Zolbetuximab: A Narrative Drug Review

Abstract

Claudin-18.2 (CLDN18.2) is a tight junction protein selectively expressed in a subset of gastric and gastroesophageal junction (GEJ) adenocarcinomas, making it a promising therapeutic target. Zolbetuximab is a first-in-class chimeric IgG1 monoclonal antibody that binds to CLDN18.2-positive tumor cells and induces cell death through complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity. Antitumor efficacy was further enhanced when combined with platinum-based chemotherapy. This review focuses on the pharmacology, pharmacokinetics, clinical applications, dosing, adverse events, and storage and administration of zolbetuximab. Data were compiled through an extensive search of databases such as PubMed, Google Scholar, ScienceDirect, and regulatory sources such as the U.S. Food and Drug Administration (FDA). Relevant search terms included “Zolbetuximab,” “CLDN18.2,” and “advanced gastric cancer.” Additional information was drawn from the clinical trial results and conference proceedings. Zolbetuximab has received FDA approval for the treatment of HER2-negative, CLDN18.2-positive advanced gastric and GEJ adenocarcinoma, supported by evidence from pivotal clinical trials, such as SPOTLIGHT and GLOW, which showed significantly improved progression-free and overall survival compared with chemotherapy alone.

Keywords

zolbetuximab - gastric cancer - gastroesophageal junction cancer - CLDN18.2 - monoclonal antibody

Introduction

Gastric cancer (GC) and gastroesophageal junction (GEJ) cancers are among the leading causes of cancer-related deaths worldwide. Despite surgical intervention, recurrence or metastasis often occurs in patients with resectable tumors. For patients with advanced metastatic disease, survival remains poor, with a median survival ranging between 9 and 14 months. The current standard of care for HER2-negative advanced GC/GEJ includes chemotherapy with platinum-fluoropyrimidine, although new treatments that target specific molecular pathways are urgently needed.

Zolbetuximab, a monoclonal antibody targeting claudin 18.2 (CLDN18.2), has shown promise in improving survival outcomes in advanced GC/GEJ adenocarcinomas, making it a potential therapeutic advancement.[1]

CLDN18.2, an isoform of claudin-18, belongs to the class of transmembrane proteins called claudins, which are elements of epithelial cell tight junctions. It is normally expressed in nonmalignant gastric epithelium, becomes exposed on the cell surface during malignant transformation due to altered cell polarity, presenting a promising therapeutic target. Overall, 38.4% of gastric and GEJ (G/GEJ) adenocarcinomas exhibit CLDN18.2 positivity, which is defined by moderate to strong CLDN18.2 immunoreactivity in at least 75% of tumor cells, with a higher incidence in HER2-negative subgroups. Clinically, diffuse-type histology and advanced stages are associated with a higher prevalence of CLDN18.2-positive tumors. Genomically, CLDN18.2-positive GCs are associated with specific molecular features, including enrichment in stromal/fibrotic remodeling and a potentially immune-cold tumor microenvironment characterized by low T cell infiltration, high fibroblast activity, and immunosuppressive elements, which may limit responses to immune checkpoint inhibitors (ICIs) alone and necessitate broader biomarker testing. Testing for CLDN18.2 is performed via immunohistochemistry (IHC) using validated assays like the VENTANA CLDN18 (43–14A) RxDx Assay, a qualitative IHC method employing a mouse monoclonal anti-CLDN18 antibody (clone 43–14A) on formalin-fixed, paraffin-embedded tissue. The 43–14A clone specifically targets CLDN18.2 isoform, minimizing cross-reactivity with CLDN18.1. The FAST study demonstrated that zolbetuximab provided a stronger therapeutic benefit at higher CLDN18 expression levels (≥ 2+ in ≥ 70% of tumor cells) than at lower levels. In phase III trials (GLOW and SPOTLIGHT), the Ventana IHC automated platform employed staining intensity in ≥ 75% of tumor cells, which has been demonstrated to be equal to the 70% cutoff used with the manual test in the FAST clinical trial.[2]

