Usage
Trastuzumab deruxtecan is prescribed for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting. It is also approved for treating adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen. Furthermore, it is indicated for adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) with HER2 activating mutations, as detected by an FDA-approved test, who have received a prior platinum-containing regimen. It is classified as an antineoplastic agent, specifically a HER2-targeted antibody-drug conjugate (ADC). Trastuzumab deruxtecan functions by targeting HER2-expressing cancer cells and delivering a topoisomerase I inhibitor payload, deruxtecan, which disrupts DNA replication and leads to cell death.
Alternate Names
Trastuzumab deruxtecan is also known by its international nonproprietary name (INN), trastuzumab deruxtecan. It is marketed under the brand name Enhertu®.
How It Works
Pharmacodynamics: Trastuzumab deruxtecan binds to the HER2 receptor on cancer cells. Upon internalization, the cleavable linker releases deruxtecan, a topoisomerase I inhibitor. Deruxtecan creates DNA double-strand breaks, preventing DNA repair and ultimately leading to apoptosis (programmed cell death) of the cancer cells.
Pharmacokinetics:
- Absorption: Trastuzumab deruxtecan is administered intravenously.
- Distribution: It distributes to tissues expressing the HER2 receptor.
- Metabolism: Deruxtecan is metabolized, primarily via CYP3A4, and also by UGT1A1.
- Excretion: The primary routes of elimination are hepatic metabolism and biliary excretion. The elimination half-life of the antibody component is around 21 days and 4 days for the topoisomerase I inhibitor component. The pharmacokinetics of trastuzumab deruxtecan is dose proportional between 3.2 mg/kg and 8.0 mg/kg.
Mode of Action: Trastuzumab deruxtecan functions through receptor binding (HER2) and enzyme inhibition (topoisomerase I).
Elimination Pathways: Primarily hepatic metabolism and biliary excretion.
Dosage
Standard Dosage
Adults:
The recommended dosage for HER2-positive breast cancer and gastric cancer is 5.4 mg/kg administered as an intravenous infusion every 3 weeks (21-day cycle). The recommended dosage for HER2-mutant NSCLC is 6.4 mg/kg, also administered as an intravenous infusion every 3 weeks (21-day cycle). The initial dose should be administered as a 90-minute infusion. If well-tolerated, subsequent infusions can be reduced to 30 minutes. Dose reduction may be necessary based on individual tolerability.
Children:
The safety and efficacy of trastuzumab deruxtecan in pediatric patients have not been established.
Special Cases:
- Elderly Patients: No dose adjustment is required.
- Patients with Renal Impairment: No dose adjustment is required for mild or moderate renal impairment. Limited data exists for severe renal impairment.
- Patients with Hepatic Dysfunction: No dose adjustment is required for mild hepatic impairment. Caution should be exercised with moderate hepatic impairment. There is no data for severe hepatic impairment.
- Patients with Comorbid Conditions: Individualized assessment and dose modifications may be necessary based on specific comorbidities.
Clinical Use Cases
Trastuzumab deruxtecan is not typically used in clinical settings like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations. Its primary indication is for specific cancer types as outlined above.
Dosage Adjustments
Dose reductions may be necessary based on adverse events, particularly interstitial lung disease (ILD) or pneumonitis, and/or decreased left ventricular ejection fraction (LVEF). For breast cancer, NSCLC, or IHC 3+ solid tumors, the first dose reduction is to 4.4 mg/kg and the second to 3.2 mg/kg. If further dose reductions are required, the treatment should be discontinued. For gastric cancer, the first dose reduction is to 5.4 mg/kg and the second to 4.4 mg/kg.
Side Effects
Common Side Effects
Nausea, vomiting, fatigue, alopecia, decreased appetite, diarrhea, constipation, and rash. Neutropenia, anemia, thrombocytopenia, and leukopenia have also been observed.
Rare but Serious Side Effects
Interstitial lung disease (ILD)/pneumonitis and left ventricular dysfunction. These adverse events can be fatal.
Long-Term Effects
Long-term effects are still under investigation, but potential concerns include cardiac dysfunction and pulmonary fibrosis.
