Pertuzumab, trastuzumab, and hyaluronidase-zzxf (pertuzumab/trastuzumab/hyaluronidase-zzxf) is a fixed-combination antineoplastic agent containing pertuzumab (a recombinant humanized anti-human epidermal growth factor receptor type 2 [anti-HER2/ERBB2] monoclonal antibody), trastuzumab (a recombinant humanized anti-HER2 monoclonal antibody), and hyaluronidase-zzxf (a recombinant endoglycosidase that enhances dispersion and absorption of pertuzumab and trastuzumab).1, 3
Pertuzumab, trastuzumab, and hyaluronidase-zzxf (pertuzumab/trastuzumab/hyaluronidase-zzxf) is used in combination with chemotherapy for the neoadjuvant treatment of adults with human epidermal growth factor receptor type 2 ( HER2 )-positive locally advanced, inflammatory, or early-stage breast cancer (either node positive or tumor size >2 cm in diameter) as part of a complete treatment regimen.1, 2, 3, 12
Efficacy and safety of pertuzumab/trastuzumab/hyaluronidase-zzxf for the neoadjuvant treatment of HER2-positive early-stage breast cancer are based principally on the results of an open-label, multicenter, randomized, non-inferiority phase 3 study (FeDeriCa) comparing the pharmacokinetic and safety profiles of pertuzumab/trastuzumab/hyaluronidase-zzxf versus IV pertuzumab and IV trastuzumab as well as evidence from 3 adequate and well-controlled studies (NeoSphere, TRYPHAENA, BERENICE) in patients with operable, locally advanced, or inflammatory early-stage HER2-positive breast cancer who received neoadjuvant chemotherapy regimens in combination with IV pertuzumab and IV trastuzumab.1, 2, 4, 5, 6, 7, 9
The FeDeriCa study included 500 patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (with a tumor size >2 cm or node positive).1, 2 HER2 overexpression was defined as a score of 3+ on IHC assay or a FISH amplification ratio ≥2.1 Patients were randomized (stratified according to hormone receptor status, clinical stage of disease, and chemotherapy regimen) to receive 8 cycles of neoadjuvant chemotherapy selected by the investigator with concurrent administration of 4 cycles of either subcutaneous pertuzumab/trastuzumab/hyaluronidase-zzxf or IV pertuzumab plus IV trastuzumab during cycles 5-8, followed by surgery.1 Investigator's choice of neoadjuvant chemotherapy consisted of doxorubicin-cyclophosphamide every 2 weeks for 4 cycles followed by weekly paclitaxel for 12 cycles or doxorubicin-cyclophosphamide every 3 weeks for 4 cycles followed by docetaxel every 3 weeks for 4 cycles.1 Pertuzumab/trastuzumab/hyaluronidase-zzxf was administered at an initial dose of 1200 mg/600 mg by subcutaneous injection during cycle 5, followed by 600 mg/600 mg by subcutaneous injection every 3 weeks during cycles 6-8; IV pertuzumab was administered at an initial dose of 840 mg followed by maintenance doses of 420 mg by IV infusion every 3 weeks during cycles 6-8, and IV trastuzumab was administered at an initial dose of 8 mg/kg followed by maintenance doses of 6 mg/kg by IV infusion every 3 weeks during cycles 6-8 with neoadjuvant chemotherapy.1, 2 After surgery, patients continued to receive their assigned therapy for an additional 14 cycles to complete a total of 18 cycles of HER2-targeted therapy.1, 2
The primary measure of efficacy was noninferiority of pertuzumab trough serum concentration from the fixed-dose combination of pertuzumab/trastuzumab/hyaluronidase-zzxf compared to IV pertuzumab at cycle 7 (i.e., pre-dose cycle 8 concentration); secondary end points included pathological complete response (pCR) (defined as the absence of invasive neoplastic cells in the breast and axillary lymph nodes) and noninferiority of trastuzumab trough serum concentration at cycle 7.1, 2 The median age of patients enrolled in the study was 51 years; 66% were white, 61% were hormone receptor-positive, and 58% were node-positive.1 The cycle 7 pertuzumab trough serum concentration from pertuzumab/trastuzumab/hyaluronidase-zzxf was noninferior to the IV pertuzumab trough serum concentration.1, 2 The cycle 7 trastuzumab trough serum concentration from the fixed-combination preparation also was noninferior to the IV trastuzumab trough serum concentration.1, 2 Total pCR rates were similar between the 2 treatment groups (59.7% in patients receiving pertuzumab/trastuzumab/hyaluronidase-zzxf and 59.5% in those receiving IV pertuzumab and IV trastuzumab).1, 2
