Efficacy and Safety of Zolbetuximab in Gastric Cancer

Abstract

Gastric cancer remains a major global health concern with high incidence and mortality rates, particularly in East Asia. Patients often have poor outcomes due to limited treatment efficacy. Zolbetuximab, a monoclonal antibody targeting claudin 18.2 (CLDN18.2)—overexpressed in 50% to 80% of gastric cancers—demonstrates promise by initiating antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity in CLDN18.2-positive cells. In clinical trials, zolbetuximab with chemotherapy improved progression-free survival (PFS) and overall survival (OS). The FAST trial showed a median OS increase from 8.4 months to 13.2 months (HR, 0.72; P < .01). The SPOTLIGHT trial found PFS extended to 11.0 months vs. 8.9 months (HR, 0.73; P = .0024) with OS reaching 18.2 months in the zolbetuximab arm. The GLOW trial also confirmed efficacy, with median OS improving from 12.16 months to 14.39 months (HR, 0.771; P = .0118). Zolbetuximab’s targeted action, combined with manageable adverse effects, positions it as a promising therapy for advanced gastric cancer.

Introduction

Gastric cancer continues to be a significant global health issue, with more than 1 million new cases and approximately 800,000 deaths annually.¹ The largest incidence rates are seen in East Asia, particularly Japan, South Korea, China, and some Eastern European nations. Despite breakthroughs in diagnostic and treatment procedures, patients with advanced-stage stomach cancer continue to have a dismal prognosis. This is primarily due to the limited efficacy of current therapies and the need for more effective treatment options for metastatic and locally advanced disease. Zolbetuximab is a novel therapeutic drug that targets claudin 18.2 (CLDN18.2), a protein overexpressed in many gastric tumors. Zolbetuximab, an anti-CLDN18.2 monoclonal antibody, binds exclusively to cancer cells that express CLDN18.2, causing their destruction by mechanisms such as antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).² This targeted approach represents a promising development in the management of gastric cancer, offering potential benefits over traditional therapies and addressing an urgent need for more effective treatment options in this challenging disease setting.

Mechanism of Action

CLDN18.2 is a tight junction protein in the stomach mucosa that regulates epithelial barrier integrity. CLDN18.2 is aberrantly expressed on tumor cells in gastric cancer, making it a promising therapeutic target. CLDN18.2 is expressed in 50% to 80% of stomach malignancies, and its limited presence in normal tissues reduces the danger of off-target effects.² However, its predominance in tumors suggests a possible path for targeted therapy. Zolbetuximab, when bound to CLDN18.2 on the surface of cancer cells, activates 2 major modes of action that result in cell death. First, immune cells such as natural killer cells recognize and bind to zolbetuximab-coated cancer cells via ADCC. This connection causes immune cells to produce poisonous chemicals that directly destroy cancer cells. Second, zolbetuximab activates the complement system, causing CDC. This mechanism causes the creation of a membrane attack complex on the cancer cell, which disrupts the cell membrane and, eventually, causes cell death. Zolbetuximab is a highly successful targeted therapy for CLDN18.2-positive gastric tumors because of its multiple mechanisms. The Figure illustrates zolbetuximab’s mechanism of action, where the antibody binds to CLDN18.2 on gastric cancer cells, activating immune effector mechanisms such as ADCC and CDC, resulting in targeted cancer cell destruction.

FIGURE. Mechanism of Action of Zolbetuximab

Efficacy of Zolbetuximab

Several major clinical trials, including phase 2 FAST (NCT01630083),³ phase 3 SPOTLIGHT (NCT03504397),⁴ and phase 3 GLOW (NCT03653507),⁵ have investigated the efficacy of zolbetuximab in individuals with advanced gastric or gastroesophageal junction tumors that express CLDN18.2. The FAST trial investigators focused on zolbetuximab in combination with chemotherapy (epirubicin, oxaliplatin, and capecitabine) vs chemotherapy alone.³ The results showed significantly improved progression-free survival (PFS; HR, 0.64; 95% CI, 0.49-0.84; P < .01) and overall survival (OS; HR, 0.72; 95% CI, 0.62-0.83;
P < .83) in patients receiving zolbetuximab, with a notable increase in median OS from 8.4 months to 13.2 months in the zolbetuximab arm.

The SPOTLIGHT trial investigators studied the combination of zolbetuximab and chemotherapy (leucovorin calcium, fluorouracil, and oxaliplatin; FOLFOX) in patients with CLDN18.2-positive advanced gastric cancer⁴ The trial’s primary goal was met, demonstrating a significant increase in PFS of 11.0 months (95% CI, 9.70-12.5) in the zolbetuximab arm vs 8.9 months (95% CI, 8.2-10.4) in the chemotherapy arm (HR, 0.73; 95% CI, 0.59-0.91; P = .0024). In the zolbetuximab arm, the OS was 18.2 months (95% CI, 16.1-20.6) vs 15.6 months (95% CI, 13.7-16.9) in the chemotherapy arm (HR, 0.78; 95% CI, 0.64-0.95; P = .0075).

