Metastatic HER2-positive Breast Cancer

Sequencing for HER2-positive metastatic breast cancer: taxane + dual HER2 blockade first line, trastuzumab deruxtecan second line, and a CNS-guided third-line choice between the tucatinib triplet and T-DM1.

1L: Docetaxel + trastuzumab + pertuzumab (THP)

Dual HER2 blockade with a taxane is the frontline standard; drop the taxane and continue trastuzumab + pertuzumab maintenance after best response. Monitor LVEF.

Evidence: CLEOPATRA

• Progression → Trastuzumab deruxtecan (T-DXd)

2L: Trastuzumab deruxtecan (T-DXd)

Superior to T-DM1 in the second line. Vigilantly monitor for interstitial lung disease/pneumonitis; hold and evaluate for any new respiratory symptoms.

Evidence: DESTINY-Breast03

• Progression → Active CNS (brain) involvement?

Active CNS (brain) involvement?

• Active brain metastases → Tucatinib + trastuzumab + capecitabine
• No active CNS disease → Trastuzumab emtansine (T-DM1) or other HER2-directed options

3L+: Tucatinib + trastuzumab + capecitabine

Preferred with active/progressing brain metastases given demonstrated intracranial activity. Monitor LFTs and diarrhea.

Evidence: HER2CLIMB

3L+: Trastuzumab emtansine (T-DM1) or other HER2-directed options

Without active CNS disease, T-DM1 and the tucatinib triplet are both reasonable; additional lines include margetuximab and lapatinib-based regimens.