Interstitial lung disease (ILD) and pneumonitis, including fatal cases, have been reported with fam-trastuzumab deruxtecan. Monitor for and promptly investigate signs and symptoms including cough, dyspnea, fever, and other new or worsening respiratory symptoms. Permanently discontinue fam-trastuzumab deruxtecan in all patients with ≥ grade 2 ILD/pneumonitis. Advise patients of the risk and the need to immediately report symptoms.
Exposure to fam-trastuzumab deruxtecan during pregnancy can cause embryo-fetal harm. Advise patients of these risks and the need for effective contraception.
Note: Do not substitute fam-trastuzumab deruxtecan for or with ado-trastuzumab emtansine, conventional trastuzumab (or trastuzumab biosimilars), pertuzumab/trastuzumab/hyaluronidase, or trastuzumab/hyaluronidase; products are different and are NOT interchangeable. Fam-trastuzumab deruxtecan is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting (ASCO [Hesketh 2020]); delayed nausea and/or vomiting may occur.
Breast cancer, unresectable or metastatic, HER2-low: IV: 5.4 mg/kg once every 3 weeks until disease progression or unacceptable toxicity (Modi 2022).
Breast cancer, unresectable or metastatic, HER2-positive: IV: 5.4 mg/kg once every 3 weeks until disease progression or unacceptable toxicity (Cortés 2022; Modi 2020).
Colorectal cancer, metastatic, HER2-expressing (off-label use): IV: 6.4 mg/kg once every 3 weeks until disease progression or unacceptable toxicity (Siena 2021). Refer to protocol for dosage adjustment details.
Gastric cancer, locally advanced or metastatic, HER2-positive: IV: 6.4 mg/kg once every 3 weeks until disease progression or unacceptable toxicity (Shitara 2020).
Non–small cell lung cancer, unresectable or metastatic, HER2-mutant: IV: 5.4 mg/kg once every 3 weeks until disease progression or unacceptable toxicity.
Missed dose: If a planned dose is delayed or missed, administer the dose as soon as possible (do not wait until the next planned cycle) and then adjust the administration schedule to maintain a 3-week interval between doses. Infuse the missed/delayed dose at the dose and rate the patient tolerated in the most recent infusion.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
CrCl ≥30 mL/minute: No dosage adjustment necessary. Monitor more frequently for interstitial lung disease in patients with moderate impairment.
CrCl <30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling (a recommended dose has not been established).
Mild (total bilirubin ≤ ULN and any AST > ULN or total bilirubin >1 to 1.5 times ULN and any AST) or moderate (total bilirubin >1.5 to 3 times ULN and any AST) impairment: No dosage adjustment necessary. Monitor closely for toxicities in patients with moderate impairment.
Severe impairment (total bilirubin >3 to 10 times ULN and any AST): There are no dosage adjustments provided in the manufacturer's labeling (a recommended dose has not been established).
Refer to adult dosing.
Adverse reaction management may require treatment interruption, dosage reduction, and/or discontinuation. Do not re-escalate the fam-trastuzumab deruxtecan dose after a dosage reduction is made.
