Pertuzumab

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous [preservative free]:

Perjeta: 420 mg/14 mL (14 mL)

Pharmacology

Mechanism of Action

Pertuzumab is a recombinant humanized monoclonal antibody which targets the extracellular human epidermal growth factor receptor 2 protein (HER2) dimerization domain. Inhibits HER2 dimerization and blocks HER downstream signaling halting cell growth and initiating apoptosis. Pertuzumab binds to a different HER2 epitope than trastuzumab so that when pertuzumab is combined with trastuzumab, a more complete inhibition of HER2 signaling occurs (Baselga 2012).

Pharmacokinetics/Pharmacodynamics

Distribution

V_d: 5.12 L (Gianni 2010)

Half-Life Elimination

Terminal: 18 days

Use: Labeled Indications

Breast cancer, metastatic: Treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (in combination with trastuzumab and docetaxel) in patients who have not received prior anti-HER2 therapy or chemotherapy to treat metastatic disease.

Breast cancer, early (adjuvant): Adjuvant treatment of HER2-positive early breast cancer at high risk of recurrence (in combination with trastuzumab and chemotherapy).

Breast cancer, early (neoadjuvant): Neoadjuvant treatment of locally advanced, inflammatory, or early stage HER2-positive, breast cancer (either greater than 2 cm in diameter or node positive) in combination with trastuzumab and chemotherapy (as part of a complete treatment regimen for early breast cancer).

Contraindications

Known hypersensitivity to pertuzumab or any component of the formulation

Dosage and Administration

Dosing: Adult

Note: For pertuzumab, trastuzumab (or trastuzumab/hyaluronidase), and taxane combination regimens, pertuzumab and the trastuzumab product may be administered in any order; however, the taxane should be given after pertuzumab and the trastuzumab product. Pertuzumab (and the trastuzumab product) should be administered following completion of the anthracycline therapy in patients receiving anthracycline-based regimens. Observe patients for 30 to 60 minutes after each pertuzumab infusion and before subsequent doses of trastuzumab products or docetaxel.

Breast cancer, metastatic HER2+: IV: 840 mg over 60 minutes followed by a maintenance dose of 420 mg over 30 to 60 minutes every 3 weeks until disease progression or unacceptable toxicity (in combination with trastuzumab [or trastuzumab/hyaluronidase] and docetaxel) (Baselga 2012; Swain 2015).

Breast cancer, early HER2+ (adjuvant treatment): IV: 840 mg over 60 minutes followed by a maintenance dose of 420 mg over 30 to 60 minutes every 3 weeks for a total of 1 year (up to 18 cycles) or until disease progression or unacceptable toxicity (whichever occurs first); as part of a combination regimen containing trastuzumab (or trastuzumab/hyaluronidase) and including standard anthracycline- and/or taxane-based therapy; pertuzumab and trastuzumab (or trastuzumab/hyaluronidase) should begin on day 1 of the first taxane-containing cycle (von Minckwitz 2017).

Breast cancer, early HER2+ (neoadjuvant treatment): IV: 840 mg over 60 minutes followed by a maintenance dose of 420 mg over 30 to 60 minutes every 3 weeks for 3 to 6 cycles; may be administered as one of the regimens below. Postoperatively, continue pertuzumab and trastuzumab (or trastuzumab/hyaluronidase) to complete 1 year of treatment (up to 18 cycles); refer to specific protocol for details.

Four preoperative cycles of pertuzumab, trastuzumab (or trastuzumab/hyaluronidase), and docetaxel, followed by 3 postoperative cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC) (Gianni 2012) or

Three or four preoperative cycles of FEC (alone) followed by 3 or 4 preoperative cycles of pertuzumab, trastuzumab (or trastuzumab/hyaluronidase), and docetaxel (Schneeweiss 2013; Swain 2018) or

Six preoperative cycles of pertuzumab, trastuzumab (or trastuzumab/hyaluronidase), docetaxel, and carboplatin (Schneeweiss 2013)

Four preoperative cycles of dose-dense doxorubicin and cyclophosphamide alone, followed by 4 preoperative cycles of pertuzumab, trastuzumab (or trastuzumab/hyaluronidase), and paclitaxel (Swain 2018).

