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PERT+TRAS

Cancer Type: Breast  Intent: Palliative
Regimen Category: Evidence-Informed
Funding:
New Drug Funding Program
    Pertuzumab-Trastuzumab - Unresectable Locally Recurrent or Metastatic - Breast Cancer
A - Regimen Name

PERT+TRAS Regimen
PERT+TRAS


Disease Site
Breast

Intent
Palliative

Regimen Category
Evidence-Informed :

Regimen is considered appropriate as part of the standard care of patients; meaningfully improves outcomes (survival, quality of life), tolerability or costs compared to alternatives (recommended by the Disease Site Team and national consensus body e.g. pan-Canadian Oncology Drug Review, pCODR).  Recommendation is based on an appropriately conducted phase III clinical trial relevant to the Canadian context OR (where phase III trials are not feasible) an appropriately sized phase II trial. Regimens where one or more drugs are not approved by Health Canada for any indication will be identified under Rationale and Use.


Rationale and Uses

For the treatment of patients with HER2 positive unresectable locally recurrent or metastatic breast cancer, following taxane chemotherapy/pertuzumab/trastuzumab treatment.

Refer to NDFP eligibility forms for detailed funding information.

 

 


Supplementary Public Funding

PERTuzumab
New Drug Funding Program (Pertuzumab-Trastuzumab - Unresectable Locally Recurrent or Metastatic - Breast Cancer) (NDFP Website) (

PDRP (NDFP) funding is contingent on the patient previously receiving chemotherapy.

)

 
B - Drug Regimen

PERTuzumab
420* mg IV Day 1
trastuzumab
6* mg /kg IV Day 1

 

*For treatment delays ≥ to 3 weeks (i.e. ≥ 6 weeks from last dose), consider reloading with loading dose (Baselga et al, 2012). Please refer to the day 1 loading dose outlined in DOCE+PERT+TRAS.

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C - Cycle Frequency

REPEAT EVERY 21 DAYS

Until disease progression or unacceptable toxicity.

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

Minimal

Other Supportive Care:

• Nausea and vomiting are usually symptoms that are related to infusion-associated reactions. To prevent recurrence of infusion-associated reactions, consider premedication with corticosteroids, antihistamines and/or antipyretics before subsequent infusions.

 
E - Dose Modifications

Doses should be modified according to the protocol by which the patient is being treated. The following recommendations have been adapted from clinical trials or product monographs and could be considered.

Dosage with toxicity

Dose reductions are not recommended. Doses are held or discontinued due to toxicity.

Toxicity

Recommendation

Reversible chemotherapy-induced myelosuppression

Continue pertuzumab and trastuzumab;

monitor for complications of neutropenia (i.e. infections) and treat appropriately

Severe diarrhea

Start anti-diarrheal treatment. Hold pertuzumab if no improvement; restart pertuzumab when diarrhea is under control

Cardiotoxicity:

Left Ventricular Ejection Fraction

Trastuzumab and Pertuzumab

 
Action
LVEF at re-assessment
Dose
<40% and asymptomatic
Hold and repeat MUGA in 3 weeks
  • >45% OR
  • 40-45% and <10% ↓ from baseline
Restart

40-50%* AND ≥10% points below baseline, and asymptomatic

  • <40% OR
  • 40-50%* and ≥ 10% points below baseline OR
  • symptomatic
Discontinue
Symptomatic
Considering discontinuing
Not applicable
Not applicable

* In the CLEOPATRA trial, trastuzumab and pertuzumab treatments were held if LVEF is 40-45% and ≥10% below baseline and asymptomatic. At LVEF reassessment, pertuzumab and trastuzumab may restart if LVEF "≥46%" or "40-45% and <10% ↓ from baseline"; otherwise, discontinue.

 

 

 

 

 

Hypersensitivity:

Toxicity
Action (pertuzumab, trastuzumab)
Mild hypersensitivity reaction

↓ infusion rate (and/ or hold)  and use beta-agonists, antihistamines, antipyretics, and/or corticosteroids as appropriate. Consider premedication for next infusion.