|
Dose reduction schedule |
Breast cancer and non–small cell lung cancer |
Gastric cancer |
|---|---|---|
|
Initial (usual) dose |
5.4 mg/kg |
6.4 mg/kg |
|
First dose reduction level |
4.4 mg/kg |
5.4 mg/kg |
|
Second dose reduction level |
3.2 mg/kg |
4.4 mg/kg |
|
Further dosage adjustment required |
Discontinue treatment |
Discontinue treatment |
|
Toxicity |
Severity |
Fam-Trastuzumab Deruxtecan Dose Modification | |
|---|---|---|---|
|
Neutropenia |
Grade 3 (ANC 500 to 1,000/mm3) |
Interrupt fam-trastuzumab deruxtecan until resolved to ≤ grade 2, then maintain dose. | |
|
Grade 4 (ANC <500/mm3) |
Interrupt fam-trastuzumab deruxtecan until resolved to ≤ grade 2, then reduce dose by one dose level. | ||
|
Neutropenic fever |
ANC <1,000/mm3 and temperature >38.3°C or a sustained temperature of ≥38°C for >1 hour |
Interrupt fam-trastuzumab deruxtecan until resolved, then reduce dose by one dose level. | |
|
Thrombocytopenia |
Grade 3 (platelets 25,000 to <50,000/mm3) |
Interrupt fam-trastuzumab deruxtecan until resolved to ≤ grade 1, then maintain dose. | |
|
Grade 4 (platelets <25,000/mm3) |
Interrupt fam-trastuzumab deruxtecan until resolved to ≤ grade 1, then reduce dose by one dose level. | ||
|
Cardiotoxicity: Left ventricular dysfunction |
Left ventricular ejection fraction (LVEF) >45% and absolute decrease from baseline is 10% to 20% |
Continue fam-trastuzumab deruxtecan treatment. | |
|
LVEF 40% to 45% |
And absolute decrease from baseline is <10% |
Continue fam-trastuzumab deruxtecan treatment and repeat LVEF assessment within 3 weeks. | |
|
And absolute decrease from baseline is 10% to 20% |
Interrupt fam-trastuzumab deruxtecan treatment. Repeat LVEF assessment within 3 weeks. If LVEF has not recovered to within 10% from baseline, permanently discontinue fam-trastuzumab deruxtecan. If LVEF recovers to within 10% from baseline, resume fam-trastuzumab deruxtecan treatment at the same dose. | ||
|
LVEF <40% or absolute decrease from baseline is >20% |
Interrupt fam-trastuzumab deruxtecan treatment. Repeat LVEF assessment within 3 weeks. If LVEF of <40% or absolute decrease from baseline of >20% is confirmed, permanently discontinue fam-trastuzumab deruxtecan. | ||
|
Symptomatic heart failure |
Permanently discontinue fam-trastuzumab deruxtecan. | ||
|
Infusion reaction |
Infusion-related symptoms |
Interrupt infusion or slow infusion rate. | |
|
Severe infusion reaction |
Permanently discontinue fam-trastuzumab deruxtecan. | ||
|
Pulmonary toxicity: Interstitial lung disease (ILD)/pneumonitis |
Asymptomatic ILD/pneumonitis (grade 1) |
Interrupt fam-trastuzumab deruxtecan until resolved to grade 0, then: • If resolved in ≤28 days from date of onset, maintain dose. • If resolved in >28 days from date of onset, reduce dose by one dose level. • Consider corticosteroid treatment as soon as ILD/pneumonitis is suspected (eg, ≥0.5 mg/kg/day prednisolone [or equivalent], followed by a gradual taper, if necessary). • Consider consultation with a pulmonologist. | |
|
Symptomatic ILD/pneumonitis (≥ grade 2) |
Permanently discontinue fam-trastuzumab deruxtecan. Promptly initiate systemic corticosteroid treatment as soon as ILD/pneumonitis is suspected (eg, ≥1 mg/kg/day prednisolone [or equivalent] for at least 14 days followed by a gradual taper over at least 4 weeks). Consider consultation with a pulmonologist. | ||
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Reconstituted, Intravenous [preservative free]:
Enhertu: fam-trastuzumab deruxtecan-nxki 100 mg (1 ea) [contains polysorbate 80]
No
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Reconstituted, Intravenous:
Enhertu: 100 mg (1 ea) [contains polysorbate 80]
An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761139s022lbl.pdf#page=31, must be dispensed with this medication.
IV: Administer the first infusion over 90 minutes. If initial infusion was tolerated well, administer subsequent infusions over 30 minutes. Do not administer as an IV push or bolus. Administer only with an infusion set made of polyolefin or polybutadiene and a 0.2- or 0.22-micron in-line polyethersulfone or polysulfone filter. If solution prepared for infusion was refrigerated, allow solution to reach room temperature prior to administration. Cover infusion bag during infusion to protect from light. Slow or interrupt the infusion rate if infusion-related symptoms develop; discontinue permanently for severe infusion reactions. Do not administer with other drugs through the same IV line.
Fam-trastuzumab deruxtecan is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting (ASCO [Hesketh 2020]; delayed nausea and/or vomiting may occur.
