Dr Rimm on Conceptual Considerations Surrounding ADC Mechanisms in Breast Cancer

"It's not definitively shown that ADCs are either chemotherapy or targeted therapy. There is some evidence that they're just chemotherapy and that the ADC gets cleaved externally, [meaning] it's just a lower or different type of dosing of the chemotherapeutic payload. There's plenty of evidence that the target makes a difference, that bringing the payload to the target makes the drug much more effective. In my experience, when there's a controversy like this, both parties are correct.”

David Rimm, MD, PhD, the Anthony N. Brady Professor of Pathology and Professor of Medical Oncology at Yale Cancer Center, discussed key conceptual considerations regarding the mechanisms of action of antibody-drug conjugates (ADCs) as highlighted in his presentation at the 2025 San Antonio Breast Cancer Symposium and how these principles should inform oncologists’ interpretation of emerging data in breast cancer and across tumor types.

Although not specific to a single disease setting, his commentary highlighted the evolving understanding of how ADCs exert antitumor activity and underscored why the field continues to debate whether these agents function primarily as targeted therapies, as modified forms of cytotoxic chemotherapy, or as a hybrid of both.

Rimm emphasized that despite the widespread classification of ADCs as “targeted therapies,” definitive mechanistic clarity remains elusive. He noted that there is credible evidence supporting 2 contrasting but not mutually exclusive models. In one model, ADCs act largely as chemotherapeutic agents, with the cytotoxic payload being cleaved extracellularly—prior to internalization—resulting in nonspecific delivery of the drug in a manner analogous to traditional chemotherapy but at different concentrations and local exposures. Conversely, substantial experimental data indicate that the presence and density of the target antigen meaningfully influence therapeutic effect, suggesting that the intended mechanism—selective delivery of cytotoxic payload to antigen-expressing tumor cells—remains operational and clinically relevant.

Rimm stressed that the coexistence of these datasets and viewpoints suggests a dual-mechanism model, rather than an either/or explanation. In his experience, when scientific controversy arises in oncology over seemingly competing mechanisms, it is often because elements of both models contribute to clinical activity. He anticipates that this will likely prove true for ADCs, with target-dependent internalization and target-independent extracellular payload release both influencing efficacy to varying degrees depending on the tumor type, antigen expression, microenvironment, and ADC design.

For practicing oncologists, Rimm underscored that recognition of this dual contribution is essential. Target expression remains an important determinant of benefit, but it should not be viewed as the sole factor guiding selection or predicting therapeutic activity. Instead, he encouraged clinicians to approach ADC interpretation with nuance by recognizing that the therapeutic behavior of these agents may fall along a mechanistic spectrum rather than fitting neatly into a single paradigm.

Ultimately, Rimm noted that the goal of discussions like this is to provide clinicians with a balanced understanding of ADC mechanisms so that treatment decisions can incorporate both biological plausibility and the evolving clinical evidence base.