Moderate hypersensitivity reaction

Hold and use beta-agonists, antihistamines, antipyretics, and/or corticosteroids as appropriate; complete infusion at ↓ rate if possible. Use premedication for next infusion.

Severe hypersensitivity reaction or Pulmonary Toxicity

Hold and manage symptoms aggressively with beta-agonists, antihistamines, antipyretics, and/or corticosteroids.  Discontinue permanently and do not rechallenge



Hepatic Impairment

No dosage adjustment is required.


Renal Impairment

No adjustment required for mild to moderate renal function. No data in severe renal impairment (< 30 mL/min).

 

Dosage in the elderly:

No dosage adjustment required. The risk of cardiac dysfunction and myelosuppression may be increased in elderly patients. 


 
F - Adverse Effects

Refer to PERTuzumab, trastuzumab drug monograph(s) for additional details of adverse effects

The following side effects are a summary of those reported in the drug monographs. Certain side effects may be more common when pertuzumab and trastuzumab are combined with chemotherapy (e.g. myelosupression, anorexia).


Very common (≥ 50%)

Common (25-49%)

Less common (10-24%)

Uncommon (< 10%),

but may be severe or life-threatening

  • Diarrhea (may be severe)
  • Myelosuppression +/- infection, bleeding; may be severe)

 

  • Nausea, vomiting
  • Rash
  • Anorexia, weight loss
  • Mucositis
  • Headache
  • Cough, dyspnea
  • Musculoskeletal pain
  • Peripheral neuropathy
  • Fever
  • Dysgeusia
  • Insomnia
  • Dizziness
  • Dyspepsia
  • Hypersensitivity (may be severe)
  • Hypertension

 

  • Cardiotoxicity
  • Arrhythmia
  • Arterial thromboembolism
  • Venous thromboembolism
  • Pancreatitis
  • Renal failure
  • Secondary malignancy
  • Pneumonitis
 
G - Interactions

Refer to PERTuzumab, trastuzumab drug monograph(s) for additional details


  • Avoid concomitant use with anthracyclines or other cardiotoxic drugs (extreme caution with anthracyclines up to 27 weeks after stopping trastuzumab)
  • No evidence of a drug interaction was found between pertuzumab and trastuzumab, docetaxel, gemcitabine, erlotinib and capecitabine
 
H - Drug Administration and Special Precautions

Refer to PERTuzumab, trastuzumab drug monograph(s) for additional details


Administration:

Pertuzumab:

  • Dilute required dose in 250 mL Normal Saline.  Do not administer as an intravenous push or bolus.
  • Avoid shaking the solution in order to avoid foaming.
  • Give loading dose IV over 60 minutes; maintenance dose should be given IV over 30-60 minutes.
  • Monitor patient for 60 minutes after the first infusion, and 30 minutes after subsequent doses for any infusion reactions before starting trastuzumab.
  • Do not use D5W for dilution since pertuzumab is chemically and physically unstable in this solution.  Do not admix with other drugs.
  • Compatible with PVC, polyethylene or non-PVC polyolefin bags
  • Refrigerate unopened vials at 2-8°C; protect from light.

Trastuzumab:

  • NOTE:  Herceptin® (trastuzumab) and Kadcyla® (trastuzumab emtansine) are NON-INTERCHANAGEABLE. There have been fatal reports where the incorrect trastuzumab product was administered to patients with breast cancer in the clinical trials setting.
  • Mix in 250 mL bag NS. Do not use D5W as it causes protein aggregation. Do not shake.
  • Infuse loading dose IV over 90 minutes; subsequent infusions may be given over 30 minutes if the initial loading dose is well-tolerated.
  • DO NOT ADMINISTER AS AN IV PUSH OR BOLUS.
  • Should not be mixed or diluted with other drugs.
  • Diluent supplied - Bacteriostatic Water for Injection (BWFI) - contains benzyl alcohol 1.1%; if patient is hypersensitive to benzyl alcohol, may reconstitute with Sterile Water for Injection, but must be used immediately and discard unused portion.
  • Solution reconstituted with the supplied BWFI is stable up to 28 days refrigerated.
  • Do not freeze the reconstituted solution.

