Is Imfinzi (durvalumab) recommended as first-line treatment for gastric cancer with claudin 18 positive status?

Imfinzi (Durvalumab) is NOT Currently Recommended for First-Line Treatment of Claudin 18.2 Positive Gastric Cancer

Zolbetuximab plus chemotherapy, not Imfinzi (durvalumab), is the recommended targeted therapy for first-line treatment of Claudin 18.2 positive, HER2-negative gastric cancer. 1

Current Treatment Recommendations for Claudin 18.2 Positive Gastric Cancer

Biomarker Testing

Before initiating first-line treatment for gastric cancer, testing for the following biomarkers is strongly recommended:

• HER2 status
• PD-L1 Combined Positive Score (CPS)
• Microsatellite instability (MSI) status
• Claudin 18.2 expression 1

Treatment Algorithm for Claudin 18.2 Positive Gastric Cancer

1. First determine HER2 status:

   • If HER2-positive: Trastuzumab plus chemotherapy remains the standard first-line treatment regardless of Claudin 18.2 status 1
   • If HER2-negative: Proceed to step 2

2. For HER2-negative, Claudin 18.2 positive cases:

   • Definition of Claudin 18.2 positivity: Moderate to strong (2+/3+) membranous staining in ≥75% of tumor cells 1
   • Recommended treatment: Zolbetuximab plus chemotherapy 1, 2

Evidence Supporting Zolbetuximab

The recommendation for zolbetuximab is based on two pivotal phase III clinical trials:

• SPOTLIGHT trial: Demonstrated significantly prolonged progression-free survival (PFS) and overall survival (OS) with zolbetuximab plus chemotherapy compared to chemotherapy plus placebo in Claudin 18.2 positive, HER2-negative gastric and gastroesophageal junction adenocarcinoma 1
• GLOW trial: Similarly showed improved PFS and OS with zolbetuximab plus chemotherapy 1

These trials established zolbetuximab plus chemotherapy as a new standard of care for patients with Claudin 18.2-positive, HER2-negative locally advanced or metastatic gastric cancer 3.

Important Considerations for Claudin 18.2 Testing

Analytical Requirements

• Testing should be performed on formalin-fixed, paraffin-embedded tissues
• Both isoform-specific or pan-claudin-18 antibodies can be used (CLDN18.1 expression in gastric tissues is negligible) 1

Staining Evaluation

• Positive staining requires crisp membranous staining (complete, basolateral, or lateral)
• Staining intensity is scored from 0 to 3+ (absent, weak, moderate, strong)
• The cutoff for treatment eligibility is moderate to strong (2+/3+) positive membrane staining in ≥75% of tumor cells 1

Potential Pitfalls in Testing

• Intratumoral heterogeneity is common with CLDN18.2 expression
• Superficial areas tend to have higher CLDN18.2-positive rates than the invasive front
• Precursor lesions (intestinal metaplasia and dysplasia) may express CLDN18.2 but should not be included in scoring 1, 4
• Cases with 60-80% positivity should be reviewed by a second pathologist 1

Clinical Characteristics of Claudin 18.2 Positive Gastric Cancer

Claudin 18.2 positive gastric cancer is associated with:

• Younger age
• Female sex
• Non-gastroesophageal junction location
• Diffuse histological phenotype
• Higher rates of peritoneal dissemination
• Lower rates of liver metastasis
• Lower expression of HER2 and PD-L1 4, 5

Why Not Durvalumab (Imfinzi)?

There is no evidence in the provided guidelines or research supporting the use of durvalumab (Imfinzi) for first-line treatment of Claudin 18.2 positive gastric cancer. The current guidelines and clinical trials specifically recommend zolbetuximab in combination with chemotherapy for this patient population 1, 2, 6, 3.

Future Directions

Research is ongoing to explore:

• Combinations of anti-CLDN18.2 therapy with immunotherapy
• Newer CLDN18.2-targeting approaches including antibody-drug conjugates, CAR-T cell therapy, and bispecific antibodies 3
• Optimal treatment for patients with dual positivity for CLDN18.2 and other biomarkers 5