Pertuzumab/trastuzumab/hyaluronidase-zzxf is used in combination with chemotherapy for the adjuvant treatment of early-stage HER2-positive breast cancer at high risk of recurrence.1, 2, 3
Efficacy of pertuzumab/trastuzumab/hyaluronidase-zzxf for this indication is based on results of the FeDeriCa study in adults with operable, locally advanced, or inflammatory HER2-positive breast cancer, with supporting data from adequate and well-controlled studies of IV pertuzumab and IV trastuzumab in combination with chemotherapy for the treatment of HER2-positive breast cancer.1, 2 An additional randomized, open-label, multicenter, cross-over phase 2 study was conducted to assess patient preference for the fixed-dose combination of pertuzumab and trastuzumab administered by subcutaneous injection in patients with HER2-positive early breast cancer (PHranceSCa).1, 2, 3, 9
The PHranceSCa study included patients with early-stage HER2-positive breast cancer who had completed neoadjuvant treatment with pertuzumab, trastuzumab, and chemotherapy and had surgery.1, 9 A total of 160 patients were randomized to receive 3 cycles of IV pertuzumab and IV trastuzumab followed by 3 cycles of pertuzumab/trastuzumab/hyaluronidase-zzxf by subcutaneous injection or 3 cycles of pertuzumab/trastuzumab/hyaluronidase-zzxf by subcutaneous injection followed by 3 cycles of IV pertuzumab and IV trastuzumab; all patients received 18 total cycles of HER2-targeted therapy.1, 3, 9 After cycle 6, 85% of patients reported preferring subcutaneous administration of pertuzumab/trastuzumab/hyaluronidase-zzxf over IV administration of pertuzumab and trastuzumab; 14% of patients reported preferring IV administration of pertuzumab and trastuzumab over subcutaneous administration of pertuzumab/trastuzumab/hyaluronidase-zzxf, and 1% of patients had no preference for route of administration.1, 9
Pertuzumab/trastuzumab/hyaluronidase-zzxf is used in combination with docetaxel for the treatment of metastatic breast cancer in patients whose tumors overexpress HER2 and who have not received prior anti- HER2 therapy or chemotherapy for metastatic disease.1
Efficacy and safety of pertuzumab/trastuzumab/hyaluronidase-zzxf for this use are based on the results of a randomized, double-blind, placebo-controlled study (CLEOPATRA) in adults with HER2-positive metastatic breast cancer who received pertuzumab and trastuzumab by IV infusion in combination with docetaxel in addition to pharmacokinetic and safety data from an open-label, multicenter, randomized, noninferiority study (FeDeriCa).1, 11 In the CLEOPATRA study, median overall survival was prolonged in patients who received IV pertuzumab and IV trastuzumab in combination with docetaxel compared with patients who received placebo and trastuzumab in combination with docetaxel (56.5 versus 40.8 months).11
Dispensing and Administration Precautions
Pertuzumab/trastuzumab/hyaluronidase-zzxf is administered by subcutaneous injection only; do not administer by IV or by IM injection .1
Pertuzumab/trastuzumab/hyaluronidase-zzxf injection is commercially available in single-dose vials containing the fixed combination of 1200 mg pertuzumab, 600 mg trastuzumab, and 30,000 units hyaluronidase-zzxf in 15 mL of solution (for initial dose) or the fixed combination of 600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units hyaluronidase-zzxf in 10 mL of solution (for maintenance doses).1 A single dose of pertuzumab/trastuzumab/hyaluronidase-zzxf requires administration of the entire contents of one vial.1 The drug should not be diluted.1 Vials of pertuzumab/trastuzumab/hyaluronidase-zzxf injection contain no preservatives and are intended for single-use only; any unused portions should be discarded.1
Pertuzumab/trastuzumab/hyaluronidase-zzxf injection vials should be stored at 2-8°C in the original carton protected from light, and should not be frozen or shaken.1 The drug should be inspected for particulate matter and discoloration prior to administration.1 The solution should appear clear to opalescent and colorless to light brown, and should not be used if it is cloudy, discolored, or contains particulate matter.1