Additionally, the GLOW trial investigators focused on zolbetuximab plus capecitabine and oxaliplatin as first-line treatment for CLDN18.2-positive gastric cancer.⁵ The investigators found higher response rates and survival improvements than with chemotherapy alone. PFS in the zolbetuximab arm was 8.21 months vs 6.80 months in the placebo arm (HR, 0.687; 95% CI, 0.544-0.866; P = .0007) Notably, the median OS in each arm was 14.39 months vs 12.16 months, respectively (HR, 0.771; 95% CI, 0.615-0.965; P = .0118). Zolbetuximab excelled over existing therapies in terms of PFS and OS. The ability to preferentially target CLDN18.2-positive tumors decreases off-target damage, making it an intriguing addition to the therapy landscape for advanced gastric cancer.³

Safety of Zolbetuximab

Zolbetuximab had a manageable safety profile in the FAST, SPOTLIGHT, and GLOW trials. Common adverse effects (AEs) included nausea, vomiting, fatigue, and gastrointestinal discomfort. Other AEs such as anemia, neutropenia, and infusion-related reactions also were noted, although they were manageable. AEs were managed with antiemetic medications for gastrointestinal issues and growth factors such as granulocyte colony-stimulating factor for neutropenia. Infusion-related reactions were treated with premedication, including antihistamines and corticosteroids, alongside slower infusion rates. Compared with standard therapies, zolbetuximab’s targeted mechanism allows for reduced off-target toxicity, making AE management relatively straightforward.⁴

Conclusion

The FAST, SPOTLIGHT, and GLOW trial results indicated that the success of zolbetuximab is dependent on the selection of patients with CLDN18.2-positive cancers. Testing for CLDN18.2 expression is required before prescribing zolbetuximab, ensuring that the treatment is reserved for patients with high CLDN18.2 expression, maximizing efficacy while preventing unnecessary treatment in others. Zolbetuximab is expected to become part of standard gastric cancer treatments, especially in combination with chemotherapy regimens such as FOLFOX, because of its ability to improve PFS and OS. It may also be used, likely in first- or second-line treatments, with other targeted therapies or immunotherapies, particularly for patients who are CLDN18.2 positive and HER2 negative.⁵

Future development of zolbetuximab will likely focus on exploring its use in combination with other therapies, such as immunotherapies or novel targeted agents, to enhance its efficacy. Ongoing trials should aim to expand its applicability beyond first-line treatments, possibly extending to other cancers expressing CLDN18.2. Additionally, further research is needed to investigate biomarker-driven strategies to optimize patient selection and treatment outcomes. Zolbetuximab is a promising advancement in the treatment of patients with CLDN18.2-positive gastric cancer, providing a targeted approach that has demonstrated considerable improvements in clinical trials. As it becomes integrated into standard treatment protocols, it may provide a novel therapeutic option for patients with advanced gastric cancer, especially those with few therapy options.

References

1. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209-249. doi:10.3322/caac.21660
2. Liang Z, Liu L, Li W, et al. Efficacy and safety of zolbetuximab for first-line treatment of advanced claudin 18. 2-positive gastric or gastro-esophageal junction adenocarcinoma: a systematic review and meta-analysis of randomized controlled trials. Front Oncol. 2023;13:1258347. doi:10.3389/fonc.2023.1258347
3. de Moraes FCA, Pasqualotto E, Chavez MP, Ferreira ROM, De Castria TB, Burbano RMR. Efficacy and safety of zolbetuximab plus chemotherapy for advanced CLDN18.2-positive gastric or gastro-oesophageal adenocarcinoma: a meta-analysis of randomized clinical trials. BMC Cancer. 2024;24(1):240. doi:10.1186/s12885-024-11980-w
4. Shitara K, Van Custem E, Lordick F, et al. Final overall survival results from phase 3 SPOTLIGHT study evaluating zolbetuximab+ mFOLFOX6 as first-line (1L) treatment for patients (pts) with claudin 28 isoform 2 (CLDN18.2)+, HER2-, locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma. J Clin Oncol. 2024;42 (suppl 16): 4036. doi:10.1200/JCO.2024.42.16 suppl.4036
5. Shah MA, Shitara K, Ajani JA, et al. Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 GLOW trial. Nat Med. 2023;29(8):2133-2141. doi:10.1038/s41591-023-02465-7

Corresponding Author

Abdul Baseer Wardak, MBBS

Institute: Razia Bahlol Hospital, Afghanistan

Phone: +93 79 542 1983

Email: a.baseer21@gmail.com

Address: Madina-Township Kabul, Afghanistan

ORCID id: 0000-0002-9929-6088