Check label to ensure appropriate product is being administered; fam-trastuzumab deruxtecan, trastuzumab/hyaluronidase, conventional trastuzumab products, ado-trastuzumab emtansine, and pertuzumab/trastuzumab/hyaluronidase are different products and are NOT interchangeable.
Hazardous agent (NIOSH [group 1]).
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
Breast cancer, unresectable or metastatic, HER2-low: Treatment of unresectable or metastatic HER2-low (immunohistochemical [IHC] 1+ or IHC 2+ and negative in situ hybridization [ISH-]) breast cancer (as determined by an approved test) in adults who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant therapy.
Breast cancer, unresectable or metastatic, HER2-positive : Treatment of unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer in adults who have received a prior anti–HER2-based regimen either in the metastatic setting, or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within 6 months of completing therapy.
Gastric cancer, locally advanced or metastatic, HER2-positive: Treatment of locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma in adults who have received a prior trastuzumab-based regimen.
Non–small cell lung cancer, unresectable or metastatic, HER2-mutant: Treatment of unresectable or metastatic non–small cell lung cancer with activating HER2 (ERBB2) mutations (as detected by an approved test) in adults who have received a prior systemic therapy.
Colorectal cancer, metastatic, HER2-expressing
Fam-trastuzumab deruxtecan may be confused with ado-trastuzumab emtansine, brentuximab vedotin, pertuzumab, pertuzumab/trastuzumab/hyaluronidase, trastuzumab (conventional [or trastuzumab biosimilars]), trastuzumab/hyaluronidase.
This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.
Fam-trastuzumab deruxtecan (Enhertu) may be confused with ado-trastuzumab emtansine (Kadcyla), conventional trastuzumab (Herceptin), pertuzumab/trastuzumab/hyaluronidase (Phesgo), trastuzumab biosimilars, and/or trastuzumab/hyaluronidase (Herceptin Hylecta); products are not interchangeable.
Neutropenia, including severe grades 3 and 4 toxicity, and febrile neutropenia, may occur. Therapy interruption and/or dose reduction may be warranted, depending on severity.
Mechanism: Dose-related
Onset: Varied; median time to first onset of decreased neutrophil count was 16 days (range: 4 to 187) for locally advanced or metastatic gastric cancer and 22 days (range: 2 to 664) for metastatic breast cancer.
Patients treated with fam-trastuzumab deruxtecan may be at an increased risk of left ventricular dysfunction. Decreased left ventricular ejection fraction (LVEF) has been observed with anti-human epidermal growth factor receptor 2 (HER2) therapies, including fam-trastuzumab deruxtecan. Therapy interruption and/or permanent discontinuation may be warranted, depending on severity. Patients with a history of clinically significant cardiac disease or LVEF <50% prior to treatment have not been studied.
Nausea, vomiting, constipation, diarrhea, and stomatitis were commonly reported with fam-trastuzumab deruxtecan. Fam-trastuzumab deruxtecan is associated with a moderate emetic potential; antiemetics are recommended for prevention (Ref).
Interstitial lung disease (ILD) and pneumonitis have been reported with fam-trastuzumab deruxtecan. Fatal cases have occurred; however, most patients experienced Grade 1 or 2 events (Ref). Similar HER2-directed therapies, such as trastuzumab, trastuzumab emtansine, and topoisomerase I inhibitors have also been associated with pulmonary toxicity (Ref). Therapy interruption and/or permanent discontinuation may be warranted, depending on severity.
Mechanism of action: Dose-related; not clearly established. May involve alveolar macrophage uptake and redistribution of trastuzumab deruxtecan (Ref).
Onset: Delayed; median time to first onset was 2.8 months (range: 1.2 to 21) for locally advanced or metastatic gastric cancer and 5 months (range: 0.9 to 23) for metastatic breast cancer. In a pooled analysis of nine phase I and II monotherapy studies, the median time to onset was 5.4 months (range: <0.1 to 46.8 months) in heavily pretreated patients across all doses and tumor types (Ref).
