Sequencing Beyond T-DXd: TKIs, ADCs, and Individualized Decision-Making

This segment addresses one of the most uncertain and clinically challenging areas in HER2-positive metastatic breast cancer: treatment sequencing after progression on T-DXd. Dr. Gadi frames his approach around a guiding principle, using the most effective therapy as early as possible, while acknowledging that evidence becomes increasingly limited once patients progress beyond T-DXd, the current cornerstone of care.

After T-DXd progression, Dr. Gadi favors changing the mechanism of action rather than continuing within the same therapeutic class. From this perspective, tucatinib-based regimens combined with chemotherapy and trastuzumab are particularly appealing, even though prospective data in the post–T-DXd setting are lacking. He notes that these regimens demonstrated strong efficacy before T-DXd entered the landscape and, importantly, offer CNS penetration, an essential consideration given the high frequency of brain metastases at progression.

The discussion then turns to the controversial concept of ADC-after-ADC sequencing. Although this strategy raises concerns in other breast cancer subtypes where many ADCs share similar payloads, HER2-positive disease may be more flexible. Dr. Gadi highlights that T-DM1 differs mechanistically from T-DXd, using a microtubule-inhibitor payload rather than a topoisomerase I inhibitor, which may allow sequential use. He also stresses the importance of reassessing HER2 expression through biopsy at progression, as loss or reduction of HER2 could meaningfully influence therapeutic choices. Importantly, he cautions against rigid assumptions, noting early-phase experiences where ADCs with similar mechanisms still demonstrate activity, potentially due to differences in linker technology or drug delivery.

Dr. Mouabbi adds real-world insight, citing a single-institution report suggesting preserved T-DM1 activity after T-DXd, offering early reassurance that ADC sequencing may be feasible. Finally, Dr. Gradishar grounds the discussion in patient-centered care, emphasizing that toxicity profiles, comorbidities, adherence, organ function, and patient preferences all critically shape regimen selection, even when efficacy remains the primary goal in the metastatic setting.