A New Era in HER2-Negative Gastric Cancer Treatment with Zolbetuximab
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Gastric cancer is the fifth most commonly diagnosed cancer worldwide, and its incidence has increased in recent years. Often causing few symptoms in its early stages, it is frequently diagnosed only after it has become advanced or metastatic (stage 4) . According to the US National Cancer Institute, the 5-year survival rate for patients with metastatic gastric cancer is only 7%. There is therefore an increasingly urgent need for first-line treatment options for patients with HER2-negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma.
For patients with gastric cancer or gastroesophageal junction adenocarcinoma, available targeted therapy options are very limited. Patients whose tumors express the PD-L1 protein can receive immunotherapy , while patients with HER2-positive tumors can be treated with trastuzumab or trastuzumab deruxtecan . However, patients with HER2-negative tumors may not fit either of these treatment categories or may be unable to receive targeted therapies. These patients often have levels of CLDN18.2, which is normally found in gastric mucosal cells and becomes more highly expressed as gastric cancer develops.
Zolbetuximab: New Hope
Zolbetuximab is an investigational monoclonal antibody directed against isoform 2 of Claudin-18 (CLDN18.2). It is being studied for the treatment of gastrointestinal and pancreatic cancers. In 2016, Astellas acquired the rights to zolbetuximab through its purchase of Ganymed. As of November 2021, the drug was in phase III clinical trials for gastric cancer.
The GLOW Study: Methods and Findings
The international phase III GLOW study, published on July 31, 2023 in Nature Medicine , evaluated 507 patients with previously untreated, HER2-negative, unresectable advanced or metastatic gastric cancer or gastroesophageal junction adenocarcinoma expressing CLDN18.2. Patients were randomly assigned to two groups: zolbetuximab plus chemotherapy containing capecitabine and oxaliplatin (CAPOX), or CAPOX plus placebo.
The study was conducted at 166 centers in 18 countries between November 2018 and February 2022.
- The researchers found that zolbetuximab plus CAPOX significantly improved progression-free survival compared with placebo plus CAPOX.
- Zolbetuximab plus CAPOX reduced the risk of disease progression or death by 31%.
- Median progression-free survival was 8.2 months in the zolbetuximab group and 6.8 months in the placebo group.
- Patients treated with zolbetuximab had a median overall survival of 14.4 months, compared with 12.2 months among those treated with placebo plus CAPOX.
- Adding zolbetuximab to standard chemotherapy (CAPOX) also doubled the likelihood of remaining free from disease progression for 2 years. This likelihood was 14% among patients receiving zolbetuximab, compared with only 7% among those receiving placebo.
In a separate international phase III study, SPOTLIGHT, recently published by Shitara and colleagues in The Lancet, researchers reported strong survival outcomes among patients receiving zolbetuximab with a different chemotherapy regimen containing modified folinic acid or levofolinate, fluorouracil and oxaliplatin (mFOLFOX).
Adverse Effects
Zolbetuximab is an intravenously administered monoclonal antibody that binds to CLDN18.2, directly killing cancer cells and activating the immune system. The most frequently reported treatment-related adverse effects were nausea, vomiting and reduced appetite.
Conclusion: Progress Toward a New Treatment
Following publication of the GLOW and SPOTLIGHT results, the FDA (US Food and Drug Administration) granted priority review to the manufacturer's biologics license application for zolbetuximab and set a target decision date of January 12, 2024.
For US patients with previously untreated HER2-negative, CLDN18.2-positive advanced gastric cancer or gastroesophageal junction adenocarcinoma, zolbetuximab could, if approved, become the first targeted treatment.
With evidence now available from two large studies, zolbetuximab appears to provide a meaningful survival benefit for CLDN18.2-positive gastric cancers.
This could fill an important treatment gap and prolong survival for patients with HER2-negative gastric cancer or gastroesophageal junction adenocarcinoma with low PD-L1 expression.
Sources
2. Shitara K, Lordick F, Bang YJ, et al. Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (SPOTLIGHT): a multicentre, randomised, double-blind, phase 3 trial. Lancet. 2023 May 20
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