For more than ten years, the standard first treatment for HER2-positive metastatic breast cancer was taxane chemotherapy combined with two antibodies, trastuzumab and pertuzumab (THP). In DESTINY-Breast09, replacing the chemotherapy and trastuzumab with trastuzumab deruxtecan (Enhertu) plus pertuzumab increased the average time the disease was kept under control from about 27 months to about 41 months, and complete disappearance of the tumour almost doubled. Lung inflammation is an important side effect that must be followed carefully. Overall survival data are still awaited.
HER2-positive metastatic disease, first-line
| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Trastuzumab deruxtecan (T-DXd) | 5.4 mg/kg | IV | Day 1 |
| Pertuzumab | Cycle 1: 840 mg; then 420 mg | IV, 30 min after T-DXd | Day 1 |
Because of the risk of ILD and the absence of crossover, NCCN lists this combination among “other recommended options”.
On the page “Breast cancer” · Advanced HER2-positive and HER2-low disease
HER2-positive metastatic or unresectable breast cancer, first line
| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Trastuzumab deruxtecan | 5.4 mg/kg | IV infusion; initial 90 minutes, then 30 minutes | Day 1 |
| Pertuzumab | Cycle 1: 840 mg; then 420 mg | IV, 30 minutes after trastuzumab deruxtecan | Day 1 |
As in the Enhertu label; pertuzumab must not be given alone.
On the page “Pertuzumab (Perjeta)” · With trastuzumab deruxtecan (Enhertu label)
HER2-positive metastatic or unresectable breast cancer, first line
| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Trastuzumab deruxtecan (Enhertu) | 5.4 mg/kg | IV infusion; initial 90 minutes, then 30 minutes if tolerated | Day 1 |
| Pertuzumab | Cycle 1: 840 mg; then 420 mg | IV, 30 minutes after Enhertu | Day 1 |
Pertuzumab must not be given alone.
On the page “Trastuzumab deruxtecan (Enhertu)” · Dose and schedule (FDA label)
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 5.4 mg per kg with pertuzumab, both by IV infusion every 3 weeks, until disease progression or unacceptable toxicity. Pertuzumab dose per the FDA-approved dosing for this combination: 840 mg on day 1 of the first cycle, then 420 mg on day 1 of subsequent cycles.
A taxane (docetaxel or paclitaxel, investigator's choice) with trastuzumab and pertuzumab, IV in 3-week cycles. THP drug doses are not stated in the available sources (label and ClinicalTrials.gov).
Trastuzumab deruxtecan 5.4 mg per kg every 3 weeks with a pertuzumab-matching placebo. Results of this arm remain blinded until the final progression-free survival analysis and are not reported in this paper.
Source of the regimen details: FDA label for Enhertu (DailyMed, sections 2 and 14; trastuzumab deruxtecan + pertuzumab) and ClinicalTrials.gov NCT04784715 (investigator's choice of taxane: docetaxel or paclitaxel); THP drug doses are not stated in the available sources
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 advanced or metastatic HER2-positive breast cancer (IHC 3+ or ISH-positive, centrally confirmed) with no prior chemotherapy or anti-HER2 therapy for metastatic disease. According to the FDA label, neoadjuvant or adjuvant anti-HER2 therapy more than 6 months before diagnosis of metastatic disease and one prior line of endocrine therapy for advanced disease were allowed.
Primary endpoint: progression-free survival (PFS) by blinded independent central review.
Secondary endpoints: objective response, duration of response and safety (and overall survival).
Grade 3 or higher adverse events: 63.5% with trastuzumab deruxtecan + pertuzumab and 62.3% with THP; the most common were neutropenia, hypokalaemia and anaemia in the trastuzumab deruxtecan + pertuzumab group, and neutropenia, leucopenia and diarrhoea in the THP group. Drug-related interstitial lung disease or pneumonitis occurred in 12.1% of the trastuzumab deruxtecan + pertuzumab group (grade 1 or 2 in 44 patients and grade 5 [death] in 2 patients) and in 1.0% of the THP group (all grade 1 or 2).
On 15 December 2025 the FDA approved trastuzumab deruxtecan with pertuzumab for first-line treatment of adults with HER2-positive (IHC 3+ or ISH-positive) metastatic or unresectable breast cancer; the first new first-line option in this disease in more than a decade. The trastuzumab deruxtecan + placebo arm has not yet been reported.
Results are from an interim analysis and overall survival data are immature. The trastuzumab deruxtecan monotherapy arm (with placebo) has not yet been reported, so the contribution of pertuzumab to the observed benefit is unclear. In the THP group, treatment continued with the antibodies after the taxane was stopped, whereas trastuzumab deruxtecan continued until progression. The risk of interstitial lung disease with long-term use requires 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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