Keun-Wook Lee; Sang Cheul Oh; Jong Gwang Kim; Sun Jin Sym; Byoung Yong Shim; Seok Yun Kang; In-Ho Kim; Jwa Hoon Kim; Hong Jae Chon; Sang-Hee Cho; Eun-Kee Song; Do-Youn Oh; Jin-Soo Kim; Young Iee Park; Won Ki Kang; Hyung-Don Kim; Janise Lee; Miri Yi; Min-Hee Ryu

doi:10.4143/crt.2025.935

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Original Article Zolbetuximab Plus Chemotherapy as First-Line Treatment in Patients with Claudin 18.2–Positive, HER2-Negative, Locally Advanced Unresectable or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma: Korean Population Subgroup—Combined Efficacy and Safety Analysis from SPOTLIGHT and GLOW: Keun-Wook Lee¹, Sang Cheul Oh², Jong Gwang Kim³, Sun Jin Sym⁴, Byoung Yong Shim⁵, Seok Yun Kang⁶, In-Ho Kim⁷, Jwa Hoon Kim⁸, Hong Jae Chon⁹, Sang-Hee Cho¹⁰, Eun-Kee Song¹¹, Do-Youn Oh^12,13, Jin-Soo Kim¹⁴, Young Iee Park¹⁵, Won Ki Kang¹⁶, Hyung-Don Kim¹⁷, Janise Lee¹⁸, Miri Yi¹⁹, Min-Hee Ryu¹⁷; DOI: https://doi.org/10.4143/crt.2025.935
Published online: December 5, 2025

¹Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea

²Department of Internal Medicine, Korea University Guro Hospital, Seoul, Korea

³Department of Oncology/Hematology, Kyungpook National University Chilgok Hospital, Daegu, Korea

⁴Department of Medical Oncology, Gachon University Gil Medical Center, Incheon, Korea

⁵Division of Medical Oncology, Department of Internal Medicine, The Catholic University of Korea St. Vincent's Hospital, Suwon, Korea

⁶Department of Hematology-Oncology, Ajou University School of Medicine, Suwon, Korea

⁷Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea

⁸Division of Medical Oncology, Department of Internal Medicine, Korea University Anam Hospital, Seoul, Korea

⁹Department of Medical Oncology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea

¹⁰Division of Hemato-Oncology, Department of Internal Medicine, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Hwasun, Korea

¹¹Division of Oncology and Hematology, Department of Internal Medicine, Jeonbuk National University Hospital, Jeonbuk National University Medical School, Jeonju, Korea

¹²Division of Medical Oncology, Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea

¹³Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea

¹⁴Department of Internal Medicine, SMG-SNU Boramae Medical Center, Seoul, Korea

¹⁵Center for Gastric Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Korea

¹⁶Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

¹⁷Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

¹⁸Astellas Pharma Singapore Pte. Ltd., Singapore

¹⁹Medical Affairs, Astellas Pharma Korea Inc., Seoul, Korea

Correspondence: Min-Hee Ryu, Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea
Tel: 82-2-3010-5935 E-mail: miniryu@amc.seoul.kr

^*Some content from this manuscript was previously presented at the 2024 American Association for Cancer Research – Korean Cancer Association (AACR-KCA) Joint Conference on Precision Medicine in Cancer; November 21-22, 2024; Seoul, Korea.

• Received: August 28, 2025 • Accepted: December 4, 2025

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Abstract

Purpose
The phase 3 SPOTLIGHT and GLOW trials in patients with claudin 18 isoform 2–positive, human epidermal growth factor receptor 2–negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma demonstrated statistically significant and clinically meaningful improvement in progression-free survival (PFS) and overall survival (OS) with first-line zolbetuximab plus chemotherapy versus placebo plus chemotherapy. This analysis evaluated efficacy and safety in the Korean subgroup from SPOTLIGHT and GLOW.
Materials and Methods
Patients were randomly assigned 1:1 to receive zolbetuximab plus chemotherapy or placebo plus chemotherapy (mFOLFOX6 [modified folinic acid, 5-fluorouracil, and oxaliplatin] or CAPOX [capecitabine and oxaliplatin]). Primary endpoint was PFS, assessed per Response Evaluation Criteria in Solid Tumors version 1.1 by an independent review committee. Other efficacy and safety parameters were assessed.
Results
The Korean subgroup consisted of 49 patients in the zolbetuximab group and 47 in the placebo group. Median PFS (95% confidence interval) was 12.3 months (7.3 to 15.3), and median OS was 30.5 months (16.1 to 45.5) with zolbetuximab versus 8.1 months (4.2 to 10.4) and 15.8 months (11.8 to 19.7) with placebo, respectively. Most common treatment-emergent adverse events (TEAEs) in patients who received zolbetuximab versus placebo were nausea (79.6% vs. 53.2%), vomiting (55.1% vs. 21.3%), and decreased appetite (53.1% vs. 23.4%). Treatment-related TEAEs led to discontinuation of zolbetuximab and placebo in 4.1% and 2.1% of patients, respectively.
Conclusion
Zolbetuximab plus chemotherapy demonstrated favorable PFS and OS versus placebo plus chemotherapy in the Korean subgroup, with numerically greater efficacy compared with the overall pooled population. This may be potentially attributable to low rates of zolbetuximab discontinuation and toxicity management.
Key words: Zolbetuximab, Drug therapy, Stomach neoplasms, Adenocarcinoma, Claudins, Korea, Asia

Introduction

Gastric cancer is the fifth most common cancer in the world, with a global incidence of more than 950,000 new cases in 2022, comprising about 5% of all cancer cases [1]. Moreover, mortality is high, representing almost 7% of all cancer deaths, with approximately 650,000 deaths worldwide in 2022.

