In urgent clinical scenarios with very sick patients, chemotherapy remains the core initial treatment. Targeted or immunotherapies can be added later once results for key biomarkers like MSI, HER2, PD-L1, and CLDN18.2 are available. This prioritizes immediate patient stability over a delayed precision approach.

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.

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.

With the rise of targeted therapies, about 25% of gastric cancers are now considered "triple negative": Claudin-negative, HER2-negative, and PD-L1 negative. This newly defined subgroup represents a significant unmet need and highlights the necessity for novel treatment strategies beyond current biomarkers.

In the increasingly common scenario of gastric cancer with multiple biomarkers (HER2, PD-L1, Claudin), experts recommend a clear hierarchy. Based on data maturity, HER2-targeted therapy is the first choice, followed by PD-L1 immunotherapy, with Claudin-targeted therapy third.

While the monoclonal antibody zolbituximab requires high Claudin 18.2 expression (>=75%), newer antibody-drug conjugates (ADCs) like AZD-091 are effective in patients with much lower expression (>=25%). This evolution in drug modality significantly broadens the eligible patient population for a given therapeutic target.

Due to selective pressure from first-line treatment, 30-40% of HER2-positive gastroesophageal cancers lose HER2 expression by the time of progression. It is crucial to re-test these patients, either via tissue biopsy or ctDNA, to confirm continued HER2 positivity before initiating second-line HER2-targeted therapy like TDXD.

In the increasingly common scenario of a patient with multiple positive biomarkers, a clear hierarchy exists for treatment decisions. Based on the robustness and maturity of clinical trial data, HER2-directed therapy is the top priority, followed by PD-L1 immunotherapy, with Claudin-18.2 targeting considered third.

The HORIZON-GEA1 trial demonstrated that zanidatumab, a bispecific antibody, provides a significant survival benefit in HER2-positive gastroesophageal cancers, even in patients with PD-L1 negative tumors. This finding challenges the conventional wisdom that checkpoint inhibitors are the primary driver of benefit in combination therapies.