Pertuzumab, trastuzumab, and docetaxel for HER2-positive* metastatic breast cancer^[1]

Cycle length: Every 21 days. Duration of therapy: Until disease progression or unacceptable toxicity.
Drug	Dose and route	Administration	Given on days
Pertuzumab (loading dose)^¶Δ	840 mg IV	Dilute in 250 mL NS^◊ and administer over 60 minutes. DO NOT mix with D5W and DO NOT infuse as an IV push or bolus.	Cycle 1: Day 1
Pertuzumab^¶Δ	420 mg IV	Dilute in 250 mL NS^◊ and administer over 30 to 60 minutes. DO NOT mix with D5W and DO NOT infuse as an IV push or bolus.	Cycle 2 and after: Day 1
Trastuzumab (loading dose)*^§	8 mg/kg IV	Dilute in 250 mL NS^◊ and administer over 90 minutes for the loading dose. DO NOT mix with D5W and DO NOT infuse as an IV push or bolus.	Cycle 1: Day 1
Trastuzumab*^§	6 mg/kg IV	Dilute in 250 mL NS^◊ and administer over 30 to 90 minutes. DO NOT mix with D5W and DO NOT infuse as an IV push or bolus.	Cycle 2 and after: Day 1
Docetaxel	75 mg/m² IV^¥	Dilute in 250 mL NS^◊ to a final concentration of 0.3 to 0.74 mg/mL and administer over 60 minutes.	Day 1
Pretreatment considerations:
Emesis risk	LOW (10 to 30% risk of emesis). Refer to UpToDate topics on prevention of chemotherapy-induced nausea and vomiting in adults.
Prophylaxis for infusion reactions	Premedicate with dexamethasone prior to docetaxel administration.^[2] Premedication is not routinely indicated for pertuzumab. Most clinicians do not routinely premedicate prior to the first trastuzumab dose. However, patients may be instructed to self-administer acetaminophen or an NSAID if flu-like symptoms develop within 24 hours of drug administration. Refer to UpToDate topics on infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy and infusion reactions to systemic chemotherapy.
Vesicant/irritant properties	Docetaxel is an irritant but can cause significant tissue damage; avoid extravasation. Refer to UpToDate topics on extravasation injury from chemotherapy and other non-antineoplastic vesicants.
Infection prophylaxis	In the original study, the risk of febrile neutropenia was 14%.^[1] The decision to use primary prophylaxis with hematopoietic growth factors should be individualized, and considered for patients who may be at risk for increased complications from prolonged neutropenia. Refer to UpToDate topics on prophylaxis of infection during chemotherapy-induced neutropenia in high-risk adults.
Dose adjustment for baseline liver or renal dysfunction	Docetaxel should not be administered to patients with a serum bilirubin above the ULN or to patients with transaminase elevations >1.5 times the ULN in conjunction with alkaline phosphatase >2.5 times the ULN. Refer to UpToDate topics on chemotherapy hepatotoxicity and dose modification in patients with liver disease, conventional cytotoxic agents and chemotherapy hepatotoxicity and dose modification in patients with liver disease, molecularly targeted agents.
Cardiopulmonary issues	Trastuzumab and pertuzumab are associated with cardiotoxicity;^[3,4] assess baseline LVEF prior to therapy and then as clinically indicated. Patients with a baseline LVEF <50% were excluded from the study.^[1] Trastuzumab may cause serious pulmonary toxicity and should be used with caution in patients with preexisting pulmonary disease. Refer to UpToDate topics on cardiotoxicity of trastuzumab and other HER2-targeted agents.
Dose adjustment for known drug interactions	Caution is required if administering docetaxel with strong CYP3A4 inhibitors.^‡ According to the United States Prescribing Information, avoid the use of docetaxel with strong CYP3A4 inhibitors (if possible). If concomitant therapy cannot be avoided, monitor closely for toxicity and consider a docetaxel dose reduction.^[2] Docetaxel dose reductions for concomitant therapies should be individualized based on patient factors (eg, performance status) and the intent of therapy (ie, curative or palliative). Refer to "Suggested dose modifications for toxicity" below.
Monitoring parameters:
Obtain CBC with differential and platelet count prior to each treatment cycle.
Assess electrolytes and liver and renal function prior to each treatment cycle.
It is recommended to observe the patient for one hour after the initial dose of pertuzumab and for 30 minutes after all subsequent doses for signs of infusion reactions.^[4] Refer to UpToDate topics on infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy.
Assess cardiac function at baseline and then as clinically indicated. In the clinical trial, LVEF was measured at screening and then every nine weeks.^[1] Refer to UpToDate topics on cardiotoxicity of trastuzumab and other HER2-targeted agents.
Assess changes in neurologic function prior to each cycle of docetaxel.
Patients with renal impairment, hyperuricemia, and bulky tumors are at risk for TLS and should undergo correction of dehydration and lowering of high serum uric acid levels prior to treatment initiation, and be closely monitored for TLS during and after treatment. Refer to UpToDate topics on tumor lysis syndrome.
Suggested dose modifications for toxicity:
Myelotoxicity	Reduce docetaxel dose by 25% for subsequent cycles in patients who develop severe prolonged neutropenia (<500/microL lasting seven days or more), febrile neutropenia, or a grade 4 infection (ie, an infection with life-threatening consequences).^[1,2]
Hepatotoxicity	A 20% dose reduction in the dose of docetaxel may be needed for patients who develop significant alterations in transaminases and alkaline phosphatase during therapy.^[2] Refer to UpToDate topics on chemotherapy hepatotoxicity and dose modification in patients with liver disease, conventional cytotoxic agents and chemotherapy hepatotoxicity and dose modification in patients with liver disease, molecularly targeted agents.
Cardiotoxicity	Hold both trastuzumab and pertuzumab if the LVEF drops to <40% or if the LVEF is 40-45% with a 10% or greater absolute decrease below baseline.^[4] Guidelines for managing cardiac dysfunction during therapy with HER2-targeted agents are available. Refer to UpToDate topics on cardiotoxicity of trastuzumab and other HER2-targeted agents.
Pulmonary toxicity	Discontinue trastuzumab for serious pulmonary toxicity. Refer to UpToDate topics on pulmonary toxicity associated with antineoplastic therapy, molecularly targeted agents.
Infusion reactions	Respond as clinically indicated with supportive care and possible discontinuation of therapy for severe reactions. Refer to UpToDate topics on infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy.
Cutaneous, mucosal, and neurologic toxicity	For severe or cumulative cutaneous reactions (erythema and desquamation), grade 3 or 4 stomatitis, or moderate neurosensory signs and/or symptoms, reduce docetaxel dose by 25%.^[1] Discontinue if toxicity persists.^[2] Refer to UpToDate topics on cutaneous side effects of conventional chemotherapy agents.
If there is a change in body weight of at least 10%, doses should be recalculated.