Missed doses or delays: If <6 weeks has elapsed, administer pertuzumab 420 mg (maintenance dose) as soon as possible; do not wait until the next planned dose. If ≥6 weeks has elapsed, readminister pertuzumab 840 mg (loading dose) over 60 minutes, and then follow with a maintenance dose of pertuzumab 420 mg (over 30 to 60 minutes) every 3 weeks thereafter.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

Note: Dose reductions are not recommended for pertuzumab; if trastuzumab (or trastuzumab/hyaluronidase) is withheld, pertuzumab should also be withheld; if the trastuzumab product is discontinued, pertuzumab should be discontinued. For concomitant chemotherapy dosage adjustments, refer to individual chemotherapy drug monographs.

Infusion-related reaction: Slow or interrupt the infusion.

Serious hypersensitivity or anaphylaxis: Discontinue immediately.

Cardiotoxicity:

Metastatic breast cancer: Pretreatment left ventricular ejection fraction (LVEF) should be ≥50%.

LVEF decline to <40% or LVEF 40% to 45% with fall of ≥10% points below pretreatment values: Withhold treatment (pertuzumab and trastuzumab [or trastuzumab/hyaluronidase]) for at least 3 weeks; may resume if LVEF either returns to >45% or to 40% to 45% with fall of <10% points below pretreatment values. If LVEF declines and has not improved, or has declined further at the subsequent assessment, strongly consider discontinuing pertuzumab (and the trastuzumab product).

Early breast cancer: Pretreatment LVEF should be ≥55% (LVEF should be ≥50% after completion of anthracycline therapy [before starting pertuzumab/trastuzumab treatment]).

LVEF decline to <50% with fall of ≥10% points below pretreatment values: Withhold treatment (pertuzumab and trastuzumab [or trastuzumab/hyaluronidase]) for at least 3 weeks; may resume if LVEF either returns to ≥50% or <10% points below pretreatment values. If LVEF declines and has not improved, or has declined further at the subsequent assessment, strongly consider discontinuing pertuzumab (and the trastuzumab product).

Reconstitution

Dilute in 250 mL NS only (do not use dextrose 5% solutions) in PVC or non-PVC (polyolefin) bags. Gently invert to mix (avoid foaming); do not shake. Do not mix with other medications.

Administration

IV: For IV infusion only, as a short infusion; infuse initial dose (840 mg) over 60 minutes; infuse maintenance dose (420 mg) over 30 to 60 minutes. Do not administer IV push or as a rapid bolus. Do not mix with other medications. For pertuzumab, trastuzumab (or trastuzumab/hyaluronidase), and taxane combination regimens, pertuzumab and the trastuzumab product may be administered in any order; however, the taxane should be given after pertuzumab and the trastuzumab product. Pertuzumab (and the trastuzumab product) should be administered following completion of the anthracycline therapy in patients receiving anthracycline-based regimens. Observe patients for 30 to 60 minutes after each pertuzumab infusion and before subsequent infusions of the trastuzumab product or docetaxel. Monitor for hypersensitivity reactions for 60 minutes following the initial pertuzumab infusion and for 30 minutes following subsequent infusions.

Storage

Store intact vials at 2°C to 8°C (36°F to 46°F) until time of use. Protect from light. Do not freeze. Do not shake. Solutions diluted for infusion in NS should be used immediately; if not used immediately, may be stored at 2°C to 8°C (36°F to 46°F) for up to 24 hours.

Drug Interactions

There are no known significant interactions.

Adverse Reactions

Reactions reported in combination therapy with trastuzumab and docetaxel unless otherwise noted.

>10%:

Central nervous system: Fatigue (26% to 36%), headache (11% to 21%), decreased left ventricular ejection fraction (8% to 16%), insomnia (8% to 13%), dizziness (3% to 13%)

Dermatologic: Alopecia (52% to 65%), skin rash (11% to 34%), pruritus (4% to 14%), palmar-plantar erythrodysesthesia (11%), xeroderma (9% to 11%)

Gastrointestinal: Diarrhea (46% to 67%), nausea (39% to 53%), vomiting (13% to 36%), decreased appetite (11% to 29%), mucositis (20% to 28%), constipation (23%), stomatitis (17% to 19%; grades 3/4: <1%), dysgeusia (13% to 18%)

