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.

In the SPOTLIGHT trial, adding zolbituximab to FOLFOX for Claudin-18.2 positive patients improved progression-free and overall survival. However, it did not significantly increase the objective response rate, demonstrating that survival benefit can be decoupled from tumor shrinkage metrics.

To mitigate the severe toxicity of promising pan-RAS inhibitors, companies are adopting antibody-drug conjugate (ADC) technology. This marks a strategic expansion for ADCs, moving beyond traditional cytotoxic chemotherapy payloads to delivering highly specific targeted therapies, aiming to improve the therapeutic window of potent new drug classes.

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.

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.

Zolbituximab causes significant nausea and vomiting as a direct result of binding its Claudin 18.2 target in the stomach. Its clinical success depends on aggressively managing this on-target effect with prophylactic multi-drug antiemetics and adjusted infusion rates, particularly during the initial treatment cycle.

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 prior speculation of a slowdown, the prominence of Antibody-Drug Conjugates (ADCs) in first-in-human trials at ASCO is "skyrocketing." The volume of new ADC trials now nearly equals that of small molecules and far surpasses traditional monoclonal antibodies.

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.