Trastuzumab deruxtecan (Enhertu) — Clinical FAQs

Q: How does Trastuzumab deruxtecan work (mechanism of action)?

HER2-directed antibody-drug conjugate (ADC) consisting of a humanized anti-HER2 IgG1 monoclonal antibody (same as trastuzumab) conjugated to a cleavable tetrapeptide linker attached to a topoisomerase I inhibitor payload (deruxtecan, DXd — an exatecan derivative). Drug-to-antibody ratio (DAR) = ~8 (high payload compared to T-DM1's DAR of ~3.5). Upon internalization, lysosomal cathepsins cleave the linker and release DXd intracellularly. DXd is highly membrane-permeable, enabling a potent "bystander killing effect" — DXd diffuses into adjacent tumor cells (including HER2-low or HER2-negative neighboring cells), providing activity beyond the direct HER2-targeted population.

Q: How is Trastuzumab deruxtecan administered?

Trastuzumab deruxtecan is administered Intravenous (IV). Standard dose: 5.

Q: What are the most common side effects of Trastuzumab deruxtecan?

The most commonly reported side effects of Trastuzumab deruxtecan (≥10% incidence) include: Nausea (70–80% — most common; moderate emetic risk), Fatigue, Alopecia, Vomiting, Constipation and others (8 total). Consult your oncologist for complete prescribing information.

Q: Does Trastuzumab deruxtecan have a black box warning?

Yes. Trastuzumab deruxtecan carries FDA black box warning(s) regarding: 1. Interstitial lung disease (ILD) / pneumonitis: ILD/pneumonitis, including fatal cases, has occurred (~15% any grade in breast cancer trials; Grade ≥3 ~2–3%). Even low-grade ILD can progress rapidly — evaluate every new/worsening cough, dyspnea, or fever promptly with chest CT. Grade 1 (asymptomatic): interrupt T-DXd immediately, do not resume until fully resolved to Grade 0, and consider systemic corticosteroids if clinical suspicion is high. Grade ≥2 (symptomatic): permanently discontinue T-DXd and promptly start high-dose systemic corticosteroids (e.g. prednisone 1–2 mg/kg/day or equivalent) with a slow taper over ≥4 weeks. Corticosteroids are not used as prophylaxis. 2. Embryo-fetal toxicity: causes fetal harm. Contraception required.

Q: Is Trastuzumab deruxtecan safe during pregnancy?

Trastuzumab deruxtecan pregnancy safety: Category D — Both the antibody component (anti-HER2 antibody) and the DXd payload cause fetal harm. Contraception required during and for 7 months after last dose.. Oncologists should review the complete prescribing information and discuss reproductive risks with patients before initiating therapy.

Question 1

What is Trastuzumab deruxtecan FDA-approved to treat?

Accepted Answer

Trastuzumab deruxtecan is FDA-approved for the following oncology indications: 1. HER2-positive breast cancer — unresectable or metastatic, after ≥1 prior anti-HER2 regimen (DESTINY-Breast03 — superior to T-DM1) 2. HER2-low breast cancer (IHC 1+ or IHC 2+/ISH−) — unresectable or metastatic, after prior chemotherapy in HR+/HER2-low; after prior chemo + targeted therapy in TNBC/HER2-low (DESTINY-Breast04) 3. HER2-ultralow breast cancer (IHC >0 and <1+) — HR+, metastatic, ≥2 prior lines of endocrine therapy (DESTINY-Breast06) 4. HER2-positive gastric or gastroesophageal junction adenocarcinoma — locally advanced or metastatic, after prior trastuzumab-containing regimen (DESTINY-Gastric01/02) 5. HER2-mutant non-small cell lung cancer — locally advanced or metastatic, after prior platinum-based chemotherapy (DESTINY-Lung02).

Question 2

How does Trastuzumab deruxtecan work (mechanism of action)?

Accepted Answer

HER2-directed antibody-drug conjugate (ADC) consisting of a humanized anti-HER2 IgG1 monoclonal antibody (same as trastuzumab) conjugated to a cleavable tetrapeptide linker attached to a topoisomerase I inhibitor payload (deruxtecan, DXd — an exatecan derivative). Drug-to-antibody ratio (DAR) = ~8 (high payload compared to T-DM1's DAR of ~3.5). Upon internalization, lysosomal cathepsins cleave the linker and release DXd intracellularly. DXd is highly membrane-permeable, enabling a potent "bystander killing effect" — DXd diffuses into adjacent tumor cells (including HER2-low or HER2-negative neighboring cells), providing activity beyond the direct HER2-targeted population.

Question 3

How is Trastuzumab deruxtecan administered?

Accepted Answer

Trastuzumab deruxtecan is administered Intravenous (IV). Standard dose: 5.

Question 4

What are the most common side effects of Trastuzumab deruxtecan?

Accepted Answer

The most commonly reported side effects of Trastuzumab deruxtecan (≥10% incidence) include: Nausea (70–80% — most common; moderate emetic risk), Fatigue, Alopecia, Vomiting, Constipation and others (8 total). Consult your oncologist for complete prescribing information.

Question 5

Does Trastuzumab deruxtecan have a black box warning?

Accepted Answer

Yes. Trastuzumab deruxtecan carries FDA black box warning(s) regarding: 1. Interstitial lung disease (ILD) / pneumonitis: ILD/pneumonitis, including fatal cases, has occurred (~15% any grade in breast cancer trials; Grade ≥3 ~2–3%). Even low-grade ILD can progress rapidly — evaluate every new/worsening cough, dyspnea, or fever promptly with chest CT. Grade 1 (asymptomatic): interrupt T-DXd immediately, do not resume until fully resolved to Grade 0, and consider systemic corticosteroids if clinical suspicion is high. Grade ≥2 (symptomatic): permanently discontinue T-DXd and promptly start high-dose systemic corticosteroids (e.g. prednisone 1–2 mg/kg/day or equivalent) with a slow taper over ≥4 weeks. Corticosteroids are not used as prophylaxis. 2. Embryo-fetal toxicity: causes fetal harm. Contraception required.

Question 6

Is Trastuzumab deruxtecan safe during pregnancy?

Accepted Answer

Trastuzumab deruxtecan pregnancy safety: Category D — Both the antibody component (anti-HER2 antibody) and the DXd payload cause fetal harm. Contraception required during and for 7 months after last dose.. Oncologists should review the complete prescribing information and discuss reproductive risks with patients before initiating therapy.

Trastuzumab deruxtecan — Drug Monograph

Fam-Trastuzumab Deruxtecan (Enhertu) — HER2-Directed ADC Overview

Indications (FDA / NCCN)

Dosing

Monitoring

Mechanism of Action

FDA Indications

Common Side Effects

Clinical Pearl

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