Many breast cancers counted as "HER2-negative" actually have a small amount of the HER2 protein (HER2-low). Before this study, anti-HER2 drugs were of no use for these patients. In DESTINY-Breast04, people with metastatic disease who had already had one or two kinds of chemotherapy received a drug called trastuzumab deruxtecan (Enhertu); this is an "antibody linked to a drug" that delivers chemotherapy directly to cells carrying HER2. Compared with usual chemotherapy, this drug roughly doubled the time the disease was kept under control and helped patients live several months longer. The most important side effect to watch for is lung inflammation; if you develop a new cough, shortness of breath or fever, tell your care team straight away.
HER2-positive after prior anti-HER2 therapy; HER2-low (IHC 1+ or 2+ with negative ISH) after prior chemotherapy; HR-positive HER2-low or HER2-ultralow (IHC 0 with membrane staining) after one or more lines of hormone therapy
| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Trastuzumab deruxtecan (T-DXd) | 5.4 mg/kg | IV | Day 1 |
On the page “Breast cancer” · Advanced HER2-positive and HER2-low disease
Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.
Trastuzumab deruxtecan (Enhertu) 5.4 mg per kg of body weight, IV infusion every 3 weeks, until disease progression or unacceptable toxicity.
Single-agent chemotherapy of the physician's choice (chosen before randomisation): capecitabine, eribulin, gemcitabine, paclitaxel or nab-paclitaxel, at the dose per each drug's label (ClinicalTrials.gov NCT03734029).
Source of the regimen details: FDA label for Enhertu (ENHERTU, 2026-05 version, sections 2 and 14); control drugs from ClinicalTrials.gov NCT03734029 (dose per each drug's label).
Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.
Adults with metastatic or unresectable breast cancer with low HER2 expression (HER2-low; IHC 1+ or IHC 2+ with negative ISH) who had received one or two prior lines of chemotherapy in the metastatic setting (or had relapsed during or within 6 months after adjuvant chemotherapy). Hormone receptor-positive patients had to have received at least one endocrine therapy or be ineligible for it. Of the 557 patients, 494 (88.7%) were hormone receptor-positive and 63 (11.3%) hormone receptor-negative.
Primary endpoint: progression-free survival (PFS) in the hormone receptor-positive cohort.
Key secondary endpoints: progression-free survival in all patients and overall survival (OS) in the hormone receptor-positive cohort and in all patients.
Grade 3 or higher adverse events occurred in 52.6% of the trastuzumab deruxtecan group and 67.4% of the chemotherapy group. Drug-related interstitial lung disease (ILD) or pneumonitis (adjudicated by an independent committee) occurred in 12.1% of the trastuzumab deruxtecan group, and 0.8% had a grade 5 (fatal) event.
This study brought "HER2-low" into practice as a new treatment category. In August 2022 (5 August 2022) the US Food and Drug Administration (FDA) approved trastuzumab deruxtecan for metastatic or unresectable HER2-low breast cancer in patients who have received prior chemotherapy in the metastatic setting (or relapsed within 6 months of adjuvant chemotherapy), and this indication remains in the current label.
The trial was open-label (unblinded). The number of hormone receptor-negative patients (63) was small and results in this subgroup are exploratory. HER2-low assessment by IHC has limited reproducibility between laboratories. The risk of interstitial lung disease requires close monitoring.
This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.
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