eisai; research funding from Celgene, AstraZeneca, BeiGene, and Incyte; and speaking honoraria from AstraZeneca, Incyte, Servier, Roche, and Eisai. LC, MR, SL, AZ, AC, VG, CA, EM, and JM have declared no conflicts of interest.

Contributor Information

E. Terán, Email: eduardoteran@vhio.net.

T.V. Tian, Email: tiantian@vhio.net.

T. Macarulla, Email: macarulla@clinic.cat.

Supplementary data

Supplementary Tables

mmc1.docx^{(489.9KB, docx)}

Supplementary Figures

mmc2.docx^{(1.3MB, docx)}

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PERMALINK

Claudin 18.2 expression in gastroesophageal adenocarcinoma: biomarker overlap and association with clinical outcomes in a European cohort

E Terán

R Pazo

L Caritá

M Alsina

C Hierro

C Blanco

M Reboredo

S Landolfi

A Zucchiatti

L Visa

A Calvo

A López

R Vidal-Tocino

C Agra

I Alés

S Foti

B García-Paredes

V Genovesi

L Fornaro

T Sauri

I Macías

E Martínez

J Martínez

C Buges

P Ribera

JM Herranz

D Acosta

A Vivancos

J Tabernero

E Élez

TV Tian

T Macarulla

Abstract

Background

Methods

Results

Conclusions

Highlights

Background

Methods

Patient selection

Molecular evaluation

Statistical analysis and oncological outcomes

Results

Clinicopathological and molecular features

Figure 1.

Table 1.

CLDN18.2 biomarker overlap

Figure 2.

Next-generation sequencing results

Clinical outcomes of standard first-line therapy according to CLDN18.2 expression status

First-line chemotherapy

First-line targeted HER2-based targeted therapy

Immunotherapy outcomes (first- and second-line treatments)

Figure 3.

Figure 4.

Discussion

Acknowledgements

Funding

Disclosure

Contributor Information

Supplementary data

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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