Although gastric cancer occurs worldwide, its incidence is higher in Eastern Asia than in any other global region, with Korea bearing a particularly high burden [1-5]. In Korea, 2021 data revealed that stomach cancer was the fourth most commonly diagnosed cancer, with almost 30,000 new cases and > 7,000 deaths [3,4]. Despite decreases in mortality due to gastric cancer in Korea from 1990 to 2020 [6,7], it still carries a significant burden of disease. According to a 2020 claims analysis of the socioeconomic burden of cancer in Korea from 2011 to 2015, incidence and mortality rates for stomach cancer were among the highest of all cancer types, and one of the most costly for patients [8]. This is supported by another claims analysis using data from 2008 to 2018 from the National Health Insurance Service of Korea [9]. Of all cancer types assessed, stomach cancer had the second-highest rates of disability-adjusted life-years.

Guidelines from the United States, Europe, and Asia recommend platinum/fluoropyrimidine-based chemotherapy for first-line treatment of metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma [3,10-14]. More specific recommendations depend on molecular biomarkers, including human epidermal growth factor receptor 2 (HER2), level of microsatellite instability, and programmed death ligand 1 combined positive score [3,10-12,14,15]. Combining chemotherapy with agents that specifically target these markers and others can potentially improve survival and clinical outcomes [15-17].

Another potential molecular target in the treatment of mG/GEJ adenocarcinoma is claudin 18 isoform 2 (CLDN18.2) [18,19]. CLDN18 is a tight junction protein normally expressed only in the stomach mucosa. However, during malignant transformation, changes in cell polarity may cause CLDN18.2 to become exposed on the surface of adenocarcinoma cells, thereby making it an accessible target for monoclonal antibody-based therapies. CLDN18.2 expression has been observed in 77% of primary gastric adenocarcinomas, with 56% of these demonstrating CLDN18.2 staining intensity of ≥ 2+ in at least 60% of tumor cells; of note, CLDN18.2 expression has also been observed in gastric cancer metastases [18].

Zolbetuximab (Astellas Pharma, Inc.) is a first-in-class, chimeric IgG1 monoclonal antibody that targets CLDN18.2 and mediates death of CLDN18.2-positive G/GEJ adenocarcinoma cells through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity [19]. Two global, randomized, double-blind, placebo-controlled, phase 3 trials investigated efficacy and safety of first-line zolbetuximab plus chemotherapy in patients with HER2-negative, locally advanced (LA) unresectable or mG/GEJ adenocarcinoma whose tumors were CLDN18.2-positive [20,21].

The SPOTLIGHT trial evaluated zolbetuximab in combination with intravenous infusion of modified folinic acid, 5-fluorouracil, and oxaliplatin (mFOLFOX6) compared with placebo plus mFOLFOX6 [21]. The GLOW trial assessed zolbetuximab plus capecitabine and oxaliplatin (CAPOX) versus placebo plus CAPOX [20]. In SPOTLIGHT, zolbetuximab plus mFOLFOX6 demonstrated prolonged median progression-free survival (PFS; 11.0 vs. 8.9 months; hazard ratio [HR], 0.73; 95% confidence interval [CI], 0.59 to 0.91) and prolonged median overall survival (OS; 18.2 vs. 15.6 months; HR, 0.78; 95% CI, 0.64 to 0.95) compared with placebo plus mFOLFOX6 [22]. In GLOW, zolbetuximab plus CAPOX demonstrated prolonged median PFS (8.2 vs. 6.8 months; HR, 0.69; 95% CI, 0.55 to 0.86) and prolonged median OS (14.3 vs. 12.2 months; HR, 0.76; 95% CI, 0.62 to 0.94) compared with placebo plus CAPOX [22].

These clinically meaningful and statistically significant results showed the benefit of zolbetuximab combined with chemotherapy in the treatment of patients with CLDN18.2-positive, HER2-negative, LA unresectable or mG/GEJ adenocarcinoma. Given the high prevalence of gastric cancer in Asia, particularly in Korea [1-3], a subgroup analysis of the pooled SPOTLIGHT and GLOW data was conducted in Korean patients. To place results from Korea in context, efficacy and safety were also assessed in a pan-Asian subgroup of the combined SPOTLIGHT and GLOW patient population. The aim of this exploratory post hoc subgroup analysis was to investigate the efficacy and safety of zolbetuximab plus chemotherapy in Korean patients with CLDN18.2-positive, HER2-negative, LA unresectable or mG/GEJ adenocarcinoma.