Prior to administration, the drug should be withdrawn from the vial into a syringe using a transfer needle.1 If not used immediately, syringes containing pertuzumab/trastuzumab/hyaluronidase-zzxf solution may be stored at room temperature for up to 4 hours or in the refrigerator at 2-8°C for up to 24 hours.1 Prior to storage, the transfer needle should be replaced with a syringe cap and labeled.1
Subcutaneous injections of pertuzumab/trastuzumab/hyaluronidase-zzxf should be administered with a 25- to 27-gauge, (3/8)-(5/8)-inch hypodermic needle into the thigh.1 Immediately prior to administration, the hypodermic needle should be attached to the syrin the volume of drug solution in the syringe should be adjusted to 15 mL for the initial dose and 10 mL for maintenance doses.1 The injection site should be alternated between the left and right thigh and should be at least 1 inch (2.5 cm) from the previous injection site; avoid any area that is tender, red, bruised, or hard.1 A single dose of pertuzumab/trastuzumab/hyaluronidase-zzxf should not be split into 2 syringes or administered into two different administration sites.1 During the treatment course with pertuzumab/trastuzumab/hyaluronidase-zzxf, other medications for subcutaneous administration should preferably be injected at different sites.1
Pertuzumab/trastuzumab/hyaluronidase-zzxf is compatible with stainless steel, polypropylene, polycarbonate, polyethylene, polyurethane, polyvinyl chloride, and fluorinated ethylene polypropylene.1
The initial dose of pertuzumab/trastuzumab/hyaluronidase-zzxf should be administered by subcutaneous injection over approximately 8 minutes; subsequent doses are administered by subcutaneous injection over approximately 5 minutes.1
Clinicians should consult published protocols for information on the dosage, method of administration, and administration sequence of other antineoplastic agents used in combination regimens with pertuzumab, trastuzumab, and hyaluronidase.1
If a dose of pertuzumab/trastuzumab/hyaluronidase-zzxf is missed or delayed and the time between 2 sequential injections is less than 6 weeks, the maintenance dose of pertuzumab/trastuzumab/hyaluronidase-zzxf should be administered as soon as possible; do not wait until the next planned dose.1 If the time between 2 sequential injections is 6 weeks or longer, readminister the initial dose of pertuzumab/trastuzumab/hyaluronidase-zzxf followed every 3 weeks thereafter by a maintenance dose.1
In patients receiving pertuzumab/trastuzumab/hyaluronidase-zzxf in combination with anthracycline-based chemotherapy for early breast cancer, administer pertuzumab/trastuzumab/hyaluronidase-zzxf after administration of the anthracycline is completed.1
In patients receiving pertuzumab/trastuzumab/hyaluronidase-zzxf with taxane-based chemotherapy (docetaxel or paclitaxel) for early breast cancer, administer the taxane-based chemotherapy after administration of pertuzumab/trastuzumab/hyaluronidase-zzxf.1
In patients receiving pertuzumab/trastuzumab/hyaluronidase-zzxf for metastatic breast cancer with docetaxel, administer docetaxel after pertuzumab/trastuzumab/hyaluronidase-zzxf.1
Dosage adjustment is not necessary for concomitant chemotherapy.1
Neoadjuvant Treatment of Early-stage Breast Cancer
For the neoadjuvant treatment of HER2-positive early-stage breast cancer, pertuzumab/trastuzumab/hyaluronidase-zzxf is administered as part of a treatment regimen for early breast cancer.1 The recommended initial dose of the fixed combination of pertuzumab/trastuzumab/hyaluronidase-zzxf is 1200 mg pertuzumab/600 mg trastuzumab/30,000 units hyaluronidase in 15 mL (administered by subcutaneous injection over approximately 8 minutes), followed by maintenance doses of 600 mg pertuzumab/600 mg trastuzumab/20,000 units hyaluronidase in 10 mL (administered by subcutaneous injection over approximately 5 minutes) every 3 weeks for 3-6 cycles prior to surgery. 1
In the FeDeriCa trial, pertuzumab/trastuzumab/hyaluronidase-zzxf was administered as part of the following neoadjuvant treatment regimens: 4 preoperative cycles of dose-dense doxorubicin and cyclophosphamide alone followed by 4 preoperative cycles of pertuzumab/trastuzumab/hyaluronidase in combination with paclitaxel or docetaxel.1
Following surgery, pertuzumab/trastuzumab/hyaluronidase-zzxf should be continued to complete 1 year of therapy (up to 18 cycles) or until disease progression or unacceptable toxicity, whichever occurs first, as part of a complete regimen for early breast cancer.1
