Dr McCann on Sequential ADC Use in HER2+ Metastatic Breast Cancer

“Using ADC after ADC, if the payload is the same, there is a significant cross-resistance, which we’ve seen in many retrospective analyses, but now this is a prospective trial that also bore that out.”

Kelly Elizabeth McCann, MD, PhD, an associate professor at the University of California San Diego, discussed the clinical implications of findings from the phase 2 SATEEN trial (NCT05113251), which evaluated sacituzumab govitecan-hziy (Trodelvy) plus trastuzumab (Herceptin) following prior fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) in patients with HER2-positive metastatic breast cancer.

McCann explained that this clinical evaluation is essential as the oncology field navigates the complexities of antibody-drug conjugate (ADC) sequencing, particularly when sequential treatments share nearly identical cytotoxic components. Similar to the focus on survival outcomes in other breast cancer paradigms, this trial sought to provide clarity on the objective response rate (ORR) when patients receive sequential agents with similar mechanisms of action, she contextualized.

McCann emphasized that the most significant consideration in this clinical context is the similarity between the payloads of T-DXd and sacituzumab govitecan. Although various retrospective analyses have previously indicated cross-resistance with the use of these 2 agents, this prospective trial offered definitive evidence of the phenomenon, showing a low ORR, with only 1 patient in the trial achieving a response, she said. These findings suggest that the clinical utility of using one ADC immediately after another is limited if the payload of the ADCs remains the same, she reported. Furthermore, the trial incorporated the drawing of biomarkers to better understand the underlying biology of cross-resistance, providing data that could influence future treatment algorithms and the selection of subsequent therapeutic lines, she added.

However, McCann noted that these results underscore a broader challenge in clinical practice regarding the treatment of patients who have already received heavy pretreatment. This necessitates a shift in how the oncology field should approach ADC sequencing, she continued. Ultimately, McCann concluded that although the SATEEN trial was relatively small, its prospective nature confirms the risks of payload redundancy, highlighting the need for more diverse therapeutic strategies for patients who have progressed on initial ADC therapies.