Contraindications:

  • Patients with known hypersensitivity to trastuzumab, pertuzumab, Chinese Hamster Ovary (CHO) cell proteins, or any components of these products.
  • Trastuzumab should only be used in patients whose tumours overexpress HER2

Other warnings or precautions:

  • The risk of cardiotoxicity must be weighed against the potential benefits of treatment, especially in older patients, patients with pre-existing cardiac disease (including LVEF < 55%) and patients who have had prior cardiotoxic therapy (e.g. prior cumulative anthracycline exposure to > 360 mg/m2 doxorubicin or equivalent. Note: in the adjuvant trials, patients with cardiac risk factors were excluded from the trials.
  • Exercise caution in patients with pre-existing pulmonary disease or patients with extensive pulmonary tumour involvement, as they may experience more severe lung toxicities. 
  • Use with caution before or after anthracyclines (for up to 27 weeks after trastuzumab discontinuation due to long half-life).
  • Life-threatening infusion-related reactions associated with the administration of trastuzumab may occur (see the trastuzumab drug monograph for details).

Pregnancy and Lactation:

  • Pertuzumab and trastuzumab are contraindicated in pregnancy.  Adequate contraception should be used by both sexes during treatment, and for 7 months after the last dose.
  • Monitor for oligohydramnios in patients who become pregnant during pertuzumab therapy. Perform appropriate fetal testing if oligohydramnios occurs. The efficacy of intravenous hydration in the management of oligohydramnios due to pertuzamab is not known.
  • Breastfeeding is not recommended
 
I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Recommended Clinical Monitoring

  • Cardiac assessment, including evaluation of left ventricular function (Echocardiogram or MUGA scan);; more frequent with asymptomatic reductions in LVEF; baseline, q3 months during treatment, then q6 months after trastuzumab discontinuation x2 years (and annually up to 5 years after last trastuzumab dose in adjuvant breast cancer patients who received anthracyclines), also as clinically indicated
  • Infusion reactions; 60 minutes after the first infusion and 30 minutes after subsequent infusions
  • CBC; Baseline and at each visit
  • Clinical toxicity assessment for infection, bleeding, neurotoxicity, fluid retention, hypersensitivity, lethargy, cutaneous reactions, musculoskeletal pain, cardiovascular, ophthalmic, GI or respiratory effects; At each visit
  • Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version

Suggested Clinical Monitoring

Liver function tests; baseline and periodic


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J - Administrative Information

Pharmacy Workload (average time per visit)
25.251 minutes
Nursing Workload (average time per visit)
72.500 minutes
 
K - References

Baselga J, Cortés J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 2012;366(2):109-19.

Pertuzumab and trastuzumab drug monographs, Cancer Care Ontario.

October 2017 Added reference to drug regimen section


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M - Disclaimer

Regimen Abstracts
A Regimen Abstract is an abbreviated version of a Regimen Monograph and contains only top level information on usage, dosing, schedule, cycle length and special notes (if available). It is intended for healthcare providers and is to be used for informational purposes only. It is not intended to constitute or be a substitute for medical advice, and all uses of the Regimen Abstract are subject to clinical judgment. Such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability, and Cancer Care Ontario disclaims all liability for the use of this information, and for any claims, actions, demands or suits that arise from such use.
Information in regimen abstracts is accurate to the extent of the ST-QBP regimen master listings, and has not undergone the full review process of a regimen monograph.  Full regimen monographs will be published for each ST-QBP regimen as they are developed.
Regimen Monographs
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.
The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.
Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.
While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability.
CCO and the Formulary’s content providers shall have no liability, whether direct, indirect, consequential, contingent, special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person’s use of the information in the Formulary.