Hematologic & oncologic: Neutropenia (47% to 53%; grades 3/4: 43% to 49%), anemia (3% to 23%; grades 3/4: 2% to 4%), leukopenia (9% to 16%; grades 3/4: 5% to 12%), febrile neutropenia (8% to 14%; grades 3/4: 9% to 13%)

Hypersensitivity: Hypersensitivity (1% to 11%)

Neuromuscular & skeletal: Asthenia (15% to 26%), myalgia (11% to 22%), arthralgia (10% to 12%)

Respiratory: Upper respiratory tract infection (4% to 17%), epistaxis (11%)

Miscellaneous: Fever (9% to 19%), infusion reactions (13%)

1% to 10%:

Cardiovascular: Left ventricular dysfunction (3% to 4%), peripheral edema (3% to 4%)

Central nervous system: Peripheral sensory neuropathy (8%; grades 3/4: <1%), peripheral neuropathy (1%)

Dermatologic: Nail disease (7%), paronychia (1% to 7%)

Gastrointestinal: Dyspepsia (8%)

Hematologic & oncologic: Thrombocytopenia (1%)

Hepatic: Increased serum alanine aminotransferase (3%)

Ophthalmic: Increased lacrimation (4% to 5%)

Respiratory: Dyspnea (8%), nasopharyngitis (7%), oropharyngeal pain (7%), cough (5%)

<1%, postmarketing, and/or case reports: Left systolic heart failure, pleural effusion, sepsis, tumor lysis syndrome

Warnings/Precautions

Concerns related to adverse effects:

• Cardiotoxicity: [US Boxed Warning]: May result in cardiac failure (clinical and subclinical) manifesting as decreased left ventricular ejection fraction (LVEF) and heart failure (HF). Assess cardiac function at baseline and at regular intervals during treatment. Discontinue for confirmed clinically significant decline in left ventricular function. Decreases in LVEF are associated with HER2 inhibitors, including pertuzumab. Patients who received prior anthracycline therapy or chest irradiation may be at an increased risk for cardiotoxicity. In studies of pertuzumab (versus placebo) in combination with trastuzumab and docetaxel for the treatment of metastatic breast cancer, the rate of cardiotoxicity (LVEF decline or symptomatic LV systolic dysfunction) was not increased in the pertuzumab group when compared to placebo. In the early breast cancer neoadjuvant setting, the incidence of LV dysfunction was higher in patients treated with pertuzumab. In the early breast cancer adjuvant setting, the incidence of symptomatic heart failure was slightly higher in patients treated with pertuzumab (most of these events were reported in anthracycline-treated patients); approximately half of the pertuzumab-treated patients who experienced symptomatic heart failure recovered. Of note, patients with pretreatment LVEF ≤50%, congestive heart failure, LVEF decreases to <50% during prior trastuzumab treatment, or conditions which could impair LV function (eg, uncontrolled hypertension, recent myocardial infarction, serious arrhythmia requiring treatment, or cumulative lifetime anthracycline exposure >360 mg/m² doxorubicin or its equivalent) were excluded from studies. Assess LVEF at baseline and approximately every 12 weeks during treatment. Withhold pertuzumab and trastuzumab (or trastuzumab/hyaluronidase) for at least 3 weeks if LVEF declines below the threshold for metastatic or early breast cancer; repeat LVEF assessment in ~3 weeks; consider discontinuing pertuzumab (and the trastuzumab product) if LVEF has not improved or has declined further.
• GI adverse events: Diarrhea occurred more frequently in patients receiving pertuzumab in combination with trastuzumab and docetaxel, compared to patients receiving only trastuzumab and docetaxel. Diarrhea occurred more frequently in the first pertuzumab cycle and was generally grade 1 or 2; diarrhea was usually managed with loperamide and rarely required treatment delay (Swain 2017).
• Hypersensitivity: Severe hypersensitivity, including anaphylaxis has been reported; some events were fatal. Angioedema has also been reported. The overall incidence of hypersensitivity/anaphylaxis was slightly higher in the group receiving pertuzumab (compared to placebo) in combination with trastuzumab and docetaxel. Monitor for hypersensitivity. Medications and equipment for the treatment of hypersensitivity should be available for immediate use during infusion.
• Infusion reaction: Infusion reactions (either during or on the day of infusion), including fatal events, have been associated with pertuzumab. Infusion reaction was defined as hypersensitivity, anaphylactic reaction, acute infusion reaction, or cytokine release during the infusion or on the same day as the infusion; other common infusion reactions included fever, chills, fatigue, headache, weakness, myalgia, abnormal taste, and/or vomiting. Grade 3 or 4 infusion reactions occurred rarely. Monitor for 1 hour after the first infusion and for 30 minutes after subsequent infusions. For significant infusion reactions, interrupt or slow infusion rate and administer appropriate supportive management; for severe infusion reactions, consider permanently discontinuing.

