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Trastuzumab
Indications
Trastuzumab is a biologic antineoplastic agent that was FDA-approved in 1998, making it one of the first available “targeted” chemotherapies. Trastuzumab deruxtecan is a trastuzumab conjugate that releases its cytotoxic components after binding and entering HER2-expressing cells, effectively treating HER2-positive gastric, lung, colorectal, and metastatic breast cancer.[1]
FDA-Approved Indications
HER2-positive gastric cancer: Trastuzumab is administered with cisplatin-based chemotherapy, a combination that modestly improves survival (median 13.8 months vs. 11.1 months).[2][3] Trastuzumab deruxtecan is a newer antibody-drug conjugate associated with positive outcomes, particularly during later-line therapy. As a first-line treatment, the combination of pembrolizumab, trastuzumab, and chemotherapy demonstrated a remarkable response rate, prompting its quick FDA approval.[3][2]
Non-small cell lung cancer: Trastuzumab deruxtecan is approved for HER2-mutant (unresectable or metastatic) NSCLC in adults who have previously received systemic therapy.[4] Per the American Society of Clinical Oncology (ASCO) 2024 guidelines regarding Stage IV Non–Small Cell Lung Cancer with driver alterations, clinicians may offer treatment with trastuzumab deruxtecan.[5]
HER2-positive breast cancer: Trastuzumab is FDA-approved in combination with anthracycline or taxane-based chemotherapy. The maximum recommended duration of adjuvant treatment with trastuzumab is 12 months.
Metastatic HER2-positive breast cancer: Trastuzumab is approved as monotherapy or in combination with paclitaxel.[6] In June 2020, the FDA approved a combination of pertuzumab, trastuzumab, and hyaluronidase (subcutaneous) for patients with HER2-positive early-stage and metastatic breast cancer.[7] Trastuzumab has also been administered in combination with lapatinib, anastrozole, cyclophosphamide, pertuzumab, and several other agents to treat metastatic breast cancer.[8][9][10][11] According to the American Society of Clinical Oncology (ASCO), HER2-targeted therapy is recommended for patients with HER2-positive advanced breast cancer, except for patients with congestive heart failure or a significantly reduced left ventricular ejection fraction, which should be evaluated individually. As a first-line treatment, ASCO recommends trastuzumab, pertuzumab, and taxanes. If pertuzumab is not available, clinicians may offer a combination of chemotherapy and trastuzumab.[6][11]
Colorectal cancer: The FDA approved trastuzumab and tucatinib as treatments for colorectal cancer in January 2023.[12] This combination is approved specifically for HER2-positive, chemotherapy-refractory, RAS wild-type unresectable, or metastatic colorectal cancer.[12]
Off-Label Uses
Endometrial cancer: Trastuzumab is used off-label to treat HER2-positive serous endometrial cancer.[13] In 25% to 30% of serous endometrial carcinomas, HER2 protein overexpression or gene amplification is observed, suggesting trastuzumab as a potentially effective component of targeted therapy.[14]
HER2-positive (IHC 3+) unresectable or metastatic solid tumors: Trastuzumab deruxtecan is administered to adult patients with unresectable or metastatic HER2-positive (IHC 3+/immunohistochemistry 3+) solid tumors who have received prior treatment and have no sufficient alternative treatment options.[15]
Mechanism of Action
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Mechanism of Action
Trastuzumab is a monoclonal antibody against human epidermal growth factor receptor 2 (HER2) that binds to an extracellular domain of this receptor and inhibits its homodimerization, preventing HER2-mediated signaling. Trastuzumab is also thought to facilitate antibody-dependent cellular cytotoxicity, leading to the death of cells that express HER2.[16] Antibody-drug conjugates (ADCs) are pharmacological agents that deliver cytotoxic payloads to cells expressing a target protein. Trastuzumab deruxtecan (T-DXd) is a third-generation ADC comprising a humanized monoclonal anti-HER2 antibody (trastuzumab) and a cytotoxic topoisomerase I inhibitor (DXd) linked together by a cleavable tetrapeptide linker. T-DXd has a characteristically high drug-to-antibody ratio of 8:1. In comparison, trastuzumab emtansine (T-DM1) is a second-generation ADC that combines trastuzumab with the cytotoxic agent emtansine.[17]
Pharmacokinetics
Absorption: Trastuzumab administered with hyaluronidase demonstrates enhanced subcutaneous absorption. Trastuzumab's peak and trough plasma concentrations at steady state are typically observed between weeks 16 and 32.