Risk factors:
• Dose >6.4 mg/kg (Ref)
• Age <65 years (Ref)
• Baseline oxygen saturation <95% (Ref)
• Moderate to severe kidney impairment (Ref)
• Pulmonary comorbidities (ie, asthma, COPD, prior ILD/pneumonitis, pulmonary fibrosis, pulmonary emphysema, radiation pneumonitis) (Ref)
• Time since initial diagnosis >4 years (Ref)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reported adverse reactions are for adults.
>10%:
Dermatologic: Alopecia (21% to 46%), skin rash (3% to 13%; including bullous rash, dermatitis, erythema multiforme, maculopapular rash, palmar-plantar erythrodysesthesia)
Endocrine & metabolic: Decreased serum albumin (39%), hypokalemia (17% to 35%), weight loss (16% to 17%)
Gastrointestinal: Abdominal pain (9% to 21%), constipation (24% to 35%), decreased appetite (29% to 60%), diarrhea (19% to 32%; grades 3/4: 1% to 2%), dyspepsia (11% to 12%), nausea (61% to 79%; grades 3/4: 3% to 7%), stomatitis (11% to 20%; grades 3/4: ≤2%), vomiting (26% to 49%; grades 3/4: 2% to 4%)
Hematologic & oncologic: Anemia (31% to 58%; grades 3/4: 7% to 38%), decreased neutrophils (52% to 72%; grades 3/4: 12% to 51%), decreased platelet count (37% to 68%; grades 3/4: 3% to 12%), decreased white blood cell count (60% to 74%; grades 3/4: 4% to 29%), hemorrhage (16%), lymphocytopenia (43% to 70%; grades 3/4: 14% to 28%)
Hepatic: Increased serum alanine aminotransferase (34% to 53%), increased serum alkaline phosphatase (22% to 54%), increased serum aspartate aminotransferase (35% to 67%), increased serum bilirubin (16% to 24%)
Nervous system: Dizziness (10% to 13%), fatigue (32% to 59%; including asthenia and malaise), headache (4% to 22%), peripheral neuropathy (13%; grades 3/4: <1%)
Neuromuscular & skeletal: Musculoskeletal pain (15% to 32%)
Ophthalmic: Dry eye syndrome (11%)
Renal: Increased serum creatinine (15% to 16%)
Respiratory: Cough (10% to 20%), dyspnea (5% to 13%), epistaxis (3% to 13%), interstitial lung disease (6% to 12%; including pneumonitis and respiratory failure), respiratory tract infection (22%; including bronchitis, influenza, lower respiratory tract infection, pneumonia, and respiratory syncytial virus infection), upper respiratory tract infection (4% to 15%)
Miscellaneous: Fever (12% to 24%)
1% to 10%:
Cardiovascular: Decreased left ventricular ejection fraction (3% to 8%; may be asymptomatic), peripheral edema (10%), troponin increased in blood specimen (can be severe)
Dermatologic: Cellulitis (can be severe), pruritus (3% to 8%), skin hyperpigmentation (3% to 6%)
Endocrine & metabolic: Dehydration (2% to 6%), hypercalcemia (can be severe)
Gastrointestinal: Abdominal distention (5%), dysgeusia (6% to 10%), flatulence (2%), gastritis (3%), intestinal obstruction (can be severe)
Genitourinary: Urinary tract infection (can be severe)
Hematologic & oncologic: Febrile neutropenia (≤5%; grades 3/4: 5%), tumor hemorrhage (can be severe)
Hepatic: Cholestatic jaundice (can be severe), hepatic impairment (8%)
Hypersensitivity: Infusion-related reaction (≤3%; including hypersensitivity reaction)
Infection: Sepsis
Ophthalmic: Blurred vision (4% to 5%; including visual impairment)
Respiratory: Pleural effusion (can be severe)
Frequency not defined:
Cardiovascular: Myocarditis
Endocrine & metabolic: Hypomagnesemia
There are no contraindications listed in the manufacturer's US labeling.
Canadian labeling: Hypersensitivity to fam-trastuzumab deruxtecan or any component of the formulation.
