Modern antibody-drug conjugates (ADCs) like trastuzumab deruxtecan can kill nearby cancer cells that don't express the target protein. This 'bystander effect' is a game-changer, allowing ADCs to be effective even in tumors with varied (heterogeneous) protein expression, which has historically been a major clinical challenge.

Unlike early ADCs requiring high biomarker expression (e.g., mirvetuximab), next-generation agents show efficacy even in low-expressing tumors. This allows for broader, "all-comer" clinical trial inclusion criteria instead of biomarker-gated entry, potentially expanding patient access to these novel therapies.

The long-term separation of survival curves for zolbetuximab, a Claudin 18.2 antibody, suggests it does more than just target a protein. The "tail on the curve" effect is similar to that seen with immunotherapies, indicating that zolbetuximab may be activating a durable, sustained anti-tumor immune response.

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.

The difficulty in finding a single predictive biomarker for antibody-drug conjugate (ADC) efficacy suggests that complex, multi-marker classifiers, like those in the ISPY 2.2 trial, represent the future for guiding ADC therapy selection over simple IHC cutoffs.

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.

Unlike older antibody-drug conjugates (ADCs), newer agents are designed so their chemotherapy payload can diffuse out of the target cell and kill nearby tumor cells that may not even express the target antigen. This "bystander effect" significantly enhances their anti-tumor activity.

Despite being "targeted therapies," multiple promising antibody-drug conjugates (ADCs) for small cell lung cancer (SCLC) show no correlation between the target protein's expression level and patient response. This suggests the payload or other factors are the primary drivers of efficacy, complicating biomarker development for patient selection.

Clinicians are cautioned against oversimplifying ADCs. Factors like linker chemistry, cleavability, and drug-antibody ratio are critical variables. Even with the same target and payload class, these biochemical nuances can lead to profoundly different efficacy and toxicity profiles.