Distribution: Trastuzumab's mean apparent volume of distribution is ~44 mL/kg, similar to its serum volume. Whether trastuzumab traverses the blood-brain barrier or penetrates the cerebrospinal fluid remains unclear.
Metabolism: Following HER2 binding, trastuzumab is metabolized intracellularly into peptides and amino acids. Trastuzumab is thought to be eliminated by IgG clearance through the reticuloendothelial system.[18]
Elimination: Trastuzumab exhibits nonlinear kinetics (dose-dependent). Renal excretion of trastuzumab is minimal. The estimated elimination half-life of trastuzumab is 28 days, which may increase with tumor burden.[19][20] Individual variation in drug clearance rates is considerable; increased body weight and a reduced serum albumin level have been associated with increased trastuzumab clearance.[21]
Administration
Available Dosage Forms and Strengths
Trastuzumab is available in 50 mg (single-dose) vials and 420 mg (multidose) vials. Biosimilars of trastuzumab include trastuzumab-dkst, trastuzumab-strf, trastuzumab-pkrb, trastuzumab-dttb, trastuzumab-qyyp, and trastuzumab-anns. Trastuzumab and hyaluronidase is a combination formulation administered subcutaneously to enhance its absorption and dispersion, offering a convenient alternative to intravenous administration.[22]
Adult Dosing
Trastuzumab is administered as an intravenous infusion over 30 to 90 minutes. This drug should not be administered as a bolus or concurrently with D5W. Per the National Institute for Occupational Safety and Health (NIOSH) guidelines, double gloves, a gown, and closed-system transfer devices are required during administration, as trastuzumab is a potentially hazardous drug. The recommended maintenance dose is 2 mg/kg infused weekly or 6 mg/kg once every 3 weeks. Initial loading doses of up to 8 mg/kg may be administered.
Institutional protocols and package insert information should be consulted for toxicity-related dose adjustments before administration. Trastuzumab dosing for approved indications include:
- HER2-overexpressing breast cancer:
- As adjuvant treatment in combination with paclitaxel or docetaxel: 4 mg/kg IV for a single dose in week 1, followed by 2 mg/kg IV weekly for weeks 2 through 12, then 6 mg/kg IV every 3 weeks for weeks 13 through 52; paclitaxel and docetaxel are administered for the first 12 weeks.
- In combination with carboplatin or docetaxel: 4 mg/kg IV for a single dose in week 1, followed by 2 mg/kg IV weekly for weeks 2 through 18, then 6 mg/kg IV every 3 weeks for weeks 19 through 52; paclitaxel and docetaxel are administered for the first 18 weeks.
- HER2-overexpressing metastatic breast cancer:
- In combination with paclitaxel: 4 mg/kg IV for a single dose in week 1, then 2 mg/kg IV every week starting in week 2.
- In combination with pertuzumab: 8 mg/kg IV for a single dose on day 1 of the first 21-day cycle, then 6 mg/kg for the second 21-day cycle.
- As monotherapy for recurrent disease: 4 mg/kg IV for a single dose in the first week, then 2 mg/kg starting in week 2.
- HER2-overexpressing metastatic stomach cancer: 8 mg/kg IV for a single dose on day 1 of the first 21-day cycle, then 6 mg/kg IV for a single dose on day 1 of the second 21-day cycle.
Specific Patient Populations
Hepatic impairment: No dosage adjustments are provided on the product labeling.
Renal impairment: No dosage adjustments are provided on the product labeling.
Pregnancy considerations: The pharmacovigilance program closely monitors trastuzumab's effects during pregnancy. If administered during pregnancy or if the patient becomes pregnant within 7 months post-treatment, healthcare providers should monitor for signs of potential fetal harm, including oligohydramnios and pulmonary and skeletal abnormalities. The patient's pregnancy status should be confirmed before treatment is offered, and women who may become pregnant should use contraception during trastuzumab treatment and for 7 months afterward to prevent unintended fetal harm.[23]
Breastfeeding considerations: Information regarding the effect of trastuzumab during breastfeeding is limited. Trastuzumab is a high molecular weight protein, so the amount excreted into breast milk is likely minimal. Any ingested protein is likely partially degraded in the infant's gastrointestinal tract, so the risk of absorption is minimal. However, caution should be exercised when considering trastuzumab during breastfeeding (particularly if the nursing infant is newborn or preterm) until more data become available. The manufacturer recommends discontinuing breastfeeding during trastuzumab therapy and for 7 months after the last dose.[24]
Pediatric patients: The safety and efficacy of trastuzumab have not been established in pediatric patients.
Older patients: Older adults have demonstrated an increased risk of cardiac dysfunction compared to younger patients when using trastuzumab; caution is advised before prescribing to this patient population.