The current consensus definition of CLDN18.2 positivity is moderate (2+) or strong (3+) staining in ≥ 75% of tumor cells by IHC.[3] Importantly, CLDN18.2 was validated as a predictive but not prognostic biomarker independent of HER2, programmed death-ligand 1 (PD-L1), or mismatch repair status. CLDN18.2 positivity or PD-L1 combined positive score (CPS) > 1 has predictive value in advanced HER2-negative G/GEJ adenocarcinoma, as it correlates with improved survival in patients treated with zolbetuximab plus chemotherapy or ICIs plus chemotherapy. However, the magnitude of progression-free survival (PFS) and overall survival (OS) benefits varies according to CPS score. Although direct comparisons between trials of zolbetuximab and those of nivolumab or pembrolizumab are limited by methodological differences, the experimental arm receiving zolbetuximab showed numerically longer PFS and OS, with a median OS of 16.4 months compared with 14.4 months for nivolumab (PD-L1 CPS > 5) and 15.7 months for pembrolizumab (PD-L1 CPS > 10).[4] [5]

Although targeted therapies have improved survival rates, validated molecular targets remain limited. Trastuzumab is used as the first-line treatment for HER2-positive GC, ramucirumab with paclitaxel benefits second-line patients, and nivolumab is approved for third-line treatment. However, the prognosis remains poor, with a 5-year survival rate of only 6.6%, despite ongoing research on claudin proteins, which may uncover additional therapeutic targets.[6]

Development and Approval Status

Zolbetuximab is a recombinant chimeric IgG1 monoclonal antibody that specifically binds to isoform 2 of CLDN18.2 proteins, expressed on the surface of malignant GC and GEJ cancer cells. Developed initially by Ganymed Pharmaceuticals and later advanced by Astellas Pharma, zolbetuximab has shown promising results in clinical trials. The phase II FAST trial and phase III SPOTLIGHT and GLOW trials demonstrated significant improvements in PFS and OS when zolbetuximab was combined with standard chemotherapy in CLDN18.2-positive, HER2-negative advanced G/GEJ cancers. The SPOTLIGHT trial evaluated zolbetuximab + mFOLFOX6 versus placebo + mFOLFOX6 in untreated, HER2-negative, CLDN18.2-positive (≥ 75% 2+/3+ staining), locally advanced unresectable or metastatic G/GEJ adenocarcinoma. Primary endpoint was PFS and secondary endpoints were OS, objective response rate, safety, and health-related quality of life. Patients aged ≥ 18, Eastern Cooperative Oncology Group 0 to 1, measurable disease per RECIST 1.1, adequate function with good performance status, and adequate organ function were included.[7] The GLOW trial was similar to SPOTLIGHT but used CAPOX chemotherapy. Primary endpoints were PFS and secondary endpoints were the same as in the SPOTLIGHT trial. Note that 38% and 60% of the study populations was Asians in the SPOTLIGHT and GLOW studies, respectively.[8] In the SPOTLIGHT trial, the mFOLFOX6 regimen was administered as a total of 12 doses, delivered as 3 doses per cycle over 4 cycles.[7]

Based on these results, zolbetuximab received its first regulatory approval in Japan in December 2023, under the brand name Vyloy. It was approved by the Food and Drug Administration on October 18, 2024, for the treatment of HER2-negative, CLDN18.2-positive advanced GC and GEJ adenocarcinomas. Zolbetuximab is primarily administered in combination with chemotherapy and has shown significant improvements in both PFS and OS in clinical trials.[9]

Mechanism of Action

Zolbetuximab targets CLDN18.2, a protein involved in tumor progression and metastasis in GC cells. Its anticancer effects are mediated through two main mechanisms.

• Antibody-dependent cellular cytotoxicity: Zolbetuximab binds to CLDN18.2 on cancer cells and recruits natural killer (NK) cells, leading to the release of cytotoxic molecules (e.g., perforin and granzymes) that induce apoptosis.

• Complement-dependent cytotoxicity: Binding of zolbetuximab activates the classical complement pathway, forming the membrane attack complex, resulting in cancer cell lysis.