This table is provided as an example of how to administer this regimen; there may be other acceptable methods. This regimen must be administered by a clinician trained in the use of chemotherapy, who should use independent medical judgment in the context of individual circumstances to make adjustments, as necessary.

HER2: human epidermal growth factor receptor 2; IV: intravenous; NS: normal saline; D5W: 5% dextrose in water; NSAID: nonsteroidal anti-inflammatory drug; ULN: upper limit of normal; LVEF: left ventricular ejection fraction; CYP3A4: cytochrome P450 3A4; CBC: complete blood count; TLS: tumor lysis syndrome; IHC: immunohistochemical staining; FISH: fluorescence in situ hybridization.

* High levels of HER2 overexpression, as determined by either 3+ IHC or positive FISH, are used to select patients for therapy with trastuzumab and pertuzumab. Refer to UpToDate topic on "HER2 and predicting response to therapy in breast cancer".

¶ Administer pertuzumab, trastuzumab, and docetaxel sequentially, with either pertuzumab (followed by a 30-minute observation period for first dose then 60-minute observation period for subsequent cycles) or trastuzumab administered first; administer docetaxel after pertuzumab and trastuzumab.^[2]

Δ If adverse reactions occur for which discontinuation of trastuzumab or pertuzumab is indicated, both drugs should be discontinued. Dose modifications of trastuzumab and pertuzumab were not allowed in the original protocol.^[1] Docetaxel therapy may be discontinued without discontinuation of pertuzumab or trastuzumab.

◊ Diluent solutions should not be modified without consulting a detailed reference due to potential incompatibility(ies).

§ For patients who miss a dose of trastuzumab by more than one week, a repeat loading dose should be administered.

¥ Dose of docetaxel may be increased to 100 mg/m² based on tolerability.^[1]

‡ A list of strong and moderate CYP3A4 inhibitors is available as a separate table in UpToDate. Specific interactions may be determined by use of the Lexicomp drug interactions program included within UpToDate.

References:

Baselga J, et al. NEJM 2012; 366:109.
Docetaxel injection. United States Prescribing Information. US National Library of Medicine. (Available online at dailymed.nlm.nih.gov, accessed on March 15, 2022).
Trastuzumab injection. United States Prescribing Information. US National Library of Medicine. (Available online at dailymed.nlm.nih.gov, accessed on November 18, 2013).
Pertuzumab injection. United States Prescribing Information. US National Library of Medicine. (Available online at dailymed.nlm.nih.gov, accessed on December 16, 2013).

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Pertuzumab, trastuzumab, and docetaxel for HER2-positive* metastatic breast cancer[1]

Pertuzumab, trastuzumab, and docetaxel for HER2-positive* metastatic breast cancer^[1]