Adjuvant Treatment of Early-stage Breast Cancer
For the adjuvant treatment of HER2-positive early-stage breast cancer, pertuzumab/trastuzumab/hyaluronidase-zzxf is administered as part of a complete regimen, including standard anthracycline- and/or taxane-based chemotherapy.1
The recommended initial dose of the fixed combination of pertuzumab/trastuzumab/hyaluronidase-zzxf is 1200 mg pertuzumab/600 mg trastuzumab/30,000 units hyaluronidase in 15 mL (administered by subcutaneous injection over approximately 8 minutes).1 Pertuzumab/trastuzumab/hyaluronidase-zzxf therapy should begin on day 1 of the first taxane-containing cycle.1 The initial dose should be followed by maintenance doses of 600 mg pertuzumab/600 mg trastuzumab/20,000 units hyaluronidase in 10 mL (administered by subcutaneous injection over approximately 5 minutes) every 3 weeks for a total of 1 year (up to 18 cycles) or until disease recurrence or intolerable toxicity, whichever occurs first.1
For the treatment of HER2-positive metastatic breast cancer, the recommended initial dose of pertuzumab/trastuzumab/hyaluronidase-zzxf is 1200 mg pertuzumab/600 mg trastuzumab/30,000 units hyaluronidase in 15 mL (administered by subcutaneous injection over approximately 8 minutes) in combination with docetaxel 75 mg/m2 (administered as an IV infusion).1 The initial dose should be followed by maintenance doses of 600 mg pertuzumab/600 mg trastuzumab/20,000 units hyaluronidase in 10 mL (administered by subcutaneous injection over approximately 5 minutes) in combination with docetaxel 75 mg/m2 (administered by IV infusion); the dosage of docetaxel may be increased to 100 mg/m2 if the initial dosage is well tolerated.1 Continue therapy until disease progression or unacceptable toxicity, whichever occurs first.1
Patients Transitioning From IV Pertuzumab and IV Trastuzumab to Subcutaneous Pertuzumab/trastuzumab/hyaluronidase-zzxf
In patients previously receiving IV pertuzumab and IV trastuzumab with less than 6 weeks since their last dose, administer pertuzumab/trastuzumab/hyaluronidase-zzxf as a maintenance dosage of 600 mg pertuzumab/600 mg trastuzumab/20,000 units hyaluronidase every 3 weeks.1
In patients previously receiving IV pertuzumab and IV trastuzumab with ≥6 weeks since their last dose, administer pertuzumab/trastuzumab/hyaluronidase-zzxf as an initial dose of 1200 mg pertuzumab/600 mg trastuzumab/30,000 units hyaluronidase followed by a maintenance dosage of 600 mg pertuzumab/600 mg trastuzumab/20,000 units hyaluronidase every 3 weeks.1
Dosage Modification for Toxicity and Contraindications for Continued Therapy
Dosage reductions for adverse effects are not recommended for pertuzumab/trastuzumab/hyaluronidase-zzxf; however, therapy interruption or treatment discontinuance may be necessary.1
The prescribing information for concomitant chemotherapy (anthracycline, docetaxel, paclitaxel) should be consulted for detailed information on dosage modifications for these drugs.1
Early-stage Breast Cancer: If LVEF decreases to <50% with an absolute decrease from baseline of ≥10%, withhold pertuzumab/trastuzumab/hyaluronidase-zzxf therapy for at least 3 weeks.1
If LVEF has recovered to ≥50% or to an absolute decrease from baseline of <10%, resume therapy.1 If after a repeat assessment within approximately 3 weeks, the LVEF has not improved, has declined further, or if patient is symptomatic, permanently discontinue therapy.1
In patients receiving anthracycline-based chemotherapy, pertuzumab/trastuzumab/hyaluronidase-zzxf therapy should be initiated only if the measurement of LVEF after completion of anthracycline-based chemotherapy is within normal limits (≥50%).1
Metastatic Breast Cancer: If LVEF decreases to <40% or to 40-45% with an absolute decrease from baseline of ≥10%, withhold pertuzumab/trastuzumab/hyaluronidase-zzxf therapy for at least 3 weeks.1
If LVEF has recovered to >45% or to 40-45% with an absolute decrease from baseline of <10%, resume therapy.1 If after a repeat assessment within approximately 3 weeks, the LVEF has not improved, has declined further, or if patient is symptomatic, permanently discontinue therapy.1
Hypersensitivity and Administration-related Reactions