The effects of zolbetuximab are enhanced when administered along with chemotherapy, stimulating T cell infiltration and promoting an inflammatory response that aids tumor destruction[10] ([Fig. 1]).

Fig. 1 Mechanism of action of zolbetuximab.

Pharmacokinetics

• Administration: Zolbetuximab is delivered via intravenous infusion, with an initial loading dose over 2 to 4 hours and maintenance doses over 1 to 2 hours.

• Dose-proportional pharmacokinetics: After initial dose, zolbetuximab exhibits dose-proportional pharmacokinetics, achieving a steady-state concentration after three to four infusions. The Cmax is 415 mcg/mL, and the area under the curve tau is 3149 mcg*day/mL.

• Half-life: The mean half-life is approximately 17 days, supporting a dosing schedule every 2 to 3 weeks.

• Metabolism: Zolbetuximab undergoes catabolic degradation primarily in the reticuloendothelial system (e.g., macrophages and liver cells), with minimal renal or hepatic impact ([Table 1]).

Table 1 Features and properties of zolbetuximab

Features and properties of zolbetuximab
Alternative names	IMAB362; anti-claudin 18.2 antibody; chimeric monoclonal antibody against claudin 18 splice variant 2; claudiximab
Class	Antineoplastics, immunotherapies, monoclonal antibodies
Route of administration	IV
Pharmacodynamics	Binds with high specificity and affinity to CLDN18.2 in CLDN18.2-expressing gastric cancer and pancreatic cancer cells; increased anti-tumor activity in combination with chemotherapy
Pharmacokinetics	800 mg/m2 initial dose: Cmax 434 μg/mL, Ctrough 43.9 μg/mL, AUC21d 2164 μg·d/mL 600 mg/m2 Q3W (steady state): Cmax 425 μg/mL, Ctrough 101 μg/mL, AUC21d 3359 μg·d/mL CL 0.0150 L/h, t1/2 43.6 d
Adverse events (grade ≥ 3)	Nausea, vomiting, neutropenia (occasional) Hypersensitivity including anaphylaxis, infusion reactions
WHO ATC code	L01F-X31 (zolbetuximab)

Abbreviations: ATC, Anatomical Therapeutic Chemical; IV, intravenous; WHO, World Health Organization.

Contraindications

Zolbetuximab is contraindicated in patients with known hypersensitivity to the drug or its components owing to the risk of severe infusion-related reactions. It should not be used in tumors lacking CLDN18.2 expression, as its efficacy is dependent on this biomarker. Use is not recommended during pregnancy or breastfeeding because of the potential harm to the fetus or infant. The safety and efficacy of zolbetuximab in pediatric patients have not yet been established. Caution is advised in patients with severe uncontrolled comorbidities.

Drug Preparation and Administration

Reconstitution

The dose is calculated based on the body surface area. Each vial should be reconstituted slowly with 5 mL sterile water for injection via the walls of the vial. Therefore, the final reconstituted solution contains 20 mg/mL zolbetuximab. Do not shake the vial and slowly swirl it between the palms. After settling of bubbles, inspect for visible particles. The solution should be clear to slightly opalescent and colorless to slightly yellow. If any visible particles are noted, then it should be discarded.[11]

Dilution

The required diluted volume should be withdrawn and transferred to the infusion bag containing 0.9% sodium chloride to a final concentration of 5 mg/mL. By gentle inversion the diluted solution should be mixed without shaking the bag. After dilution, look for visible particles, if any, then it should be discarded. If any unused diluted solution is remaining, then discard the leftover solution.[11]

Storage of Diluted Infusion

The diluted solution should be stored at room temperature of 15°C to 30°C (59°F to 86°F) for not more than 6 hours from the end of preparation time. The diluted solution can be kept in refrigerator for up to 16 hours from the end of preparation at 2°C to 8°C (36°F to 46°F). The solution should not be kept in the freezer.[11]

Drug Interactions

There are no known significant drug interactions with zolbetuximab. However, it is advised not to coadminister other drugs through the same infusion line to prevent potential incompatibilities.[12]

Dosage and Administration

Zolbetuximab should be administered before chemotherapy. Combination chemotherapy regimens used in clinical trials include mFOLFOX6 and CAPOX[11] [12] ([Table 2]).