Adverse Effects
Trastuzumab is known to cause cardiotoxicity, which typically manifests as a reduced left ventricular ejection fraction (LVEF). The exact pathogenesis of this event is unknown but is thought to involve reduced clearance of reactive oxygen species in cardiac myocytes.[25] In the U.S., trastuzumab carries an FDA-boxed warning regarding subclinical and clinical cardiac failure. According to the product label, a reduction in LVEF ≥10% has been observed in up to 22% of patients, although some studies have reported an incidence as high as 44%.[26] Symptomatic congestive heart failure during treatment is less common, with an estimated incidence of 2% to 7%. The major risk factor for cardiotoxicity is concurrent treatment with anthracyclines; the risk of severe cardiotoxicity is 3 to 4 times higher in patients receiving trastuzumab and anthracyclines simultaneously.[27] Increased age, hypertension, coronary artery disease, and hyperlipidemia may also increase a patient's risk of cardiotoxicity. Clinically, most cases of trastuzumab-induced cardiotoxicity appear to be reversible after discontinuing treatment.[28][29] However, some patients demonstrate echocardiographic evidence of persistent myocardial dysfunction.[30]
Severe infusion reactions are associated with trastuzumab administration, including angioedema, anaphylaxis, interstitial pneumonitis, and acute respiratory distress syndrome. Trastuzumab also carries an FDA-boxed warning about these effects. Most severe effects occur within 24 hours of infusion. All patients should be monitored for significant dyspnea, hypotension, or signs of angioedema; trastuzumab should be discontinued if any of these effects are observed. Some patients can tolerate resumed infusion after pre-medication (eg, with acetaminophen and diphenhydramine).
Rare cases of nephrotic syndrome have been reported in patients on trastuzumab therapy, with the greatest incidence in patients with metastatic gastric cancer.
Other adverse effects commonly reported during trastuzumab monotherapy include headache, chills, nausea/vomiting, abdominal pain, diarrhea, cough, back pain, rhinitis, pharyngitis, weakness, and fatigue.
Drug-Drug Interactions
Trastuzumab should not be administered with belimumab due to an increased risk of neutropenia and infection.
Patients receiving anthracyclines (eg, doxorubicin) following trastuzumab discontinuation are at an increased risk for cardiotoxicity. To minimize cardiotoxicity risk, anthracyclines should be deferred for 7 months following trastuzumab cessation.[31] Close cardiac monitoring is necessary if anthracyclines must be administered.
Contraindications
Box Warnings
Cardiomyopathy: Trastuzumab is known to cause cardiotoxicity, which typically manifests as a reduced left ventricular ejection fraction (LVEF). The exact pathogenesis of this event is unknown but is thought to involve reduced clearance of reactive oxygen species in cardiac myocytes.[25] In the U.S., trastuzumab carries an FDA-boxed warning regarding subclinical and clinical cardiac failure. According to the product label, a reduction in LVEF ≥10% has been observed in up to 22% of patients, although some studies have reported an incidence as high as 44%.[26] Symptomatic congestive heart failure during treatment is less common, with an estimated incidence of 2% to 7%. The major risk factor for cardiotoxicity is concurrent treatment with anthracyclines; the risk of severe cardiotoxicity is 3 to 4 times higher in patients receiving trastuzumab and anthracyclines simultaneously.[27] Increased age, hypertension, coronary artery disease, and hyperlipidemia may also increase a patient's risk of cardiotoxicity. Clinically, most cases of trastuzumab-induced cardiotoxicity appear to be reversible after discontinuing treatment.[28][29] However, some patients demonstrate echocardiographic evidence of persistent myocardial dysfunction.[30] Due to the risk of cardiotoxicity, trastuzumab should be used with extreme caution in patients with a history of structural heart disease.
Pulmonary toxicity: Trastuzumab is associated with severe and potentially fatal pulmonary toxicity. Interstitial pneumonitis, non-cardiogenic pulmonary edema, pleural effusions, acute respiratory distress syndrome, and pulmonary fibrosis have also been reported. These adverse events can occur as a sequela of infusion reactions. Patients with a history of lung disease or malignancy appear to experience more severe toxicity.
Embroyofetal toxicity: Trastuzumab use during pregnancy is associated with oligohydramnios, which can lead to fatal pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Before initiating trastuzumab therapy, the pregnancy status of women who may become pregnant must be confirmed. Clinicians should advise effective contraception during treatment and for 7 months following the last dose.