If a significant injection-related reaction occurs, the injection rate should be reduced or paused, and appropriate medical therapy should be initiated.1 If a serious hypersensitivity reaction occurs, immediately discontinue the injection and permanently discontinue pertuzumab/trastuzumab/hyaluronidase-zzxf therapy.1
Dosage adjustment is not necessary based on body weight or baseline albumin concentration.1
The manufacturer makes no specific dosage recommendations for patients with hepatic impairment.1
The manufacturer makes no specific dosage recommendations for patients with renal impairment.1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
A boxed warning about the risk of cardiomyopathy has been included in the prescribing information for pertuzumab/trastuzumab/hyaluronidase-zzxf.1 Serious and potentially fatal cardiovascular effects, including hypertension, arrhythmias, left ventricular cardiac dysfunction, subclinical and disabling cardiac failure, cardiomyopathy, and cardiac death have been reported in patients receiving pertuzumab/trastuzumab/hyaluronidase-zzxf.1 In the FeDeriCa study, adverse cardiovascular effects occurred in 22% of patients treated with the combination preparation; decreases in left ventricular ejection fraction (LVEF) was the most frequently reported adverse cardiovascular effect.1 The incidence of NYHA class III or IV heart failure with a LVEF decrease to less than 50% and an absolute decrease from baseline of ≥10% in patients receiving pertuzumab/trastuzumab/hyaluronidase-zzxf was 0.8%.1 The incidence of NYHA class II (asymptomatic or mildly symptomatic) heart failure with a LVEF decrease to less than 50% and an absolute decrease from baseline of ≥10% in patients receiving pertuzumab/trastuzumab/hyaluronidase-zzxf was 1.2%.1
An increased incidence of LVEF decline has been reported with IV pertuzumab, IV trastuzumab, and docetaxel.1 In clinical studies, the incidence of symptomatic myocardial dysfunction was increased by 4 to 6 fold in patients receiving trastuzumab; the highest incidence occurred when trastuzumab was administered concomitantly with an anthracycline.1 The risk of cardiac dysfunction may be increased in patients who receive an anthracycline after discontinuance of pertuzumab/trastuzumab/hyaluronidase-zzxf therapy.1
A baseline cardiac evaluation including history, physical examination, and assessment of LVEF (i.e., echocardiogram and/or MUGA scan) should be performed prior to initiating pertuzumab/trastuzumab/hyaluronidase-zzxf therapy.1 Assess LVEF at regular intervals (e.g., every 3 months) during treatment.1 If substantial decreases in LVEF occur, temporary or permanent discontinuance of pertuzumab/trastuzumab/hyaluronidase-zzxf may be required.1
Following the completion of pertuzumab/trastuzumab/hyaluronidase-zzxf therapy, continue to monitor for cardiomyopathy and assess LVEF every 6 months for at least 2 years as a component of adjuvant therapy.1
Pertuzumab/trastuzumab/hyaluronidase-zzxf has not been studied in patients with early breast cancer or metastatic breast cancer with baseline LVEF values <55 or <50%, respectively, prior history of congestive heart failure (CHF), or conditions that could impair left ventricular function (e.g., uncontrolled hypertension, recent MI, serious cardiac arrhythmia requiring treatment, or a cumulative prior anthracycline exposure to >360 mg/m2 of doxorubicin or its equivalent).1
Fetal/Neonatal Morbidity and Mortality
Pertuzumab/trastuzumab/hyaluronidase-zzxf may cause fetal harm if administered to pregnant women.1 A boxed warning about this risk has been included in the prescribing information for the combination preparation.1 Oligohydramnios, fatal pulmonary hypoplasia, skeletal abnormalities, and neonatal death have been reported with use of IV trastuzumab during pregnancy in postmarketing experience.1 In addition, IV pertuzumab has been shown to be embryotoxic and fetotoxic in animals.1 In pregnant cynomolgus monkeys, exposure to IV pertuzumab at concentrations 2.5-20 times that of the exposure in humans at the recommended dose resulted in oligohydramnios, delayed fetal kidney development, and embryo-fetal death.1 The possibility that trastuzumab may persist in maternal tissues for up to 7 months after the last dose should be considered.1
Pregnancy should be avoided during pertuzumab/trastuzumab/hyaluronidase-zzxf therapy.1 Perform a pregnancy test prior to initiation of therapy in females of reproductive potential and advise such females to use effective contraceptive methods while receiving the drug and for 7 months after discontinuance of therapy.1
