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.

Oncologists distinguish between HER2 amplification (the target for ADCs like TDXD) and activating mutations. A patient whose tumor loses amplification but retains a mutation is considered "HER2 mutated," not "HER2 positive," and is generally not a candidate for ADC 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.

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.

Experts indicate that Tumor Mutational Burden (TMB) is losing relevance for guiding immunotherapy in GI cancers. The TMB cutoff of 10 is not considered reliable across tumor types, and clinicians still prefer combination chemo-immunotherapy even in TMB-high patients, unless MMR deficiency is also present.

While immunotherapy is approved for gastroesophageal cancer with a PD-L1 CPS score of 1 or higher, clinical data reveals the most significant and durable survival benefit is largely confined to patients with high expression (CPS ≥10) or MSI-high status. The benefit for patients with CPS scores from 1 to 9 is considered borderline.

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.

Experts recommend using the most effective first-line therapy, like zanidatumab combinations, for HER2-positive gastric cancer, despite the risk of the tumor losing HER2 expression upon progression. The substantial upfront survival benefit outweighs the concern of losing a second-line target like T-DXd.