Adverse Drug Reactions (ADR)
ILD/pneumonitis, left ventricular dysfunction, and severe myelosuppression including febrile neutropenia.
Contraindications
Hypersensitivity to trastuzumab deruxtecan or any of its components. Pregnancy and breastfeeding. Severe hepatic impairment. Pre-existing ILD or pneumonitis.
Drug Interactions
Strong CYP3A4 inducers or inhibitors may affect the pharmacokinetics of deruxtecan, and co-administration should be monitored. Trastuzumab deruxtecan is a substrate of OATP1B1 and OATP1B3 and co-administration with inhibitors of OATP1B1, CYP3A and P-gp, such as ritonavir and itraconazole, require careful monitoring. No dose adjustment is required during co-administration of trastuzumab deruxtecan with medicinal products that are inhibitors of CYP3A or OATP1B or P-gp transporters.
Pregnancy and Breastfeeding
Trastuzumab deruxtecan is contraindicated during pregnancy and breastfeeding due to the potential for fetal harm. Women of childbearing potential should use effective contraception during treatment and for at least 7 months after the last dose. Men with female partners of childbearing potential should use effective contraception during treatment and for at least 4 months after the last dose. Breastfeeding should be avoided during treatment and for 7 months after the last dose.
Drug Profile Summary
- Mechanism of Action: HER2-targeted antibody-drug conjugate that delivers a topoisomerase I inhibitor payload.
- Side Effects: Nausea, vomiting, fatigue, alopecia, neutropenia, ILD, left ventricular dysfunction.
- Contraindications: Hypersensitivity, pregnancy, breastfeeding.
- Drug Interactions: Strong CYP3A4 inducers or inhibitors. Co-administration with inhibitors of OATP1B1, CYP3A and P-gp.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: 5.4 mg/kg IV every 3 weeks for breast cancer, 6.4 mg/kg IV every 3 weeks for NSCLC, 5.4 mg/kg IV for gastric or GEJ cancer; dose adjustments based on tolerability.
- Monitoring Parameters: LVEF, pulmonary function tests, complete blood counts, liver function tests.
Popular Combinations
Currently, trastuzumab deruxtecan is typically used as a monotherapy. Combinations with other therapies are under investigation in clinical trials.
Precautions
- General Precautions: Monitor for ILD/pneumonitis and cardiac dysfunction. Monitor blood counts for myelosuppression.
- Specific Populations:
- Pregnant Women: Contraindicated.
- Breastfeeding Mothers: Contraindicated.
- Children & Elderly: Safety and efficacy not established in children. No dose adjustment for elderly patients.
- Lifestyle Considerations: Patients should discuss any potential impact on driving or operating machinery with their physician.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Trastuzumab Deruxtecan?
A: The recommended dosage is 5.4 mg/kg IV every 3 weeks for breast cancer and gastric cancer, and 6.4 mg/kg IV every 3 weeks for NSCLC.
Q2: What are the most common side effects?
A: Nausea, vomiting, fatigue, alopecia, neutropenia, diarrhea, and constipation.
Q3: What are the most serious side effects?
A: ILD/pneumonitis and left ventricular dysfunction.
Q4: How is Trastuzumab Deruxtecan administered?
A: As an intravenous infusion.
Q5: Is Trastuzumab Deruxtecan safe during pregnancy?
A: No, it is contraindicated due to potential fetal harm.
Q6: Can I breastfeed while taking Trastuzumab Deruxtecan?
A: No, breastfeeding is contraindicated.
Q7: What should be monitored during treatment?
A: LVEF, pulmonary function, complete blood counts, and liver function tests.
Q8: What if a dose is missed?
A: The missed dose should be administered as soon as possible without waiting until the next planned cycle. The schedule should then be adjusted to maintain a 3-week interval between doses.
Q9: How does Trastuzumab Deruxtecan work?
A: It’s a HER2-targeted antibody-drug conjugate. It targets HER2 on cancer cells and delivers a topoisomerase I inhibitor, deruxtecan, leading to cancer cell death.
Q10: What cancers is it indicated for?
A: Certain types of HER2-positive breast cancer, gastric cancer, and HER2-mutant NSCLC.