If pertuzumab/trastuzumab/hyaluronidase-zzxf is used during pregnancy or within 7 months prior to conception, the patient should be apprised of the potential fetal hazard and monitored for development of oligohydramnios.1 If oligohydramnios occurs, appropriate fetal testing within the standards of care should be performed.1
Pertuzumab/trastuzumab/hyaluronidase-zzxf can cause serious, sometimes fatal, pulmonary toxicity.1 A boxed warning about this risk has been included in the prescribing information for the combination preparation.1 Severe adverse pulmonary effects, including dyspnea, interstitial pneumonitis, pulmonary infiltrates, pleural effusions, non-cardiogenic pulmonary edema, pulmonary insufficiency and hypoxia, acute respiratory distress syndrome, and pulmonary fibrosis, have been reported in patients receiving IV trastuzumab.1 Patients with symptomatic intrinsic lung disease or extensive tumor involvement of the lungs causing dyspnea at rest may experience more severe pulmonary toxicity.1
Pertuzumab/trastuzumab/hyaluronidase-zzxf should be permanently discontinued if anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome develops.1 Monitor patients carefully until signs and symptoms have resolved completely.1
Other Warnings and Precautions
Hypersensitivity and Administration-related Reactions
Severe administration-related reactions including hypersensitivity, anaphylaxis, and fatal events, have been reported in patients receiving IV pertuzumab and trastuzumab.1 Patients experiencing dyspnea at rest due to complications of advanced malignancy and comorbidities may be at increased risk of a severe or fatal administration-related reaction.1 In the FeDeriCa study, hypersensitivity reactions occurred in 1.2% of patients receiving pertuzumab/trastuzumab/hyaluronidase-zzxf and an administration-related reaction occurred in 21% of patients who received the combination therapy.1
Patients should be closely monitored during and for 30 minutes after the first subcutaneous injection of pertuzumab/trastuzumab/hyaluronidase-zzxf, and during and for 15 minutes after subsequent injections of the drug.1 If a significant injection-related reaction occurs, reduce the rate or pause the injection and administer appropriate treatment; evaluate and carefully monitor patients until signs and symptoms have resolved completely.1 Permanently discontinue pertuzumab/trastuzumab/hyaluronidase-zzxf in patients who experience anaphylaxis or severe injection-related reactions.1 Pertuzumab/trastuzumab/hyaluronidase-zzxf should be administered in a setting where emergency equipment and appropriate medical support are available for the management of potential administration-related reactions.1 In patients experiencing reversible grade 1 or grade 2 hypersensitivity reactions, consider premedication with an analgesic, antipyretic, or an antihistamine prior to readministration of the combination drug.1
Pertuzumab/trastuzumab/hyaluronidase-zzxf is contraindicated in patients with known hypersensitivity to the drug or any ingredients in the formulation.1
Pertuzumab/trastuzumab/hyaluronidase-zzxf may exacerbate chemotherapy-induced neutropenia.1 In clinical trials evaluating IV trastuzumab, grade 3 or 4 neutropenia, including febrile neutropenia, was reported more frequently in patients receiving trastuzumab in combination with chemotherapy than in patients receiving chemotherapy alone.1 The incidence of deaths caused by sepsis in patients receiving trastuzumab was similar to that in patients receiving chemotherapy alone.1
As with all therapeutic proteins, there is a potential for immunogenicity with pertuzumab/trastuzumab/hyaluronidase-zzxf.1 In the FeDeriCa study, anti-pertuzumab and anti-trastuzumab antibodies were detected in 7 of 237 (3%) and 1 of 237 (0.4%) patients, respectively, receiving IV pertuzumab in combination with trastuzumab.1 Anti-pertuzumab, anti-trastuzumab, and anti-recombinant human hyaluronidase antibodies were detected in 11 of 231 (4.8%), 2 of 232 (0.9%), and 2 of 225 (0.9%) patients, respectively, receiving pertuzumab/trastuzumab/hyaluronidase-zzxf; neutralizing antibodies to pertuzumab or trastuzumab were detected in a few of these patients.1 The clinical relevance of such antibodies is not known.1