Table 2 Dosage and administration

Regimen component	Dose	Schedule	Duration
Zolbetuximab (initial)	800 mg/m2 IV	Cycle 1, day 1	Combined with either mFOLFOX or CAPOX
Zolbetuximab (ongoing)	600 mg/m2 IV every 3 weeks or 400 mg/m2 IV every 2 weeks	Starting Cycle 2	Combined with either mFOLFOX or CAPOX
mFOLFOX regimen	Oxaliplatin + 5-FU + leucovorin	Every 2 weeks	Total of 4 cycles
CAPOX regimen	Oxaliplatin + capecitabine	Every 3 weeks	Total of 8 cycles
Maintenance phase	Zolbetuximab + fluorouracil/leucovorin (mFOLFOX arm) or zolbetuximab + capecitabine (CAPOX arm)		Continue with chemotherapy until disease progression or unacceptable side effects

Abbreviation: IV, intravenous.

Clinical Trials and Efficacy

Completed and ongoing clinical trials of zolbetuximab are presented in [Table 3].[7] [8] [13] [14] [15] Overall response rates reported in major trials ranged from approximately 48 to 61% with zolbetuximab plus chemotherapy compared with 38 to 49% with chemotherapy alone.[7] [8]

Table 3 Summary of completed and ongoing clinical trials of zolbetuximab

Trial (ref)	Drug(s) used	Indication	Status	Common side effects	Median PFS (mo)	Median OS (mo)
MONO – Phase IIa[13]	Zolbetuximab monotherapy	Adenocarcinoma stomach or lower esophagus	Completed 2019	Nausea (63%), vomiting (57%), anemia (11%)	–	–
FAST-Phase II[14]	EOX ± zolbetuximab	Advanced gastric/GEJ cancer	Completed 2021	Nausea (81.8%), vomiting (67.5%)	7.5 months vs. 5.3 months (HR 0.44; 95% CI 0.29–0.67; p < 0.0005)	13.0 months vs. 8.3 months (HR 0.55; 95% CI 0.39–0.77; p < 0.0005)
SPOTLIGHT – Phase III[7]	mFOLFOX6 + zolbetuximab vs. Placebo + mFOLFOX6	HER2-, CLDN18.2+ advanced gastric/GEJ cancer	Completed 2023	Nausea, vomiting, decreased appetite (∼82%, ∼67%, 47%)	10.61 vs. 8.67 (HR 0.751; p = 0.0066)	18.23 vs. 15.54 (HR 0.750; p = 0.0053)
GLOW – Phase III[8]	CAPOX + zolbetuximab vs. Placebo + CAPOX	HER2-, CLDN18.2 + advanced gastric/GEJ cancer	Completed 2023	Grade ≥ 3 nausea 68.5%, vomiting 66.1%	8.21 vs. 6.80 (HR 0.687; p = 0.0007)	14.39 vs. 12.16 (HR 0.771; p = 0.0118)
ILUSTRO (NCT03505320–Phase I/II)[15]	Zolbetuximab + nivolumab ± chemo	Gastric or gastroesophageal junction adenocarcinoma	Some cohorts completed, other ongoing	Nausea (63–90%), vomiting (33–67%)	Cohort 1A (mono): 1.54; Cohort 2 (chemo): 17.8; Cohort 3A (pembro): 2.96	Cohort 1A: 5.62

Abbreviations: CI, confidence interval; GEJ, gastroesophageal junction; HR, hazard ratio; OS, overall survival; PFS, progression-free survival.

Safety Profile

Zolbetuximab is generally well-tolerated, but its use is associated with several adverse reactions, particularly during infusion.

• Infusion-related reactions: Anaphylaxis, fever, chills, abdominal pain, nausea, vomiting, and hypertension.