Warnings and Precautions
Pregnancy: Trastuzumab is thought to be a human teratogen. Fetal exposure is associated with oligohydramnios, leading to pulmonary hypoplasia and death. Patients who may become pregnant should use at least one form of contraception during trastuzumab therapy. Whether trastuzumab is secreted in human breast milk or not is unclear.
Infusion reactions: Severe infusion reactions have been observed during trastuzumab administration. These may include angioedema, anaphylaxis, interstitial pneumonitis, and acute respiratory distress syndrome. Trastuzumab also carries an FDA-boxed warning about these reactions. Severe effects typically occur within 24 hours of infusion. All patients should be monitored for significant dyspnea, hypotension, or signs of angioedema; trastuzumab should be discontinued if any of these effects are observed. Some patients can tolerate resuming therapy after pre-medication (eg, with acetaminophen and diphenhydramine).[32]
Neutropenia: Trastuzumab may exacerbate chemotherapy-induced neutropenia. Grade 3 and 4 neutropenia and febrile neutropenia have been observed more commonly in patients receiving trastuzumab in combination with myelosuppressive chemotherapy.
Biosimilars: Multiple biosimilar trastuzumab formulations are available; the specific product label should be verified before administering trastuzumab.[33]
Monitoring
Echocardiography is recommended before initiating trastuzumab treatment. Cardiac risk factors such as hypertension and smoking should also be noted if present. The role of echocardiography in screening asymptomatic patients during treatment is uncertain. One guideline-recommended alternative is to obtain an echocardiogram at baseline, one after treatment, and one 6 to 12 months following treatment.[34] In clinical practice, asymptomatic patients receiving anthracyclines (eg, doxorubicin or baseline cardiac risk factors) often undergo echocardiography every 2 to 3 months. Patients with metastatic disease receiving indefinite therapy may also undergo routine echocardiography.[35] Symptomatic patients should undergo immediate echocardiography, cardiac biomarker testing, and referral to cardiology. Trastuzumab should be discontinued if the LVEF is less than 50% and is reduced by more than 10% from baseline or if the LVEF is reduced by more than 16% from baseline. In some cases, trastuzumab may be restarted if the LVEF is restored.
When trastuzumab is combined with paclitaxel, an increased serum concentration of trastuzumab has been observed. Serum paclitaxel concentrations may also be decreased during trastuzumab therapy.[36] The mechanism and clinical significance of these interactions are unknown.
Trastuzumab may increase the risk of neutropenia, infections, and anemia when added to cytotoxic chemotherapy.
Toxicity
The major toxicity concerns regarding trastuzumab include cardiotoxicity, embryo-fetal toxicity, and pulmonary toxicity. There is no antidote for trastuzumab toxicity. For an accidental overdose, immediate supportive care should be provided, and consultations with oncology and toxicology specialists should be obtained.
Enhancing Healthcare Team Outcomes
Trastuzumab is a biologic agent primarily used to treat HER2-positive breast cancer and may be used as adjuvant therapy for localized disease or as first-line treatment for metastatic disease. The availability of trastuzumab has significantly increased survival associated with HER2-positive breast cancer; notably, trastuzumab also carries considerable historical importance as one of the first “targeted” chemotherapeutic agents developed. Trastuzumab is typically given in combination with one or more cytotoxic agents, most commonly anthracyclines (eg, doxorubicin) and taxanes (eg, paclitaxel). Trastuzumab has also demonstrated efficacy in the treatment of HER2-positive metastatic gastric cancer. The most significant adverse event associated with trastuzumab is cardiotoxicity; this is usually mild and reversible with discontinuation, but it may progress to irreversible, clinically significant cardiac failure.
The risk of cardiotoxicity is greatest in patients receiving concomitant anthracycline therapy. All patients should receive a baseline echocardiogram before initiating treatment and must be monitored closely for the development of palpitations, dyspnea, chest pain, and peripheral edema. Some patients may benefit from a more frequent echocardiographic assessment. Immediate discontinuation of trastuzumab is warranted for a patient with a reduced LVEF. The interprofessional healthcare team, including clinicians (particularly oncology specialists), nurses, and pharmacists, must also be aware of the potential for severe infusion reactions, especially following the initial dose. Trastuzumab likely has teratogenic effects; it should be avoided in patients who are pregnant, and patients who may become pregnant must use contraception during treatment. A cardiology consultation is recommended for patients with trastuzumab-induced cardiotoxicity. Pulmonology consultation may be required for interstitial lung disease. An interprofessional team approach and communication among clinicians (MDs, DOs, NPs, PAs), pharmacists, and nurses is crucial for optimizing patient outcomes with trastuzumab.
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