Concerns related to adverse effects:
• Bone marrow suppression: Severe neutropenia may occur, including grades 3 and 4 toxicity and neutropenic fever. The median time to first onset was 16 to 22 days (range: 2 days to ~22 months).
• Cardiotoxicity: Patients treated with fam-trastuzumab deruxtecan may be at increased risk of developing left ventricular dysfunction. Decreased left ventricular ejection fraction (LVEF) has been observed with anti-HER2 therapies, including fam-trastuzumab deruxtecan. Cases of asymptomatic LVEF decrease have been reported. Fam-trastuzumab deruxtecan has not been studied in patients with a history of clinically significant cardiac disease or LVEF <50% prior to treatment initiation.
• Pulmonary toxicity: Interstitial lung disease (ILD) and pneumonitis, including severe, life-threatening, or fatal cases, have been reported with fam-trastuzumab deruxtecan. Promptly investigate signs/symptoms (eg, cough, dyspnea, fever, other new or worsening respiratory symptoms) for suspected ILD, including radiographic imaging. Advise patients of the risk and the need to immediately report symptoms. The median time to first onset was 2.8 to 5 months (range: 0.9 to 23 months). A higher incidence of grade 1 or 2 ILD/pneumonitis has been observed in patients with moderate kidney impairment. ILD/pneumonitis may be severe or life-threatening.
Special populations:
• Older adults: Patients with breast cancer who were ≥65 years of age experienced a higher incidence of grade 3 or 4 adverse events, compared to patients <65 years of age.
Dosage form specific issues:
• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.
Other warnings/precautions:
• Do not interchange: Fam-trastuzumab deruxtecan and ado-trastuzumab emtansine, conventional trastuzumab (or trastuzumab biosimilars), pertuzumab/trastuzumab/hyaluronidase, or trastuzumab/hyaluronidase products are different and are NOT interchangeable. Do not substitute. Dosing and treatment schedules among the various trastuzumab-based products differ; confusion between the products may potentially cause harm to the patient. Verify product label prior to reconstitution and administration to prevent medication errors.
• HER2 status: For HER2-low breast cancer, select patients for therapy based on HER2 expression (immunohistochemical [IHC] 1+ or IHC 2+ and negative in situ hybridization [ISH-]). For gastric cancer, select patients for therapy based on HER2 protein overexpression or HER2 gene amplification; reassess HER2 status in between the prior trastuzumab therapy and fam-trastuzumab deruxtecan if feasible to obtain a new tumor specimen. For HER2-mutant non-small cell lunger cancer, select patients for therapy based on the presence of activating HER2 (ERBB2) mutations in tumor or plasma specimen (if no mutation is present in plasma specimen, test tumor tissue). Information on approved tests for HER2 protein expression, HER2 gene amplifications, and activating HER2 mutations is available at http://www.fda.gov/CompanionDiagnostics.
Substrate of BCRP/ABCG2, CYP3A4 (minor), OATP1B1/1B3 (SLCO1B1/1B3), P-glycoprotein/ABCB1 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
5-Aminosalicylic Acid Derivatives: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
Anthracyclines: Fam-Trastuzumab Deruxtecan may enhance the cardiotoxic effect of Anthracyclines. Management: When possible, patients treated with fam-trastuzumab deruxtecan should avoid anthracycline-based therapy for up to 7 months after stopping fam-trastuzumab deruxtecan. Monitor closely for cardiac dysfunction in patients receiving this combination. Risk D: Consider therapy modification
BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid combination
Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Risk C: Monitor therapy
Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk X: Avoid combination
CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Risk C: Monitor therapy
Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Risk D: Consider therapy modification
Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Risk X: Avoid combination
Efgartigimod Alfa: May diminish the therapeutic effect of Fc Receptor-Binding Agents. Risk C: Monitor therapy
Fexinidazole: Myelosuppressive Agents may enhance the myelosuppressive effect of Fexinidazole. Risk X: Avoid combination
Olaparib: Myelosuppressive Agents may enhance the myelosuppressive effect of Olaparib. Risk C: Monitor therapy
Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
Ropeginterferon Alfa-2b: Myelosuppressive Agents may enhance the myelosuppressive effect of Ropeginterferon Alfa-2b. Management: Avoid coadministration of ropeginterferon alfa-2b and other myelosuppressive agents. If this combination cannot be avoided, monitor patients for excessive myelosuppressive effects. Risk D: Consider therapy modification
Exposure to fam-trastuzumab deruxtecan during pregnancy can result in embryo-fetal harm. Advise patients of these risks and the need for effective contraception.
