Globally, gastric cancer is one of the major causes of cancer-related mortality. Surgical resection is a form of curative therapy, usually a total or subtotal gastrectomy with an additional lymphadenectomy. The study of several targeted therapies, immunotherapies, and cutting-edge chemotherapies has expanded the selection of possible treatments for gastric cancer or gastric adenocarcinoma (a type of gastric cancer). Despite these alternate treatments, few patients survive 2 years after beginning first-line therapy. Advanced gastric cancer patients still have an unmet medical need that may be addressed by combining multiple modalities of treatment [1–3].
How Zolbetuximab comes into the picture?
Zolbetuximab is a chimeric IgG1 monoclonal antibody that targets claudin 18.2 (CLDN18.2), a potential biomarker in individuals diagnosed with gastroesophageal or advanced gastric cancer. Zolbetuximab induces tumor cell death via antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. A class of tight junction molecules known as claudins regulates the polarity, barrier function, and permeability of epithelial layers.
The protein CLDN18.2 is exclusively expressed in the tight junctions of gastric mucosal cells in healthy normal tissue, and epitopes of this protein within the tight junction supramolecular complex are not accessible to intravenous antibodies.
When cells undergo malignant transformation, their polarity is altered, exposing CLDN18.2 epitopes that can then be bound by specific monoclonal antibodies. CLDN18.2 expression is continued in stomach malignancies and gastric metastases. Consequently, it has been determined that the tight junction protein CLDN18.2 is a promising target for the treatment of gastric cancer [1–3].
Does previous findings support the use of Zolbetuximab?
In previous investigations including patients with advanced gastric adenocarcinoma who had undergone extensive previous therapy, zolbetuximab demonstrated single-agent effectiveness and a tolerable safety profile. Additionally, patients with advanced gastric adenocarcinomas that were CLDN18.2-positive showed antitumor efficacy with zolbetuximab monotherapy [3]. A phase I trial found that zolbetuximab was well tolerated at all doses, with gastrointestinal toxicities being the most often reported adverse effect (identifier: NCT00909025) [4].
When combined with first-line EOX, zolbetuximab extended progression-free and overall survival compared to EOX alone in advanced gastric or gastroesophageal junction cancer patients who expressed CLDN18.2. Most people well-tolerated zolbetuximab plus EOX, and the adverse effects were under control. Phase III trials are evaluating zolbetuximab 800/600 mg/m2 based on clinical benefit seen in the overall population and patients with moderate-to-strong CLDN18.2 expression in ≥70% of cancer cells [1].
A study on Japanese patients with CLDN18.2+, previously treated, locally advanced/metastatic gastric or gastroesophageal cancer observed a manageable toxicity profile of zolbetuximab, further suggesting that zolbetuximab may be a suitable option to combine with other drugs [2].
Ongoing clinical trials
The following studies are currently being conducted to assess the safety and effectiveness of zolbetuximab as monotherapy or combination therapy:
Phase II trial of zolbetuximab as monotherapy, in combination with pembrolizumab, or combination with chemotherapy (with or without nivolumab) (NCT03505320, “ILUSTRO”),
Phase III trial of efficacy, safety, and tolerability of zolbetuximab with mFOLFOX6 chemotherapy (NCT03504397, “SPOTLIGHT”) treatment for patients with locally advanced or metastatic gastric or gastroesophageal junction cancer and CLDN18.2 expression.
Phase III trial of zolbetuximab with CAPOX chemotherapy (NCT03653507, “GLOW”) as first-line treatment for patients with locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma and CLDN18.2 expression.
According to earlier findings, zolbetuximab has an adequate safety or tolerability profile, and adverse effects are manageable even after extended treatment periods. Mild-to-moderate intensity adverse effects like fatigue, nausea, and vomiting are most often reported. These adverse effects may be due to the targeted effect on the stomach tissues. These adverse effects on the stomach often become milder and/or less severe with continued drug delivery. Additionally, prior studies demonstrated that adding zolbetuximab to chemotherapy did not increase unexpected toxicities [1–4].
Conclusion
Gastric cancer remains an exceedingly lethal tumor and existing therapies have inadequate pertinence and benefit to improve progression-free and overall survival, especially in patients with advanced gastric cancer. This may be due to a lack of effective targets for treatment. Consequently, further studies on zolbetuximab as a viable therapy for individuals with advanced gastric cancer, particularly in combination with chemotherapy are necessary.
References
1. Sahin, U. et al. 'FAST: a randomised phase II study of zolbetuximab (IMAB362) plus EOX versus EOX alone for first-line treatment of advanced CLDN18.2-positive gastric and gastro-oesophageal adenocarcinoma'. Ann Oncol. (2021) 32(5), 609–619. DOI: 10.1016/j.annonc.2021.02.005.
2. Shitara, K. et al. 'Phase 1 trial of zolbetuximab in Japanese patients with CLDN18.2+ gastric or gastroesophageal junction adenocarcinoma'. Cancer Sci. (2023) 114(4), 1606–1615. DOI: 10.1111/cas.15684.
3. Türeci, O. et al. 'A multicentre, phase IIa study of zolbetuximab as a single agent in patients with recurrent or refractory advanced adenocarcinoma of the stomach or lower oesophagus: the MONO study'. Ann Oncol. (2019) 30(9), 1487–1495. DOI: 10.1093/annonc/mdz199.
4. Sahin, U. et al. 'A phase I dose-escalation study of IMAB362 (Zolbetuximab) in patients with advanced gastric and gastro-oesophageal junction cancer'. Eur J Cancer. (2018) 100, 17–26. DOI: 10.1016/j.ejca.2018.05.007.
