For a significant subset of gastroesophageal cancer patients (around 30%), Claudin-18.2 positivity is their sole actionable biomarker. These patients are negative for PD-L1, HER2, and mismatch repair deficiency, making universal Claudin testing essential to identify all candidates for targeted therapy.
A pragmatic solution to prevent testing delays is for pathology departments to universally test all new gastric cancer biopsies for Claudin-18.2, MMR, HER2, and PD-1, irrespective of the patient's clinical stage. This operational decision streamlines care, even though some markers lack labels in early-stage disease.
Next-generation Claudin-18.2 antibody-drug conjugates (ADCs) demonstrate efficacy with a biomarker cutoff of just 25% staining. This is much lower than the 75% cutoff required for the antibody zolbituximab, potentially expanding the treatable patient population for this target.
In non-metastatic, mismatch repair deficient (dMMR) esophagogastric cancer, a chemotherapy-free neoadjuvant regimen of ipilimumab and nivolumab results in a ~60% pathologic complete response (pCR) rate. The subsequent long-term survival curves are nearly flat, questioning the need for chemotherapy.
In patients with multiple positive biomarkers, a clear treatment hierarchy exists. Mismatch repair (MMR) status is the most important driver, followed by HER2 positivity. The choice between targeting high PD-L1 or Claudin-18.2 is a clinical judgment call based on the level of PD-L1 expression.
The bispecific antibody zanidatumab is more effective than trastuzumab because it binds two separate HER2 receptors ("in trans"). This locks them together on the cell surface, a state cells dislike, which potently activates the complement system to induce cell death—a different primary mechanism than trastuzumab.
Unlike other subtypes of gastroesophageal cancer that rarely spread to the brain, the HER2-positive subset is an exception. Clinicians should maintain a high index of suspicion and a lower threshold for brain imaging when these specific patients present with any unusual neurological symptoms.
For the first time in metastatic gastric cancer, a clinical trial (Horizon) has demonstrated a median overall survival exceeding two years. This was achieved with zanidatumab-based combinations in HER2-positive patients, establishing a new benchmark for outcomes in this historically difficult-to-treat disease.