Pertuzumab/trastuzumab/hyaluronidase-zzxf may cause fetal harm.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.) In postmarketing reports, use of IV trastuzumab during pregnancy resulted in cases of oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death.1
If pertuzumab is used during pregnancy or if the patient becomes pregnant while receiving the drug or within 7 months after discontinuance of therapy, the patient should be apprised of the potential fetal hazard; the patient and clinician should immediately notify Genentech (1-888-835-2555).1
It is not known whether pertuzumab/trastuzumab/hyaluronidase-zzxf is distributed into milk, or if the drug has any effect on milk production or the nursing infant.1 Human immunoglobulin G (IgG) is distributed into human milk, but is not found in neonatal or infant circulation in substantial amounts.1 Trastuzumab is distributed into milk in monkeys; however, no adverse effects on neonatal development were associated with this exposure.1
Consider the benefits of breast-feeding and the importance of pertuzumab/trastuzumab/hyaluronidase-zzxf to the woman as well as potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.1 This consideration should also take into account the elimination half-life of pertuzumab and the trastuzumab wash out period of 7 months.1
Females and Males of Reproductive Potential
Pertuzumab/trastuzumab/hyaluronidase-zzxf can cause embryofetal harm.1 Verify pregnancy status in females of reproductive potential and advise such females to use effective contraceptive methods while receiving the drug and for 7 months after discontinuance of therapy.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)
Safety and efficacy of pertuzumab/trastuzumab/hyaluronidase-zzxf have not been established in pediatric patients.1
In the FeDeriCa study, 11% of patients were ≥65 years of age, and 1.6% were ≥75 years of age.1 The manufacturer states that clinical studies of pertuzumab/trastuzumab/hyaluronidase-zzxf did not include sufficient numbers of patients ≥65 years of age to determine whether geriatric patients respond differently than younger patients.1 In a population pharmacokinetic analysis, no substantial differences in pharmacokinetics were observed between geriatric and younger adults.1
In studies with IV trastuzumab, the risk of cardiac function was increased in geriatric patients compared with younger patients receiving treatment for adjuvant therapy or metastatic disease.1 In clinical trials of IV pertuzumab in combination with trastuzumab, the risk of decreased appetite, anemia, decreased weight, asthenia, dysgeusia, peripheral neuropathy, and hypomagnesemia was increased in geriatric patients compared with younger patients.1
The pharmacokinetics of pertuzumab and trastuzumab have not been studied in patients with hepatic impairment.1
In a population pharmacokinetic analysis, the pharmacokinetics of pertuzumab and trastuzumab were similar between patients with mild or moderate (creatinine clearance ≥30 mL/minute) renal impairment and those with normal renal function.1 The effect of severe renal impairment (creatinine clearance <30 mL/minute) on the pharmacokinetics of pertuzumab, trastuzumab, and hyaluronidase has not been established.1, 13
The most common adverse effects occurring in >30% of patients receiving pertuzumab/trastuzumab/hyaluronidase-zzxf for neoadjuvant and adjuvant treatment of breast cancer include alopecia, nausea, diarrhea, anemia, and asthenia.1
The most common adverse effects (based on IV pertuzumab) occurring in >30% of patients receiving IV pertuzumab in combination with trastuzumab and docetaxel for treatment of metastatic breast cancer include diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy.1
The risk of cardiac dysfunction is increased in patients receiving an anthracycline after pertuzumab/trastuzumab/hyaluronidase-zzxf therapy is discontinued.1 If possible, anthracycline therapy should be avoided for up to 7 months after the last dose of pertuzumab/trastuzumab/hyaluronidase-zzxf is administered.1 If anthracycline-based therapy is necessary, cardiac function should be monitored closely.1