Materials and Methods

1. Study design and participants

Full details of the global, randomized (1:1), placebo-controlled, double-blind, phase 3 SPOTLIGHT and GLOW trials, and the pooled analysis of the two trials, were published previously [20-22]. Eligible patients were adults (aged ≥ 18 years) with HER2-negative, previously untreated, LA unresectable or mG/GEJ adenocarcinoma whose tumors were CLDN18.2-positive [20-22]. CLDN18.2 positivity was defined as moderate-to-strong membranous CLDN18 staining in ≥ 75% of tumor cells as determined by central immunohistochemistry using the VENTANA CLDN18 (43-14A) RxDx Assay (for Investigational Use Only, Roche Diagnostics). In both trials, randomization was stratified according to region (Asia vs. non-Asia), number of organs with metastases (0-2 vs. ≥ 3), and prior gastrectomy (yes vs. no).

This pooled analysis focused on patients from Korea enrolled in SPOTLIGHT and GLOW, defined as patients who indicated Korean ethnicity in their demographic profiles. An analysis of patients from a pan-Asian subgroup (including patients from mainland China, Japan, Malaysia, Republic of Korea, Taiwan, and Thailand) was also conducted to place the Korean subgroup data in context.

2. Treatments

In SPOTLIGHT, patients received either intravenous infusions of zolbetuximab 800 mg/m² (cycle 1, day 1) followed by 600 mg/m² (cycle 1, day 22, and days 1 and 22 of subsequent cycles) plus mFOLFOX6 (folinic acid 400 mg/m²; 5-fluorouracil 400 mg/m² bolus followed by 2,400 mg/m² in a 46-hour to 48-hour infusion; and oxaliplatin 85 mg/m²) on days 1, 15, and 29 or placebo plus mFOLFOX6 for four 42-day cycles [21]. Patients without disease progression continued beyond 4 cycles with zolbetuximab or placebo, plus folinic acid and 5-fluorouracil at the investigator’s discretion. In GLOW, patients received either intravenous infusions of zolbetuximab 800 mg/m² (cycle 1, day 1) followed by 600 mg/m² (day 1 of subsequent cycles) plus CAPOX (capecitabine 1,000 mg/m² taken orally twice daily on days 1 through 14; oxaliplatin 130 mg/m² administered intravenously on day 1) or placebo plus CAPOX for eight 21-day cycles [20]. Patients without disease progression continued beyond 8 cycles with zolbetuximab or placebo plus capecitabine at the investigator’s discretion. Treatment continued until disease progression, development of toxicity, start of another anticancer treatment, or other discontinuation criteria were met.

3. Endpoints and assessments

The primary endpoint in both trials was PFS, defined as the time from the date of randomization until the date of radiological progressive disease (per Response Evaluation Criteria in Solid Tumors version 1.1 [RECIST v1.1] by independent review committee [IRC]) or death from any cause, whichever was earliest. A key secondary endpoint was OS (defined as the time from the date of randomization until the date of death from any cause), and an additional secondary endpoint was objective response rate (ORR; defined as the proportion of patients who had a best overall response of complete or partial response per RECIST v1.1 by IRC). Adverse events, graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03, were monitored throughout the trials and for 90 days after treatment discontinuation.

4. Statistical analysis

Statistical methods of the individual SPOTLIGHT and GLOW trials and the combined analysis across the two trials, have been published [20-22]. The analytical approach for the combined analysis of efficacy and safety followed the methods of the individual trials per the combined statistical analysis plan. For the individual studies, a stratified log-rank test—based on the randomization stratification factors—was used to compare efficacy (PFS and OS) between the two treatment groups. In the combined analysis, study identifier (SPOTLIGHT or GLOW) was included as an additional stratification factor. Unless otherwise specified, efficacy was assessed in the full analysis set, which included all Korean patients enrolled in SPOTLIGHT and GLOW who were randomly assigned to treatment. Safety was assessed in the safety analysis set that included all patients who received at least one dose of any study drug.

Results

1. Patient characteristics in the Korean subgroup

The data cutoff date for SPOTLIGHT was September 8, 2023 and for GLOW was January 12, 2024. Within the pooled population of patients enrolled in SPOTLIGHT and GLOW, 96 patients from Korea were included in the full analysis set: 49 patients who received zolbetuximab plus chemotherapy (zolbetuximab group) and 47 who received placebo plus chemotherapy (placebo group) (Table 1). Median age was 57.0 years (range, 28 to 78 years) versus 58.0 years (range, 22 to 83 years), and a majority of patients were male (67.3% vs. 63.8%) in the zolbetuximab versus placebo groups, respectively. The primary site of disease was the stomach for 91.8% of patients in the zolbetuximab group and 95.7% in the placebo group.

2. Efficacy in the Korean subgroup

Median PFS (95% CI) in the full analysis set, as assessed per RECIST v1.1 by IRC, was 12.3 months (7.3 to 15.3) in patients who received zolbetuximab plus chemotherapy compared with 8.1 months (4.2 to 10.4) in patients who received placebo plus chemotherapy (HR, 0.588; 95% CI, 0.350 to 0.986; p=0.022) (Fig. 1). Median follow-up (95% CI) for PFS was 26.1 months (20.8 to 40.2) in the zolbetuximab group and 23.5 months (12.0 to 40.0) in the placebo group.

In the PFS subgroup analysis, zolbetuximab plus chemotherapy numerically improved PFS over placebo plus chemotherapy among male patients and those with ≥ 3 metastatic sites (S1 Fig.).

