The Scottish Medicines Consortium (SMC) has approved zolbetuximab (Vyloy, Astellas Pharma) for treating advanced gastric and gastro-oesophageal junction (GEJ) cancer in combination with fluoropyrimidine- and platinum-containing chemotherapy. 

This precision medicine is indicated for adult patients with locally advanced unresectable or metastatic HER2-negative adenocarcinoma whose tumours express the CLDN18.2 protein. The decision marks the first national reimbursement recommendation within NHS Scotland for a CLDN18.2-targeted therapy.

Russell Petty, professor of medical oncology and director of Tayside Medical Science Centre School of Medicine at the University of Dundee, welcomed the decision, saying that “by moving beyond one-size-fits-all methods and targeting specific features of a tumour, like CLDN18.2, it’s possible to deliver more effective therapies, ultimately extending a patient’s time with their loved ones.”

How Zolbetuximab Works

Zolbetuximab is a first-in-class monoclonal antibody that targets CLDN18.2, a tight-junction protein expressed on gastric epithelial cells. When stomach lining cells become cancerous, CLDN18.2 proteins may become exposed, allowing zolbetuximab to bind to cancer cells and enable the immune system to attack and destroy them. The drug eliminates CLDN18.2-positive cells through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity mechanisms. 

It is estimated that 38% of patients with locally advanced unresectable or metastatic gastric and GEJ adenocarcinomas will be CLDN18.2-positive.

High-Mortality Cancer With Limited Options

Gastric cancer is the fifth most common cancer worldwide and the fourth leading cause of cancer death, accounting for more than 700,000 deaths in 2020. 

In the UK, gastric cancer represents around 2% of all new cancer cases. About half of all occur in people aged 75 years or older, and incidence is approximately twice as high in men as in women. 

Because early symptoms are often nonspecific, the disease is frequently diagnosed at an advanced stage, and curative treatment is not feasible for about 60% of patients. One-year survival for metastatic gastric or GEJ cancer is estimated at around 20%.

Clinical Evidence and Dosing

The SMC approval was based on results from the phase 3 SPOTLIGHT and GLOW trials, which together recruited 1072 patients. 

In the SPOTLIGHT trial, median progression-free survival (PFS) was 10.61 months with zolbetuximab plus mFOLFOX6 (folinic acid, fluorouracil, and oxaliplatin) compared with 8.67 months with placebo plus mFOLFOX6. Median overall survival (OS) was 18.23 months vs 15.54 months, respectively. 

The GLOW trial showed similar efficacy findings, with median PFS of 8.21 months vs 6.80 months, and median OS of 14.39 months vs 12.16 months with zolbetuximab plus CAPOX (capecitabine and oxaliplatin) compared with placebo plus CAPOX.

The recommended loading dose of zolbetuximab is 800 mg/m² administered intravenously (IV) on cycle 1, day 1. The recommended maintenance dose is either 600 mg/m² by IV infusion every 3 weeks or 400 mg/m² via IV infusion every 2 weeks. Treatment should continue until disease progression or unacceptable toxicity. 

The most frequently reported treatment-emergent adverse events in the zolbetuximab groups were nausea, vomiting, and decreased appetite. 

Clinical Impact and Implementation

Clinical experts consulted by the SMC considered that zolbetuximab combined with chemotherapy addresses an unmet need and represents a meaningful therapeutic advance, particularly for patients who are ineligible for or have contraindications to immunotherapy. 

Implementation may have resource implications for healthcare services, including increased chair time and additional demand on aseptic pharmacy services. Routine testing for CLDN18.2 expression will also be required, with potential impact on pathology and diagnostic workflows.

An estimated 386 patients a year in Scotland have advanced or metastatic gastric cancer that cannot be removed surgically or has spread to other parts of the body. Under current guidance, approximately 67 patients annually are expected to be eligible for treatment with zolbetuximab. The approval applies only within the framework of an NHS Scotland Patient Access Scheme, which underpins the cost-effectiveness assumptions supporting the decision.