The Shifting Paradigm in Second-Line HER2+ mBC Therapy

Second-Line Treatment Evolution

Current second-line treatment after THP progression predominantly features trastuzumab deruxtecan (T-DXd), supported by impressive DESTINY-Breast03 data showing nearly 29 months progression-free survival. This represents the standard approach for most patients, with brain metastases historically directing treatment with the HER2CLIMB regimen with tucatinib. However, recent data has shifted this paradigm, with DESTINY-Breast12 demonstrating T-DXd efficacy in central nervous system (CNS) disease through prospective enrollment of brain metastases patients.

The sequencing algorithm is evolving with new first-line options. If T-DXd moves to first-line use, HER2CLIMB regimen becomes the preferred second-line option due to its brain penetration and overall efficacy across patient subgroups. ado-trastuzumab emtansine (T-DM1) remains a viable option for patients preferring less intensive treatment, offering good tolerance with every-3-week administration and minimal alopecia, though it lacks CNS activity.

Treatment selection increasingly considers CNS-directed therapy benefits, with data suggesting tucatinib-based regimens may delay brain metastases development. This prevention aspect influences sequencing decisions, as using CNS-active agents earlier may provide long-term benefits. The approach balances immediate disease control needs with potential future CNS complications, particularly relevant given high brain metastases rates in HER2-positive disease.