ENHERTU
Clinical safety rating
cautionComprehensive clinical and safety monograph for ENHERTU (ENHERTU).
Comprehensive clinical and safety monograph for ENHERTU (ENHERTU).
Unresectable or metastatic HER2-positive breast cancer after prior anti-HER2-based regimen in metastatic settingMetastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer after prior chemotherapy in metastatic settingUnresectable or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma after prior trastuzumab-based regimenHER2-positive non-small cell lung cancer with activating HER2 mutation after prior systemic therapyHER2-positive solid tumors (tumor agnostic) after prior systemic therapy and no satisfactory alternative
Enhertu (fam-trastuzumab deruxtecan-nxki) is a HER2-directed antibody-drug conjugate (ADC). The antibody is a humanized anti-HER2 IgG1, and the small molecule DXd is a topoisomerase I inhibitor. Upon binding to HER2 on tumor cells, the ADC undergoes internalization and intracellular cleavage, releasing DXd which causes DNA damage and apoptotic cell death.
| Metabolism | DXd, the released payload, is primarily metabolized by CYP3A4. |
| Excretion | Primarily biliary/fecal excretion (approximately 95% as unchanged drug); renal excretion is negligible (<1%). |
| Half-life | Terminal elimination half-life is approximately 5.5 days (range 4.5–7.5 days) for the antibody-drug conjugate, supporting every-3-week dosing. |
| Protein binding | Trastuzumab deruxtecan: Approximately 99% bound to plasma proteins (primarily to albumin). |
| Volume of Distribution | Approximately 10–12 L (approx. 0.14–0.17 L/kg for a 70 kg adult), indicating distribution primarily in vascular space. |
| Bioavailability | Not applicable; administered intravenously (100% bioavailability). |
| Onset of Action | Intravenous: Clinical response (tumor shrinkage) typically observed after 2–3 cycles (6–9 weeks) based on clinical trials. |
| Duration of Action | Duration of response (DOR) is variable; median DOR in clinical trials is approximately 6.9–12.0 months depending on indication (e.g., breast cancer, gastric cancer). |
| Molecular Weight | ~800 Da (trastuzumab deruxtecan; payload MW 718 Da, antibody ~145 kDa). |
5.4 mg/kg intravenously every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity.
| Dosage form | INJECTABLE |
| Renal impairment | No dose adjustment recommended for mild to moderate renal impairment (CrCl ≥30 mL/min). No data for severe renal impairment (CrCl <30 mL/min). |
| Liver impairment | Child-Pugh A: No adjustment. Child-Pugh B: Reduce dose to 4.4 mg/kg. Child-Pugh C: Not recommended. |
| Pediatric use | Safety and efficacy not established; no recommended dose. |
| Geriatric use | No specific dose adjustment. Monitor for toxicity, especially in patients aged ≥65 years due to limited data. |
| 1st trimester | Avoid; embryotoxic and fetotoxic based on mechanism of action (topoisomerase I inhibitor). Human data limited; animal studies show fetal harm. |
| 2nd trimester | Avoid; continued risk of fetal toxicity and potential for oligohydramnios. |
| 3rd trimester | Avoid; risk of fetal harm and potential for myelosuppression in neonate. |
Clinical note
Comprehensive clinical and safety monograph for ENHERTU (ENHERTU).
| Placental transfer | Expected to cross placenta due to low molecular weight (MW ~800 Da); IgG conjugate may transfer via FcRn. |
| Breastfeeding | No human data on presence in breast milk; due to potential for serious adverse reactions in breastfed infants (e.g., myelosuppression, GI toxicity), advise women not to breastfeed during treatment and for at least 1 week after last dose. |
| Lactation Rating | L5 |
| Teratogenic Risk | Based on its mechanism of action (topoisomerase I inhibitor) and animal studies, trastuzumab deruxtecan is expected to cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies in pregnant women. In animal reproduction studies, administration of trastuzumab deruxtecan to pregnant rats during organogenesis resulted in embryofetal toxicity including decreased fetal weight and increased fetal malformations at exposures below the recommended human dose based on AUC. Due to the potential for genotoxicity and inhibition of rapidly dividing cells, there is a high teratogenic risk, particularly during the first trimester. During second and third trimesters, fetal growth restriction and oligohydramnios may occur due to HER2 receptor inhibition, although the deruxtecan component primarily drives toxicity. Effective contraception should be used during treatment and for at least 7 months after the last dose. |
| Fetal Monitoring | If ENHERTU is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Close fetal monitoring with ultrasound is recommended to assess for fetal growth, amniotic fluid volume, and anatomy. For maternal monitoring, complete blood counts (CBC), liver function tests, and renal function should be assessed regularly. Additionally, left ventricular ejection fraction (LVEF) should be monitored due to risk of left ventricular dysfunction. Interstitial lung disease (ILD) monitoring is essential; patients should be advised to report new or worsening respiratory symptoms. |
| Fertility Effects | Based on animal studies and its mechanism of action, ENHERTU may impair fertility in females and males. In female rats, trastuzumab deruxtecan caused disruption of estrous cycles and decreased fertility at doses below the recommended human dose. In male rats, testicular toxicity (degeneration of seminiferous tubules) was observed, which may affect spermatogenesis. Effects are likely reversible to some extent but may persist for several months after treatment discontinuation. Patients should be counseled on fertility preservation options prior to treatment. |
■ FDA Black Box Warning
WARNING: INTERSTITIAL LUNG DISEASE and EMBRYO-FETAL TOXICITY. Interstitial lung disease (ILD) and pneumonitis, including fatal cases, have occurred. Monitor for signs and symptoms of ILD and withhold, dose reduce, or permanently discontinue based on severity. Exposure during pregnancy can cause embryo-fetal harm; advise patients of these risks.
| Serious Effects |
Hypersensitivity to trastuzumab deruxtecan or any excipient
| Precautions | Interstitial lung disease/pneumonitis, Left ventricular ejection fraction (LVEF) reduction, Neutropenia, Fever, infection, or thrombocytopenia, Embryo-fetal toxicity |
| Food/Dietary | No specific food interactions are known; however, ENHERTU may cause nausea, vomiting, and diarrhea. Patients should avoid heavy, spicy, or fatty foods if gastrointestinal side effects occur and maintain adequate hydration. |
| Clinical Pearls | Monitor for interstitial lung disease (ILD) and pneumonitis; withhold ENHERTU for grade 1 ILD and permanently discontinue for grade 2 or higher. Assess left ventricular ejection fraction (LVEF) before and during treatment; withhold for any grade of reduction. Premedicate with antiemetics per institutional guidelines. Do not substitute with trastuzumab or ado-trastuzumab emtansine. |
| Patient Advice | Report new or worsening cough, shortness of breath, or fever immediately as these may be signs of lung problems. · Notify your doctor of any nausea, vomiting, diarrhea, or constipation as these can be managed with medications. · Avoid pregnancy during treatment and for 7 months after last dose; use effective contraception. · Do not breastfeed during treatment and for 1 month after last dose. · Inform your doctor of all medications you take, including over-the-counter drugs and supplements. |
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