Dr Tolaney on the Sequential Use of ADCs in Breast Cancer

Sara M. Tolaney, MD, MPH, chief, Division of Breast Oncology, associate director, Susan F. Smith Center for Women’s Cancers; senior physician, Dana-Farber Cancer Institute, associate professor, medicine, Harvard Medical School, discusses the sequential use of antibody-drug conjugates (ADCs) in the treatment of patients with breast cancer.

The optimal sequential use of ADCs in breast cancer remains unclear due to the lack of completed prospective clinical trials that clarify the sequential efficacy of these agents, Tolaney begins. The field’s current understanding is primarily derived from retrospective data of patients treated with sequential ADCs, complemented by real-world datasets, according to Tolaney. The consensus is that progression-free survival (PFS) with the second ADC tends to be shorter than with the first, she reports; however, this observation is not universally consistent, presenting a significant challenge, Tolaney explains.

For example, there are instances where individual patients exhibit varied responses when treated sequentially with ADCs, she expands. Some patients who do not respond well to the first ADC may experience a remarkable response to the second, whereas others who have an excellent response to the first ADC may have a much shorter duration of response with the subsequent ADC, Tolaney states. This variability indicates that oncologists do not fully understand why some patients benefit from a second ADC and others do not, indicating a gap in knowledge about mechanisms of resistance to ADCs, she says.

Tolaney hypothesizes that this disparity in patient responses to sequential ADCs could be related to payload resistance. The benefit from the second ADC may be limited if it contains the same type of chemotherapy as the first ADC, she adds. However, the situation is undoubtedly more complex, involving factors such as target expression and lysosomal processing, which oncologists do not fully comprehend, Tolaney emphasizes.

Given these uncertainties, there is a need for prospective studies to explore these questions further, she says. Although ongoing studies are in progress, at present, many oncologists continue to use sequential ADCs despite the limited data supporting this practice, Tolaney concludes.