Pertuzumab is a recombinant humanized monoclonal antibody that targets the extracellular dimerization domain of the human epidermal growth factor receptor 2 protein (HER2).1 Trastuzumab is a humanized IgG1 kappa monoclonal antibody that selectively binds with high affinity to the extracellular domain of HER2.1 Both drugs are produced by recombinant DNA technology in a mammalian cell (Chinese hamster ovary) culture.1 Pertuzumab and trastuzumab also are referred to as HER2/neu receptor antagonists.1
Hyaluronidase-zzxf, a recombinant endoglycosidase, is produced by recombinant DNA technology in mammalian cell (Chinese hamster ovary) culture.1 Hyaluronidase acts locally to temporarily increase permeability of subcutaneous tissue to increase dispersion and absorption of pertuzumab and trastuzumab.1 Hyaluronidase increases permeability of the subcutaneous tissue by depolymerizing hyaluronan, a polysaccharide found in the extracellular matrix of the subcutaneous tissue.1 The effects of hyaluronidase are reversible; the permeability of subcutaneous tissue is restored in 24 to 48 hours.1
Pertuzumab binds specifically to the extracellular dimerization domain (subdomain II) of the HER2 protein, blocking heterodimerization of HER2 with other ligand-bound members of the HER family (i.e., epidermal growth factor receptor [HER1/EGFR], HER3, HER4).1 Blockade of HER2 heterodimerization by pertuzumab results in inhibition of ligand-activated intracellular signaling through 2 major signal pathways, mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K/Akt), potentially causing cell growth arrest and apoptosis, respectively.1 Trastuzumab binds to the extracellular domain (subdomain IV) of the HER2 protein, blocking ligand-independent, HER2 mediated cell proliferation and inhibiting intracellular signaling through PI3K signaling pathway in human tumor cells that overexpress HER2/neu protein.1 Pertuzumab- and trastuzumab-mediated antibody-dependent cellular cytotoxicity (ADCC) occurs preferentially in cells that overexpress the HER2 protein.1
Pertuzumab alone inhibits proliferation of human tumor cells, while the combination of pertuzumab and trastuzumab has been shown to substantially augment antitumor activity in HER2-overexpressing xenograft models.1
Following subcutaneous administration, the absolute bioavailability of pertuzumab and trastuzumab is approximately 70 and 80%, respectively.1, 12 Peak plasma concentrations of pertuzumab and trastuzumab are observed at approximately 4 days.1 Following subcutaneous administration, at cycle 7, AUC and peak plasma concentrations of pertuzumab were approximately 34% lower and 5% higher, respectively, compared to that following IV administration of pertuzumab;1 AUC and peak plasma concentrations of trastuzumab were approximately 31% lower and 9% higher, respectively, compared to that following IV administration of trastuzumab.1
The pharmacokinetics of pertuzumab, trastuzumab, and hyaluronidase do not appear to be affected by age or ethnicity (Asian versus non-Asian).1, 12 Baseline serum albumin concentration and lean body weight had a minor influence on pharmacokinetic parameters.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Injection, for subcutaneous use | Pertuzumab 1200 mg/15 mL (80 mg/mL) and trastuzumab 600 mg/15 mL (40 mg/mL) and hyaluronidase-zzxf 30,000 units/15 mL (2000 units/mL) | Genentech | |
Pertuzumab 600 mg/10 mL (60 mg/mL) and trastuzumab 600 mg/10 mL (60 mg/mL) and hyaluronidase-zzxf 20,000 units/10 mL (2000 units/mL) | Phesgo® | Genentech |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions December 21, 2022. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
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6. Gianni L, Pienkowski T, Im YH et al. 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. Lancet Oncol . 2016; 17:791-800. [PubMed 27179402]
7. Swain SM, Ewer, MS, Viale G et al. Pertuzumab, trastuzumab, and standard anthracycline- and taxane-based chemotherapy for the neoadjuvant treatment of patients with HER2-positive localized breast cancer (BERENICE): a phase II, open-label, multicenter, multinational cardiac safety study. Ann Oncol . 2018; 29:646-653. [PubMed 29253081]
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14. Genentech, Inc. Perjeta® (pertuzumab) injection for intravenous use prescribing information. South San Francisco, CA; 2021 Feb.
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