Median OS (95% CI) was 30.5 months (16.1 to 45.5) in the zolbetuximab group and 15.8 months (11.8 to 19.7) in the placebo group (HR, 0.480; 95% CI, 0.279 to 0.824; p=0.003) (Fig. 2). Median follow-up (95% CI) for OS was 36.0 months (29.5 to 43.6) in the zolbetuximab group and 41.0 months (32.9 to 42.5) in the placebo group.

In the OS subgroup analysis, zolbetuximab was numerically favored over placebo among male patients, those with ≥ 3 metastatic sites, and among those without prior gastrectomy (S2 Fig.).

ORR (95% CI) in patients with measurable disease was 47.2% (30.4%-64.5%) in the zolbetuximab group and 58.6% (38.9%-76.5%) in the placebo group (Table 2).

3. Safety in the Korean subgroup

All patients in the zolbetuximab group and 95.7% of patients in the placebo group experienced at least 1 treatment-related adverse event (TRAE) (Table 3). Serious TRAEs were noted in 22.4% and 6.4% of patients in the zolbetuximab and placebo groups, respectively. TRAEs leading to discontinuation of zolbetuximab occurred in 4.1% of patients, and TRAEs leading to discontinuation of placebo occurred in 2.1% of patients. No TRAEs led to death in either treatment arm.

The most common all-grade treatment-emergent adverse event (TEAE) in both groups was nausea (79.6% in the zolbetuximab group; 53.2% in the placebo group) (Fig. 3). Other TEAEs that occurred more frequently in the zolbetuximab group versus the placebo group included vomiting (55.1% vs. 21.3%) and decreased appetite (53.1% vs. 23.4%), respectively. The most common TEAE of grade ≥ 3 in both groups was decreased neutrophil count (30.6% in the zolbetuximab group and 29.8% in the placebo group).

4. Efficacy and safety in the pan-Asian subgroup

In the pan-Asian subgroup (n=254 in the zolbetuximab group; n=255 in the placebo group in the full analysis set), median PFS (95% CI) was 10.4 months (8.5 to 12.5) in the zolbetuximab group and 7.2 months (6.2 to 8.2) in the placebo group (HR, 0.579; 95% CI, 0.459 to 0.731) (S3 Fig.). Median OS (95% CI) was 18.2 months (16.2 to 19.7) in the zolbetuximab group and 13.1 months (11.2 to 15.0) in the placebo group (HR, 0.684; 95% CI, 0.554 to 0.844) (S4 Fig.). In the safety analysis set of the pan-Asian subgroup, TEAEs led to discontinuation of zolbetuximab in 37 patients (14.6%) and to discontinuation of placebo in 32 patients (12.8%).

Discussion

In this subgroup analysis of patients from Korea enrolled in SPOTLIGHT and GLOW, the combination of zolbetuximab plus chemotherapy (mFOLFOX6 or CAPOX) demonstrated numerical and clinically meaningful improvements in both PFS and OS compared with placebo plus chemotherapy. Zolbetuximab plus chemotherapy also demonstrated a tolerable and manageable safety profile in patients from Korea. Although the results demonstrate promising efficacy in patients from Korea who were treated with zolbetuximab plus chemotherapy, this was a post hoc analysis of a subgroup that was not prespecified, and the data should be considered with that caveat.

Although direct comparisons are not possible, PFS and OS in the Korean subgroup appear to be numerically longer than those from the overall population in the pooled analysis of SPOTLIGHT and GLOW [22]. In the Korean population, median PFS was 12.3 months in the zolbetuximab group and 8.1 months in the placebo group; median OS was 30.5 months with zolbetuximab and 15.8 months with placebo. In contrast, in the overall pooled population, median PFS was 9.2 months and 8.2 months in the zolbetuximab and placebo groups, respectively (HR, 0.71; 95% CI, 0.61 to 0.83); median OS in the overall pooled population was 16.4 months in the zolbetuximab group and 13.7 months in the placebo group (HR, 0.77; 95% CI, 0.67 to 0.89) [22]. Of note, these survival outcomes in the Korean subgroup also appeared numerically favorable compared with those in the pan-Asian subgroup. In the pan-Asian subgroup, median PFS was 10.4 months with zolbetuximab and 7.2 months with placebo, while median OS was 18.2 months and 13.1 months, respectively.

Although this subgroup analysis was not designed to explore reasons for the potentially more favorable efficacy and survival outcomes of zolbetuximab plus chemotherapy in Korean patients compared with those from other regions, the observed results may have been influenced by improved toxicity management and lower rates of zolbetuximab discontinuation, leading to higher overall treatment exposure. Rates of TRAEs leading to discontinuation of zolbetuximab were lower in the Korean subgroup (4.1%) than in the overall pooled population (10.5%) [22]. Notably, approximately 45% of patients in the Korean subgroup had a gastrectomy prior to study entry, compared with approximately 29% in the overall population from the pooled analysis [22]. The higher rate of gastrectomies in the Korean subgroup could have impacted rates of nausea and vomiting, thus potentially leading to the lower rate of TRAEs that led to discontinuation of zolbetuximab. This is supported by the numerically lower rates of vomiting in the Korean subgroup compared with the overall study population. In patients from Korea, vomiting was noted in 55.1% of patients in the zolbetuximab group and 21.3% of patients in the placebo group, whereas in the overall pooled population, 66.8% of patients in the zolbetuximab group and 34.2% of patients in the placebo group experienced vomiting [22]. A registry-based observational study of 21 patients with unresectable mG/GEJ adenocarcinoma found that of the 4 patients who had a total gastrectomy prior to study entry, none had nausea or vomiting during the first-cycle zolbetuximab infusion. However, only 4 patients in this study had previously undergone total gastrectomies, thus further research is needed on the potential link between gastrectomy and patient experience of nausea and/or vomiting [23].

