HER2+ Advanced Breast Cancer: Systemic Therapy

HER2+ Advanced Breast Cancer: overview

This algorithm sequences systemic therapy for HER2-positive advanced breast cancer by line of treatment.

In the first line, the preferred regimen is THP (pertuzumab, trastuzumab and docetaxel) followed by maintenance HP, supported by CLEOPATRA, in which dual HER2 blockade plus docetaxel improved both progression-free and overall survival over trastuzumab plus docetaxel. In the second line, the antibody-drug conjugate trastuzumab deruxtecan is shown, based on DESTINY-Breast03, which demonstrated superior progression-free survival and an overall survival benefit versus T-DM1 after prior trastuzumab and taxane; the chart flags it as CNS-active. For third-line and later therapy, options include tucatinib plus trastuzumab plus capecitabine (HER2CLIMB), also flagged as CNS-active and relevant for brain metastases; T-DM1 (EMILIA), which improved survival over lapatinib plus capecitabine; neratinib or lapatinib plus capecitabine (NALA); and the Fc-engineered antibody margetuximab plus chemotherapy (SOPHIA).

Trials behind this algorithm

CLEOPATRA Swain SM et al, NEJM, 2015; PMID: 25693012
DESTINY-Breast03 Cortes J et al, NEJM, 2022; PMID: 35320644
HER2CLIMB-05 Dieras V et al, Journal of Clinical Oncology, 2025; PMID: 41369677
EMILIA Verma S et al, NEJM, 2012; PMID: 23020162

Background reading: Breast Cancer (Part 2): DCIS, Early-Stage and Metastatic Treatment board review notes.

HER2+ Advanced Breast Cancer: the algorithm in words

Starting point: HER2+ advanced breast cancer. Full background: Breast Cancer (Part 2): DCIS, Early-Stage and Metastatic Treatment notes.

First-line (first-line): Preferred: THP → maintenance HP (CLEOPATRA).
Second-line (second-line): ADC: Trastuzumab deruxtecan (DESTINY-Breast03).
Third-line + (later-line): CNS-active: Tucatinib + trastuzumab + cape (HER2CLIMB); ADC: T-DM1 (EMILIA); Oral TKI: Neratinib / lapatinib + cape (NALA); Fc-engineered: Margetuximab + chemo (SOPHIA).