Evaluate pregnancy status prior to use in patients who could become pregnant. Patients who could become pregnant should use effective contraception during therapy and for 7 months after the last fam-trastuzumab deruxtecan dose. Patients with partners who could become pregnant should use effective contraception during therapy and for 4 months after the last dose of fam-trastuzumab deruxtecan.
Based on the mechanism of action and postmarketing data, exposure to fam-trastuzumab deruxtecan during pregnancy can result in embryo-fetal harm. Advise patients of these risks and the need for effective contraception.
Oligohydramnios and oligohydramnios sequence (manifested as pulmonary hypoplasia, skeletal malformations, and neonatal death) were observed following trastuzumab exposure during pregnancy (trastuzumab is the antibody component of fam-trastuzumab deruxtecan). Monitor for oligohydramnios if trastuzumab exposure occurs during pregnancy or within 7 months prior to conception; conduct appropriate fetal testing if oligohydramnios occurs.
It is not known if fam-trastuzumab deruxtecan is present in breast milk.
Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer during therapy and for 7 months after the last fam-trastuzumab deruxtecan dose.
HER2 status:
Breast cancer (unresectable or metastatic), HER2-low: Determine HER2 expression (immunohistochemical [IHC] 1+ or IHC 2+ and negative in situ hybridization [ISH-]).
Gastric cancer (locally advanced or metastatic), HER2-positive: Determine HER2 protein overexpression or HER2 gene amplification. If feasible to obtain a new tumor specimen, reassess HER2 status in between the prior trastuzumab therapy and fam-trastuzumab deruxtecan.
Non–small cell lunger cancer (unresectable or metastatic), HER2-mutant: Determine the presence of activating HER2 (ERBB2) mutations in tumor or plasma specimen; if no mutation is present in plasma specimen, test tumor tissue.
CBC (prior to treatment initiation, prior to each dose, and as clinically indicated). Assess left ventricular ejection fraction prior to fam-trastuzumab deruxtecan initiation and at regular intervals during treatment as clinically indicated. Evaluate pregnancy status prior to therapy (in patients who could become pregnant). Monitor for signs/symptoms of interstitial lung disease/pneumonitis (eg, cough, dyspnea, fever, and/or any new or worsening respiratory symptoms [particularly in patients with kidney impairment]; promptly investigate and obtain radiographic imaging for suspected interstitial lung disease). Monitor for infusion reactions.
The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow up.
Fam-trastuzumab deruxtecan is a HER2-directed antibody-drug conjugate composed of a humanized IgG1 monoclonal antibody, which has the same amino acid sequence as trastuzumab (and targets HER2), a cleavable tetrapeptide-based linker, and the cytotoxic component, a topoisomerase I inhibitor (Modi 2020). The deruxtecan component is a cleavable linker and the topoisomerase inhibitor, DXd (an exatecan derivative). Upon binding to HER2 on tumor cells, fam-trastuzumab deruxtecan undergoes internalization and intracellular linker cleavage by lysosomal enzymes, releasing DXd and resulting in DNA damage and cell death.
Distribution: Vd: Fam-trastuzumab deruxtecan: 2.68 L.
Protein binding: DXd: ~97% (to plasma proteins).
Metabolism: Fam-trastuzumab deruxtecan: Degradation via catabolic pathways into small peptides and amino acids; DXd: Primarily via CYP3A4.
Half-life elimination: Fam-trastuzumab deruxtecan: ~5.4 to 5.7 days; DXd: 5.4 to 6.1 days.
Excretion: Clearance: Fam-trastuzumab deruxtecan: 0.41 L/day; DXd: 18.3 L/hour.
Solution (reconstituted) (Enhertu Intravenous)
100 mg (per each): $2,967.59
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