In the individual SPOTLIGHT and GLOW studies, the addition of zolbetuximab to chemotherapy did not lead to a notable improvement in ORR [20,21]. In the combined analysis from both studies in patients with measurable lesions, the ORR was 57.4% in the zolbetuximab group and 55.3% in the placebo group [22]. In contrast, the Korean subgroup analysis showed an ORR of 47.2% (17/36) with zolbetuximab versus 58.6% (17/29) with placebo, with a numerically lower ORR observed in the zolbetuximab group. This discrepancy between the response data and the PFS and OS data may be attributed to the small overall sample size in this Korean subgroup and the chance inclusion of a higher proportion of patients without measurable lesions in the placebo group compared with the zolbetuximab group. Therefore, the ORR results from the Korean subgroup should be interpreted with caution. Additional studies may be warranted to better understand ORR in Korean patients with mG/GEJ adenocarcinoma.

When PFS was analyzed in patients from Asia in SPOTLIGHT, zolbetuximab plus mFOLFOX6 was favored over placebo plus mFOLFOX6, with an HR of 0.56 (95% CI, 0.37 to 0.85), while the comparison was less meaningful in patients from other regions (HR, 0.85; 95% CI, 0.65 to 1.11) [21]. OS results were consistent with the PFS results; zolbetuximab plus mFOLFOX6 was favored over placebo plus mFOLFOX6 in patients from Asia (HR, 0.64; 95% CI, 0.44 to 0.95) but not in patients from other regions (HR, 0.80; 95% CI, 0.61 to 1.04). In GLOW, for both PFS and OS, zolbetuximab plus CAPOX was favored over placebo plus CAPOX in the Asian subgroup (PFS: HR, 0.583; 95% CI, 0.436 to 0.781; OS: HR, 0.674; 95% CI, 0.508 to 0.893) but not in the non-Asian subgroup (PFS: HR, 0.928; 95% CI, 0.645 to 1.336; OS: HR, 0.903; 95% CI, 0.630 to 1.294) [20]. These results demonstrate the efficacy and safety of zolbetuximab plus chemotherapy in the Asian population of patients whose tumors were CLDN18.2-positive.

Other studies have assessed the efficacy of combination treatment in Korean patients with mG/GEJ adenocarcinoma. ATTRACTION-4 was a double-blind, randomized, placebo-controlled trial of nivolumab plus chemotherapy (CAPOX or S-1 [tegafur-gimeracil-oteracil] plus oxaliplatin [SOX]) versus placebo plus chemotherapy; a post hoc analysis was conducted of 3-year follow-up data in the Korean subgroup of this trial [24]. Median PFS was longer among Korean patients who received nivolumab plus chemotherapy (14.75 months) versus patients who received placebo plus chemotherapy (8.34 months; HR, 0.53; 95% CI, 0.39 to 0.73). Similar to the results of the SPOTLIGHT and GLOW combined analysis, median PFS in ATTRACTION-4 was numerically longer among Korean patients than the overall population. While not statistically significant, median OS was also longer among patients who received nivolumab plus chemotherapy (19.71 months) compared with placebo plus chemotherapy (14.88 months; HR, 0.78; 95% CI, 0.60 to 1.02). Among Korean patients, 17.6% of patients who received nivolumab plus chemotherapy and 8.4% of patients who received placebo+chemotherapy experienced a serious TRAE [24]. These rates are relatively similar to those observed in the Korean population of SPOTLIGHT and GLOW.

A Korean study exploring the impact of CLDN18.2 in patients with gastric cancer determined that, of 400 patients with metastatic, recurrent, or unresectable gastric cancer who received systemic chemotherapy, 31.3% showed CLDN18.2 positivity based on immunohistochemistry staining [25]. A study of 1,000 patients with stage II-IV gastric or GEJ adenocarcinoma at Korean hospitals from 2006 to 2014 found that 34.4% of patients had CLDN18.2-positive tumors [26]. These studies demonstrate that patients in Korea with mG/GEJ adenocarcinoma whose tumors are CLDN18.2-positive represent a clinically meaningful patient population that could potentially benefit from treatment with zolbetuximab plus chemotherapy. However, additional research is needed to determine optimal treatments for patients with mG/GEJ adenocarcinoma based on expression of biomarkers, such as CLDN18.2 and programmed death ligand 1, and their interactions [17].

Limitations of the SPOTLIGHT and GLOW studies have been previously described in their primary publications [20,21]. Limitations specific to this post hoc analysis include the relatively small number of patients from Korea (ie, 96 across both zolbetuximab and placebo treatment groups), which could make it difficult to draw definitive conclusions from the data, particularly with respect to less common adverse events and in the subgroups. Statistical power was limited by patient number and the fact that this Korean subgroup analysis was not prespecified; therefore, included analyses were exploratory. Finally, although targeting CLDN18.2-positive tumors is a promising strategy to address the unmet need in mG/GEJ adenocarcinoma, the measurement and scoring criteria for CLDN18.2 positivity are not consistent across clinical trials [16,27].

