Zolbetuximab for gastroesophageal adenocarcinoma: drug review and lessons from the frontlines
Zolbetuximab, the first FDA-approved anti-CLDN18.2 monoclonal antibody for advanced gastric and gastroesophageal junction adenocarcinoma, has demonstrated impressive results in clinical trials, though real-world implementation faces challenges including significant gastrointestinal toxicity, complex administration requirements and the need for careful patient selection and supportive care management. This Drug Evaluation from Future Oncology provides practical guidance for navigating these hurdles in everyday clinical practice.
Abstract
Molecular distinctions have started to define treatment decisions in advanced gastric adenocarcinoma (GAC) and gastroesophageal junction adenocarcinoma (GEJAC), malignancies in need of improved outcomes. Claudin 18.2 (CLDN18.2) represents a new selective GAC/GEJAC target, with multiple agents currently in the developmental pipeline. Zolbetuximab, an anti-CLDN18.2 monoclonal antibody, is the first agent to market for this target. It received FDA approval following Phase III trials in which zolbetuximab combined with upfront fluoropyrimidine plus platinum therapy resulted in improved coveted endpoints compared to fluoropyrimidine plus platinum alone in CLDN18.2 positive advanced GAC patients (2+ or 3+ intensity in ≥75% of tumor cells). The most common adverse events are gastrointestinal, primarily nausea and vomiting during initial treatment cycles, particularly in those with an intact stomach (i.e. no prior surgery). Real-world implementation of zolbetuximab is complicated by cumbersome administration times, short drug stability, extended observation time, and difficult tolerability. This report describes our experience in implementing zolbetuximab in clinical practice and provides an extensive drug evaluation.
Plain Language Summary
Zolbetuximab is a new drug used to treat advanced cancers of the stomach and the area between the stomach and esophagus. It is the first drug in a new class that targets a marker on stomach or stomach esophagus junction cancer cells called claudin 18.2. Many agents are being studied that target this protein. Zolbetuximab is given in combination with chemotherapy. This increased survival compared to chemotherapy alone. The most common side effects are nausea and vomiting. Specific guidance is available on how to reduce nausea and vomiting, with changes likely to come as the drug is more widely used. Our review focuses on how this drug came to market and considerations for its use in everyday practice.
Article highlights
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Zolbetuximab is a monoclonal antibody that targets claudin 18.2 (CLDN18.2), a new target in advanced GAC/GEJAC.
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Zolbetuximab is approved to be given in combination with front-line fluoropyrimidine plus oxaliplatin in advanced CLDN18.2 positive (≥75% CLDN18.2 expression 2+ and 3+) GEAC patients.
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Nausea and vomiting are the main toxicities of zolbetuximab, particularly in patients with an intact stomach and/or in the first few cycles of therapy.
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As of current data, a high emetogenic prophylaxis regimen should be utilized in conjunction with acid suppression.
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Issues with cumbersome administration rates, potentially unnecessary observation times, short stability, and management of gastrointestinal toxicity have made zolbetuximab use in the real world challenging.