• Gastrointestinal (GI) issues: Nausea (69–82%), vomiting (66–67%), decreased appetite (41–47%), diarrhea (2.8–2.9%), and GI obstruction (3.2%).

In patients with an intact stomach, consider using an H2 blocker or proton-pump inhibitor to prevent dyspepsia, which can mimic nausea. Provide these a few days to 1 week before zolbetuximab treatment for maximal mucosal protection. High-emetic-risk regimens (NK-1 antagonist + 5-HT3 antagonist + dexamethasone + olanzapine or a three-drug regimen) should be used prophylactically irrespective of whether patients have a high or low risk of chemotherapy-induced nausea and vomiting, and whether or not they have had a prior total gastrectomy. Slow the infusion rate by 50% if symptoms occur; if infusion had already been slowed to 50%, slow rate by an additional 50% (i.e., 25% of initial rate). Begin second and subsequent infusions at the rate that was best tolerated during previous infusions. With second and/or subsequent infusions, the degree of nausea and vomiting is expected to diminish. In these cases, patients may tolerate titration of the infusion rate by increments of 25% (e.g., if infusion rate was slowed to 50% and the patient remained asymptomatic for 30–60 minutes, consider increasing to 75%) back to 100% or to the maximum tolerated dose. Continue to monitor the patient closely for any recurrent symptoms and administer additional antiemetic medications as needed to manage symptoms effectively.[16]

• Other reactions: Peripheral edema (18%), infections (2–2.5%), neutropenia (20%), pulmonary embolism (2.2–2.3%), and weight loss. In some cases, treatment discontinuation may be necessary.

Premedication with antihistamines, corticosteroids, and antiemetics is recommended to mitigate infusion-related reactions and chemotherapy-induced nausea and vomiting.[8]

Special Populations

• Hepatic impairment: Zolbetuximab clearance was not significantly affected by mild hepatic impairment. However, the effects of moderate or severe impairment remain unclear.

• Renal impairment: No clinically significant effects on zolbetuximab pharmacokinetics in mild to moderate renal impairment.

• Geriatric population: Age does not affect zolbetuximab clearance.

• Pregnancy and breastfeeding: Zolbetuximab should only be used during pregnancy if the benefits outweigh the risks. As it is unknown whether zolbetuximab is excreted in breast milk, breastfeeding should be discontinued during treatment and for 8 months after the last dose.

Applicability to India

In India, each 100 mg vial costs approximately ₹90,000 to ₹120,000.

Future Directions

The CLDN18.2 pathway has potential for further treatments beyond zolbetuximab. To improve specificity, new monoclonal antibodies—such as fully humanized versions—are being developed. In immunological-cold cancers, bispecific antibodies (BsAbs), like CLDN18.2–4-1BB (givastomig), seek to activate T cells for better immune activation.[17] Antibody-drug conjugates such as IBI343 are fully humanized anti-CLDN18.2 monoclonal antibodies attached to exatecan using site-specific glycol conjugation and a cleavable linker. A new antibody-drug combination called tectocabart vedotin (LM-302) targets CLDN18.2, a promising therapeutic target in GI malignancies.[18] Although issues like on-target off-tumor toxicity still exist, CAR-T cell treatments that target CLDN18.2 are progressing in preclinical and early clinical stages and may provide long-lasting remissions in resistant instances. For wider applicability, future studies should concentrate on biomarkers and combinations (such as with ICIs).[19]

Conclusion

Zolbetuximab represents a significant advancement in the treatment of advanced G/GEJ adenocarcinoma, particularly in patients with CLDN18.2-positive tumors. Considerable improvements in both PFS and OS were observed when combined with chemotherapy. Although the safety profile includes typical chemotherapy-related adverse reactions, these can be managed with appropriate supportive care. Given its unique mechanism of action and promising clinical trial results, zolbetuximab is poised to be a key player in the treatment of advanced GC/GEJ cancer.

Conflict of Interest

None declared.

Patient Consent

Patient consent not applicable as this is a narrative review and contains no patient-specific data.

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Publication History

Article published online:
16 February 2026