This subgroup analysis of Korean patients in the SPOTLIGHT and GLOW trials demonstrates the efficacy of zolbetuximab plus chemotherapy in patients with CLDN18.2-positive, HER2-negative, LA unresectable or mG/GEJ adenocarcinoma. Pooling data from trials with similar designs increased the sample size and enhanced the reliability of subgroup findings, including those from specific regions. Both a pan-Asian adaptation of the European Society for Medical Oncology (ESMO) guidelines and Korean practice guidelines for gastric cancer (both from 2024) have recommended the use of zolbetuximab in combination with fluoropyrimidine and oxaliplatin-based chemotherapy as a first-line treatment option for this patient population [3,28]. Our findings provide additional evidence supporting this recommendation and suggest zolbetuximab plus chemotherapy should be considered as a new standard-of-care first-line treatment for Korean patients with CLDN18.2-positive, HER2-negative, LA unresectable or mG/GEJ adenocarcinoma.

Electronic Supplementary Material

Supplementary materials are available at Cancer Research and Treatment website (https://www.e-crt.org).

crt-2025-935_S1_Fig.pdf

crt-2025-935_S2_Fig.pdf

crt-2025-935_S3_Fig.pdf

crt-2025-935_S4_Fig.pdf

crt-2025-935_S5_Supplementary_Material.pdf

NOTES

Ethical Statement

Studies were conducted in accordance with Good Clinical Practice, the International Conference on Harmonization, and the Declaration of Helsinki, and were approved by individual institutional review boards or ethics committees at each participating institution (listed in the Supplementary Material). All patients provided written informed consent before entering respective trials. An independent data monitoring committee reviewed safety and efficacy data.

Author Contributions

Conceived and designed the analysis: Lee KW, Ryu MH.

Collected the data: Lee KW, Oh SC, Kim JG, Sym SJ, Shim BY, Kang SY, Kim IH, Kim JH, Chon HJ, Cho SH, Song EK, Oh DY, Kim JS, Park YI, Kang WK, Kim HD, Lee J, Yi M, Ryu MH.

Contributed data or analysis tools: Lee J, Yi M.

Performed the analysis: Lee J, Yi M.

Wrote the paper: Lee KW, Oh SC, Kim JG, Sym SJ, Shim BY, Kang SY, Kim IH, Kim JH, Chon HJ, Cho SH, Song EK, Oh DY, Kim JS, Park YI, Kang WK, Kim HD, Lee J, Yi M, Ryu MH.

Conflicts of Interest

Keun-Wook Lee reports research funding to institution for conduct of clinical trials from Astellas Pharma, Merck Sharp and Dohme, AstraZeneca, Roche, Merck KGaA, Ono Pharmaceutical, BeiGene, Amgen, Daiichi Sankyo, ALX Oncology, Leap Therapeutics, GlaxoSmithKline, Macrogenics, Taiho Pharmaceutical, Seagen, Y-BIOLOGICS, Bolt Biotherapeutics, Trishula Therapeutics, InventisBio, MedPacto, Ildong Pharmaceutical, Genome & Company, Arcus Biosciences, Elevar Therapeutics, Jazz Pharmaceuticals, TRIO Oncology, Exelixis, IgM Biosciences, Panolos Bioscience, Metafines, Wellmarker Bio, Medicenna, and Erasca; consulting fees from Astellas Pharma, Daiichi Sankyo, Merck Sharp and Dohme, AbbVie, and Metafines; honoraria for lectures or presentations from Astellas Pharma, Bayer, Daiichi Sankyo, Merck KGaA and Sanofi/Aventis, and has an uncompensated relationship with ALX Oncology for participation on Data Safety Monitoring Board or Advisory Board. Byoung Yong Shim reports grants or contracts from Yuhan; consulting fees from Takeda, AstraZeneca, BMS, Pfizer; payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing or educational events from Pfizer, Yuhan; and participated on a Data Safety Monitoring Board or Advisory Board for Gadent, Takeda. Hong Jae Chon reports grants from Roche, BeiGene, Dong-A ST, Boryung, Corporation, Hanmi Inno-n; consulting fees from Roche, Ono Pharma, Bayer, Eisai, BMS, Sanofi, AstraZeneca, Servier, MSD, BeiGene; and payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing or educational events from Roche, AstraZeneca, Eisai, Bayer, BMS, Servier, Sanofi, Dong-A ST. Do-Youn Oh reports grants to the institution from AstraZeneca, Novartis, Array, Eli Lilly, Servier, BeiGene, MSD, Handok; and has participated on a Data Safety Monitoring Board or Advisory Board for AstraZeneca, Novartis, Genentech/Roche, Merck Serono, Bayer, Taiho, ASLAN, Halozyme, Zymeworks, BMS/Celgene, BeiGene, Basilea, Turning Point, Yuhan, Arcus Biosciences, IQVIA, MSD, LG Chem, Astellas, AbbVie, J-Pharma, Mirati Therapeutics, Eutilex, Moderna, Idience. Janise Lee is an employee of Astellas Pharma Inc. Miri Yi is an employee of Astellas Pharma Inc. Min-Hee Ryu reports support for the present manuscript from Astellas; grants to the institution from Ono, BMS; personal grants from AstraZeneca; consulting fees from BMS, Lilly, Ono, MSD, Taiho, Novartis, Daiichi Sankyo, AstraZeneca, Astellas, Dae Hwa Pharmaceutical; and payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing or educational events from BMS, Lilly, Ono, MSD, Taiho, Novartis, Daiichi Sankyo, AstraZeneca, Astellas, Dae Hwa Pharmaceutical. All remaining authors have declared no conflicts of interest.

