Trastuzumab Deruxtecan

Trastuzumab deruxtecan is a HER2-targeted antibody-drug conjugate (ADC) representing a next-generation HER2-directed therapy. It combines the targeting specificity of trastuzumab with a potent topoisomerase I inhibitor cytotoxic payload (deruxtecan, DXd) connected by a cleavable tetrapeptide linker.

Mechanism of Action

The ADC has three components:

1. Trastuzumab antibody — binds HER2-expressing cancer cells.
2. Cleavable linker — stable in circulation, cleaved inside target cells.
3. Deruxtecan (DXd) — a potent topoisomerase I inhibitor.

After binding to HER2 on the cell surface, the conjugate is internalized by receptor-mediated endocytosis and the linker is cleaved in lysosomes, releasing deruxtecan inside the cell. Deruxtecan inhibits topoisomerase I, causes DNA damage, and induces apoptosis. A “bystander effect” allows the released payload to diffuse into neighboring tumor cells, providing activity even in HER2-low tumors.

Compared to earlier HER2 ADCs, trastuzumab deruxtecan has a higher drug-to-antibody ratio (8:1), a more potent payload, and demonstrable bystander killing.

Pharmacokinetics

Trastuzumab deruxtecan (ADC) and its released payload (DXd) have distinct PK profiles:

ADC (trastuzumab deruxtecan):

• Cmax: approximately 122 µg/mL (20% CV) at the 5.4 mg/kg dose.
• AUC: approximately 735 µg·day/mL (31% CV) at steady state.
• Volume of distribution (central compartment): approximately 2.77 L — restricted distribution, consistent with a large-molecule antibody.
• Metabolism: antibody portion catabolized via proteolytic degradation; linker cleavage in tumor lysosomes mediated by cathepsins B and L, releasing free DXd payload.
• Half-life: approximately 5.8 days.
• Clearance: approximately 0.42 L/day (population PK estimate).
• Excretion: not excreted renally as intact ADC.

Free payload (DXd):

• Protein binding: approximately 97% bound to plasma proteins.
• Metabolism: primarily CYP3A4.
• Half-life: shorter than ADC; cleared as metabolites.
• Clearance: approximately 19.2 L/h.
• Excretion: primarily fecal — approximately 67% of total drug-related radioactivity recovered in feces in a mass balance study.
• Transporters: DXd is a substrate of ABCB1 (P-gp) and BCRP (ABCG2); inhibitors of SLCO1B1/1B3 (OATP1B1/1B3) and ABCC1 may affect systemic DXd exposure. MATE2 transporters also implicated.

• HER2-positive metastatic breast cancer (DESTINY-Breast03): superior to trastuzumab emtansine; progression-free survival 28.8 vs 6.8 months (HR 0.28); overall response rate 79.7%.
• HER2-low metastatic breast cancer (DESTINY-Breast04): first ADC to show benefit in HER2-low disease; PFS 10.1 vs 5.4 months; OS 23.9 vs 17.5 months.
• HER2-positive gastric cancer (DESTINY-Gastric01): response rate 51% vs 14% with chemotherapy; median OS 12.5 vs 8.4 months.

Breast cancer:

• HER2-positive (IHC 3+ or IHC 2+/ISH+) unresectable or metastatic breast cancer after prior HER2-directed therapy.
• First-line HER2-positive metastatic breast cancer in combination with pertuzumab (approved January 2025 in the US based on DESTINY-Breast09 data).
• HER2-low (IHC 1+ or IHC 2+/ISH-negative) unresectable or metastatic breast cancer after prior chemotherapy in the metastatic setting, or recurrence during/within 6 months of adjuvant chemotherapy.
• HER2-ultralow (IHC >0 and <IHC 1+) hormone receptor-positive metastatic breast cancer after prior endocrine therapy.

Gastric cancer:

• HER2-positive locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma after a prior trastuzumab-based regimen.

Non-small cell lung cancer (NSCLC):

• HER2-mutated (not HER2 amplified) unresectable or metastatic NSCLC that has received prior systemic therapy.

HER2-positive solid tumors (tissue-agnostic):

• Unresectable or metastatic HER2-positive (IHC 3+) solid tumors that have progressed on prior standard treatment and have no satisfactory alternative options (accelerated FDA approval).

• Severe hypersensitivity to trastuzumab deruxtecan or any of the excipients.
• Pregnancy (causes fetal harm).

Most common: nausea, vomiting, fatigue, alopecia, constipation, decreased appetite, diarrhea, anemia, neutropenia, thrombocytopenia.

Serious adverse events:

• Interstitial lung disease (ILD) / pneumonitis: the most serious risk (9–15% incidence; ~3% fatal in some series). Symptoms include new or worsening cough, dyspnea, and fever; requires urgent evaluation and management. Permanently discontinue for any grade of ILD (no rechallenge).
• Myelosuppression: severe neutropenia, anemia, and thrombocytopenia may occur.
• Left ventricular dysfunction: less common than with trastuzumab alone.
• Embryo-fetal toxicity.
• Infusion reactions: usually mild to moderate.
• Peripheral neuropathy: usually mild.

• Strong CYP3A4 inhibitors: may increase free DXd payload exposure; use caution.
• Strong CYP3A4 inducers: may decrease DXd exposure.
• P-gp (ABCB1) inhibitors: may increase DXd intracellular levels in normal tissues.
• OATP1B1/1B3 inhibitors (e.g., statins at high doses): potential for increased DXd systemic exposure via transporter inhibition.
• UGT1A1 inhibitors: may increase deruxtecan exposure — use caution.
• Live vaccines: avoid during treatment.

Standard Dose

5.4 mg/kg by intravenous infusion every 3 weeks. Continue until disease progression or unacceptable toxicity.

Infusion Schedule

• First infusion: over 90 minutes.
• Subsequent infusions: over 30 minutes if the first infusion was well tolerated.
• Do not administer as IV push or bolus.

Dose Modifications

• ILD/pneumonitis (any grade): permanently discontinue.
• Neutropenia: hold until recovery; consider G-CSF.
• Thrombocytopenia: hold until recovery.

Dose reductions are not used; treatment is held or discontinued.

Pre-medication

Antiemetic prophylaxis is recommended (moderately emetogenic). Premedication for infusion reactions is not routinely required.

ILD / Pneumonitis Monitoring (Critical)

• Baseline chest CT is recommended.
• Monitor for pulmonary symptoms before each dose.
• Educate patients about symptoms (new cough, dyspnea, fever).
• Investigate any new pulmonary symptoms urgently with imaging.
• Permanently discontinue for any grade of ILD; no rechallenge after ILD.

Cardiac Monitoring

Baseline left ventricular ejection fraction (LVEF) assessment, then LVEF every 3 months. Hold for symptomatic CHF or LVEF <45%.

Pregnancy

Verify pregnancy status before starting. Effective contraception is required during treatment and for 7 months after the last dose. Discontinue breastfeeding during treatment.

Handling

The active substance is cytotoxic — healthcare professionals should use protective equipment per institutional chemotherapy handling protocols.

Store unopened vials at 2–8°C in the original carton. Do not freeze or shake. Protect from light.

After reconstitution, use immediately. If necessary, the reconstituted solution may be stored at 2–8°C for up to 24 hours.

36 months when stored properly. Do not use after the expiry date.

Prescription required. For hospital and oncology-clinic use only. Must be administered by qualified healthcare professionals in settings equipped to manage serious adverse reactions, including ILD/pneumonitis.