Concomitant drug therapy issues:

• Chemotherapy administration: For pertuzumab, trastuzumab (or trastuzumab/hyaluronidase), and taxane combination regimens, pertuzumab and the trastuzumab product may be administered in any order; however, the taxane should be given after pertuzumab and the trastuzumab product. Pertuzumab and the trastuzumab product should be administered following completion of the anthracycline therapy in patients receiving anthracycline-based regimens.
• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Pregnancy: [US Boxed Warning]: Exposure to pertuzumab can result in embryo-fetal death and birth defects. Advise patients of these risks and the need for effective contraception.

Other warnings/precautions:

• HER2 expression: Establish HER2 status prior to treatment. Improper assay performance (including suboptimally fixed tissue, failure to use specified reagents, deviation from assay instructions, and failure to include appropriate assay controls) may lead to unreliable results. Information on tests is available at http://www.fda.gov/CompanionDiagnostics.

Monitoring Parameters

HER2 expression; pregnancy test (in females of reproductive potential); assess LVEF at baseline, and approximately every 12 weeks during treatment (more frequently for declines; monitor for infusion reaction, diarrhea, and hypersensitivity (monitor for hypersensitivity reactions for 60 minutes following the initial pertuzumab infusion and for 30 minutes following subsequent infusions).

Pregnancy

Pregnancy Considerations

[US Boxed Warning]: Exposure to pertuzumab can result in embryo-fetal death and birth defects. Advise patients of these risks and the need for effective contraception.

Based on the mechanism of action of pertuzumab and data from similar agents, oligohydramnios or oligohydramnios sequence may occur resulting in pulmonary hypoplasia, skeletal anomalies, and neonatal death. Monitor for oligohydramnios if exposure occurs during pregnancy or within 7 months prior to conception; conduct appropriate fetal testing if oligohydramnios occurs. Information related to inadvertent exposure to pertuzumab in combination with trastuzumab in pregnancy is limited (Yildirim 2018).

European Society for Medical Oncology (ESMO) guidelines for cancer during pregnancy recommend delaying treatment with HER2-targeted agents until after delivery in pregnant patients with HER2-positive disease (Peccatori 2013).

Evaluate pregnancy status prior to treatment in females of reproductive potential; effective contraception should be used during therapy and for 7 months after the last dose of pertuzumab in combination with trastuzumab.

Advise patients to immediately report to health care provider if pregnancy is suspected during treatment. If pertuzumab exposure occurs during pregnancy or exposure to pertuzumab in combination with trastuzumab occurs within 7 months prior to conception, report the exposure to Genentech (888-835-2555).

Patient Education

What is this drug used for?

• It is used to treat breast cancer.

Frequently reported side effects of this drug

• Dizziness
• Abdominal pain
• Mouth sores
• Mouth irritation
• Lack of appetite
• Bad taste
• Itching
• Dry skin

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Heart problems like cough or shortness of breath that is new or worse, swelling of the ankles or legs, abnormal heartbeat, weight gain of more than five pounds in 24 hours, dizziness, or passing out.
• Tumor lysis syndrome like fast heartbeat or abnormal heartbeat; any passing out; unable to pass urine; muscle weakness or cramps; nausea, vomiting, diarrhea or lack of appetite; or feeling sluggish.
• Infusion reaction
• Infection
• Chest pain
• Fast heartbeat
• Severe headache
• Severe nausea
• Vomiting
• Severe diarrhea
• Bruising
• Bleeding
• Severe loss of strength and energy
• Burning or numbness feeling
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.