Funding

The study was funded by Astellas Pharma Inc.

Acknowledgments

The authors thank the patients, caregivers, investigators, and site staff who participated in clinical trials of zolbetuximab. Medical writing support, conducted in accordance with Good Publication Practice (GPP 2022) and the International Committee of Medical Journal Editors (ICMJE) guidelines, was provided by Heather A. Mitchell, PhD, of Oxford PharmaGenesis Inc., Wilmington, DE, USA, and was funded by Astellas Pharma Inc.

Data Sharing Statement

Details for how researchers may request access to anonymized participant level data, trial level data and protocols from Astellas sponsored clinical trials can be found at https://www.clinicaltrials.astellas.com/transparency/.

Fig. 1.

Progression-free survival (PFS) in the Korean subgroup as assessed per Response Evaluation Criteria in Solid Tumors 1.1 by independent review committee. CI, confidence interval; HR, hazard ratio.

Fig. 2.

Overall survival (OS) in the Korean subgroup. CI, confidence interval; HR, hazard ratio.

Fig. 3.

All-grade treatment-emergent adverse events (TEAEs) occurring in ≥ 10% of all treated patients in the Korean subgroup in either treatment group, and TEAEs of grade ≥ 3. Preferred terms were defined according to the Medical Dictionary for Regulatory Activities terminology version 25.0. COVID-19, coronavirus disease 2019.

Table 1.

Baseline characteristics of the Korean subgroup

	Zolbetuximab+chemotherapy (n=49)	Placebo+chemotherapy (n=47)
Age (yr)	57.0 (28-78)	58.0 (22-83)
Sex
Male	33 (67.3)	30 (63.8)
Female	16 (32.7)	17 (36.2)
Organs with metastases
0-2	36 (73.5)	40 (85.1)
≥ 3	13 (26.5)	7 (14.9)
Prior gastrectomy
Yes	22 (44.9)	22 (46.8)
No	27 (55.1)	25 (53.2)
Primary site
Stomach	45 (91.8)	45 (95.7)
GEJ	4 (8.2)	2 (4.3)
Lauren classification
Diffuse	19 (38.8)	26 (55.3)
Intestinal	15 (30.6)	10 (21.3)
Mixed/Others	9 (18.4)	7 (14.9)
Unknown	6 (12.2)	4 (8.5)
ECOG PS
0	14 (28.6)	7 (14.9)
1	35 (71.4)	40 (85.1)

Values are presented as median (range) or number (%). Patients with Lauren classification “unknown” represent patients with adenocarcinoma without Lauren classification. ECOG PS, Eastern Cooperative Oncology Group performance status; GEJ, gastroesophageal junction.

Table 2.

Antitumor activity in Korean patients with measurable disease as assessed per RECIST v1.1 by independent review committee

	Zolbetuximab+chemotherapy (n=36)	Placebo+chemotherapy (n=29)
Objective response rate	17 (47.2)	17 (58.6)
95% CI (%)	30.4-64.5	38.9-76.5
Best overall response
Complete response	3 (8.3)	2 (6.9)
Partial response	14 (38.9)	15 (51.7)
Stable disease	13 (36.1)	10 (34.5)
Progressive disease	4 (11.1)	2 (6.9)
Not available	2 (5.6)	0

Values are presented as number (%) unless otherwise indicated. Responses were unconfirmed. CI, confidence interval; RECIST v1.1, Response Evaluation Criteria in Solid Tumors version 1.1.

Table 3.

Adverse events in all treated patients in the Korean subgroup

Parameter	Zolbetuximab+chemotherapy (n=49)	Placebo+chemotherapy (n=47)
TEAE
All grades	49 (100)	46 (97.9)
Grade ≥ 3	41 (83.7)	38 (80.9)
Serious	21 (42.9)	20 (42.6)
Leading to dose interruption of any study drug	36 (73.5)	22 (46.8)
Leading to dose interruption of zolbetuximab or placebo	29 (59.2)	11 (23.4)
Leading to discontinuation of any study drug	20 (40.8)	19 (40.4)
Leading to discontinuation of zolbetuximab or placebo	6 (12.2)	8 (17.0)
Leading to death	3 (6.1)	6 (12.8)
TRAE
All grades (related to any study drug)	49 (100)	45 (95.7)
Grade ≥ 3 (related to any study drug)	37 (75.5)	28 (59.6)
Serious (related to any study drug)	11 (22.4)	3 (6.4)
Leading to dose interruption of any study drug	31 (63.3)	20 (42.6)
Leading to dose interruption of zolbetuximab or placebo	18 (36.7)	4 (8.5)
Leading to discontinuation of any study drug	16 (32.7)	13 (27.7)
Leading to discontinuation of zolbetuximab or placebo	2 (4.1)	1 (2.1)
Leading to death (related to any study drug)	0	0

Values are presented as number (%). TEAE, treatment-emergent adverse event; TRAE, treatment-related adverse event.

