Second-Line Systemic Therapy Selection After ADC Exposure in HER2 Positive Metastatic Breast Cancer

This segment focuses on selecting second-line therapy following progression on trastuzumab deruxtecan, with particular attention to limited CNS involvement. The panel discusses prioritizing tucatinib-based regimens due to demonstrated CNS activity and robust systemic efficacy, especially for patients with small, asymptomatic brain metastases. The role of local CNS therapy versus immediate initiation of CNS-active systemic treatment is examined, highlighting scenarios where radiation may be deferred to preserve systemic disease control. Panelists weigh efficacy, toxicity profiles, treatment logistics, and patient preferences when choosing between HER2CLIMB-based therapy, alternative HER2-directed options, or clinical trial enrollment. The discussion reinforces individualized sequencing, emphasizing that CNS disease burden, symptom status, and prior ADC exposure are key drivers of second-line decision making.