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REFERENCES

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Claudin 18.2 Expression and Outcomes in Resected Gallbladder and Biliary Tract Adenocarcinomas: A Pilot Clinicopathologic Study
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Zolbetuximab Plus Chemotherapy as First-Line Treatment in Patients with Claudin 18.2–Positive, HER2-Negative, Locally Advanced Unresectable or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma: Korean Population Subgroup—Combined Efficacy and Safety Analysis from SPOTLIGHT and GLOW

DOI: https://doi.org/10.4143/crt.2025.935

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Abstract
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REFERENCES

Nivolumab Plus Chemotherapy versus Placebo Plus Chemotherapy in Korean Patients with HER2-Negative, Untreated, Unresectable Advanced or Recurrent Gastric or Gastroesophageal Junction Cancer: Subgroup Analysis of a Randomized, Multicenter, Double-Blind Phase 3 Trial (ATTRACTION-4)

Fig. 1. Progression-free survival (PFS) in the Korean subgroup as assessed per Response Evaluation Criteria in Solid Tumors 1.1 by independent review committee. CI, confidence interval; HR, hazard ratio.

Fig. 2. Overall survival (OS) in the Korean subgroup. CI, confidence interval; HR, hazard ratio.

Fig. 3. All-grade treatment-emergent adverse events (TEAEs) occurring in ≥ 10% of all treated patients in the Korean subgroup in either treatment group, and TEAEs of grade ≥ 3. Preferred terms were defined according to the Medical Dictionary for Regulatory Activities terminology version 25.0. COVID-19, coronavirus disease 2019.

Fig. 1.

Fig. 2.

Fig. 3.

	Zolbetuximab+chemotherapy (n=49)	Placebo+chemotherapy (n=47)
Age (yr)	57.0 (28-78)	58.0 (22-83)
Sex
Male	33 (67.3)	30 (63.8)
Female	16 (32.7)	17 (36.2)
Organs with metastases
0-2	36 (73.5)	40 (85.1)
≥ 3	13 (26.5)	7 (14.9)
Prior gastrectomy
Yes	22 (44.9)	22 (46.8)
No	27 (55.1)	25 (53.2)
Primary site
Stomach	45 (91.8)	45 (95.7)
GEJ	4 (8.2)	2 (4.3)
Lauren classification
Diffuse	19 (38.8)	26 (55.3)
Intestinal	15 (30.6)	10 (21.3)
Mixed/Others	9 (18.4)	7 (14.9)
Unknown	6 (12.2)	4 (8.5)
ECOG PS
0	14 (28.6)	7 (14.9)
1	35 (71.4)	40 (85.1)

	Zolbetuximab+chemotherapy (n=36)	Placebo+chemotherapy (n=29)
Objective response rate	17 (47.2)	17 (58.6)
95% CI (%)	30.4-64.5	38.9-76.5
Best overall response
Complete response	3 (8.3)	2 (6.9)
Partial response	14 (38.9)	15 (51.7)
Stable disease	13 (36.1)	10 (34.5)
Progressive disease	4 (11.1)	2 (6.9)
Not available	2 (5.6)	0

Parameter	Zolbetuximab+chemotherapy (n=49)	Placebo+chemotherapy (n=47)
TEAE
All grades	49 (100)	46 (97.9)
Grade ≥ 3	41 (83.7)	38 (80.9)
Serious	21 (42.9)	20 (42.6)
Leading to dose interruption of any study drug	36 (73.5)	22 (46.8)
Leading to dose interruption of zolbetuximab or placebo	29 (59.2)	11 (23.4)
Leading to discontinuation of any study drug	20 (40.8)	19 (40.4)
Leading to discontinuation of zolbetuximab or placebo	6 (12.2)	8 (17.0)
Leading to death	3 (6.1)	6 (12.8)
TRAE
All grades (related to any study drug)	49 (100)	45 (95.7)
Grade ≥ 3 (related to any study drug)	37 (75.5)	28 (59.6)
Serious (related to any study drug)	11 (22.4)	3 (6.4)
Leading to dose interruption of any study drug	31 (63.3)	20 (42.6)
Leading to dose interruption of zolbetuximab or placebo	18 (36.7)	4 (8.5)
Leading to discontinuation of any study drug	16 (32.7)	13 (27.7)
Leading to discontinuation of zolbetuximab or placebo	2 (4.1)	1 (2.1)
Leading to death (related to any study drug)	0	0

Table 1. Baseline characteristics of the Korean subgroup

Table 2. Antitumor activity in Korean patients with measurable disease as assessed per RECIST v1.1 by independent review committee

Values are presented as number (%) unless otherwise indicated. Responses were unconfirmed. CI, confidence interval; RECIST v1.1, Response Evaluation Criteria in Solid Tumors version 1.1.

Table 3. Adverse events in all treated patients in the Korean subgroup

Values are presented as number (%). TEAE, treatment-emergent adverse event; TRAE, treatment-related adverse event.