Looking for C.U.R.E.

  • Increase font size
  • Default font size
  • Decrease font size
Home Treatment Options Targeted Therapies Pertuzumab – A wonder drug for HER2 positive Breast Cancer?

Pertuzumab – A wonder drug for HER2 positive Breast Cancer?

E-mail Print
Attachments:
File
Download this file (Perjeta.pdf)PDF

 

Introduction

Breast Cancer can be divided into four types based on Immunohistochemistry typing. This takes into consideration the ER/PR status and the HER2 status of the tumor.

ER/PR positivity ensures a better prognosis and can be treated with Selective Estrogen Receptor modulators (Tamoxifen) in pre menopausal women or Aromatase Inhibitors (Anaztrozole) in postmenopausal women, in addition to standard chemotherapy.

HER2 positivity though indicative of a worse prognosis current advances in anti HER2 treatment such as the use of Trastuzumab (Herceptin), Lapatinib (Tykerb) and more recently the use of Pertuzumab (Perjeta) in addition to standard chemotherapy or Ado-trastuzumab emtansine (Kadcyla) has aided in tumor specific treatment.

Triple negative Breast cancer (ER/PR negative HER2 negative) is associated with the worst prognosis and currently has only standard chemotherapy as a treatment option.

 

What is Pertuzumab? Who is it for?

PERJETA (Pertuzumab) is a recently FDA approved targeted therapy for HER2 positive Breast Cancer. It is an anti-HER2 humanized monoclonal antibody.

Pertuzumab has been approved for use in those patients with HER2 positive breast cancers which have spread to other parts of the body (metastatic/Stage 4) which has not yet been treated with any anti HER2 therapy or chemotherapy for metastatic disease.

Pertuzumab has also been approved for use in HER2 positive breast cancer patients in the neo-adjuvant setting (pre-operatively) of locally advanced, inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer.

 

What is the mechanism of action?

Pertuzumab acts by preventing HER2 growth factor from pairing with the HER2 receptor which is essential for cancer growth and survival. Thus this drug can inhibit tumor cell growth and can ultimately cause cancer cell death[1]. Transtuzumab (Herceptin) and Pertuzumab are proven to be synergestic (that is, the combined effect of using the two molecules was far greater in effect than when using either alone)[2] and is thus successful in a more comprehensive blockade of the HER signaling pathway. Pertuzumab binds to the HER2 receptor at a different domain when compared to Trastuzumab and their interaction with each other enhances the affinity of each drug to their respective domains, acting like a “clamp”, preventing the dimerization/activation of the receptor.

 

Which trials substantiate safety and use? When was it FDA approved?

Published in NEJM January 2012: Pertuzumab, Trastuzumab and Docetaxel in Metastatic Breast Cancer (CLEOPATRA Trial) was a study conducted on 808 patients with HER2 positive metastatic Breast Cancer. This study showed prolonged disease free survival in patients following this regimen as opposed to those receiving Placebo, Trastuzumab and Docetaxel. Also, no increase in cardiac toxic effects were seen in patients who were on Pertuzumab[3]

On June 8th 2012, based on the article published in NEJM, Pertuzumab was approved by the FDA for use in patients with HER2 positive metastatic Breast cancer who have not yet received any prior anti HER2 or chemotherapy[6].

Published in Lancet, the NeoSphere Trial[4] along with the TRYPHAENA trial[5] presented at the San Antonio Breast Cancer Symposium in 2011 were two Phase II trials primarily responsible for the expedited FDA approval of Pertuzumab along with Trastuzumab and Docetaxel for use in the Neoadjuvant setting for HER2 positive Breast Cancer pre-operatively.

On September 30th 2013, Pertuzumab in the same combination along with Trastuzumab and Docetaxel was FDA approved for use in patients with HER2 positive Breast Cancer as Neoadjuvant treatment (prior to surgery) in locally advanced, inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or node positive)[7].

Currenltly the use of Pertuzumab along with Trastuzumab and Docetaxel in the Adjuvant setting for HER2 positive non metastatic Breast cancer is under trial and expected to publish results by 2023.

 

What is the dosage? How is it given?

Pertuzumab is used only as intravenous infusion[8]. The initial dose of Pertuzumab is 840mg administered in 60 minutes as an IV infusion, followed thereafter by 420mg infusion administered over 30-60 minutes every 3 weeks.

In HER2 positive metastatic Breast cancer Pertuzumab is used along with Trastuzumab and Docetaxel every 3 weeks. In HER2 positive Breast Cancer in the neoadjuvant setting Pertuzumab is used alongwith Trastuzumab and Docetaxel every 3 weeks for 3 to 6 cycles.

Docetaxel should be administered after pertuzumab and trastuzumab. An observation period of 30 to 60 minutes is recommended after each Pertuzumab infusion and before commencement of any subsequent infusion of trastuzumab or docetaxel

 

Are there special dosage considerations?

For delayed or missed doses, if the time between two sequential infusions is less than 6 weeks, the 420 mg dose of Pertuzumab should be administered immediately. There is no requirement to wait till the next cycle. If the time between two sequential infusions is 6 weeks or more, the initial dose of 840 mg Pertuzumab should be re-administered as a 60-minute intravenous infusion followed every 3 weeks thereafter by a dose of 420 mg administered as an intravenous infusion over 30 to 60 minutes[8].

Pertuzumab is used only in combination with Trastuzumab and should be discontinued if Trastuzumab treatment is discontinued. No dose adjustment based on body weight or baseline serum albumin levels are required[9]. Dose reductions are not recommended for PERJETA.

 

What is the Drug availability and Cost?

Pertuzumab is available under the trade name of Perjeta, 420mg/4ml single-use vial. It is administered by diluting in 250ml of 0.9% NaCl. The average wholesale price of Pertuzumab (Perjeta) is $4890 per 420-mg vial[9].

 

What are the Contraindications & Precautions?

Pertuzumab is contraindicated[8] in patients with hypersensitivity to Perjeta or to any of its excipients

Pre-menopausal women must be advised on pregnancy prevention and planning as Pertuzumab can cause embryo-fetal toxicity.

Nursing mothers must be advised to either discontinue nursing or discontinue Petuzumab considering the importance of the drug to the specific patient.

In case of Left ventricular dysfunction Ejection Fraction must be monitored and dosing withheld as appropriate.

In case of infusion related reactions, hypersensitivity reactions or anaphylaxis, the infusion must be slowed or interrupted and appropriate medical therapies given.

Pertuzumab is recommended only for use in patients with HER2 positive Breast cancer and the status of the HER2 receptor must be verified by testing in laboratories with demonstrated proficiency in the specific technology being utilized as improper assay performance can lead to unreliable results[8].

 

What are the Adverse effects?

Most of the expected adverse effects of Pertuzumab[8] when used in combination with Trastuzumab and chemotherapy (Docetaxel) are due to the accompanying chemotherapy. These include fatigue, diarrhea, alopecia, decrease in blood counts, nausea /vomiting, rash and peripheral neuropathy (associated with Docetaxel)

 

 

 

Shenthol Sasankan
Kasturba Medical College
Mangalore, India

 

 

 

REFERENCES

1. http://www.gene.com/media/product-information/perjeta

2. Fuentes G, Scaltriti M, Baselga J, Verma CS. Synergy between trastuzumab and pertuzumab for human epidermal growth factor 2 (Her2) from colocalization: an in silico based mechanism. Breast Cancer Res. 2011;13:R54

3. Baselga, J., Cortés, J., Kim, S. B., Im, S. A., Hegg, R., Im, Y. H., ... & Swain, S. M. (2012). Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. New England Journal of Medicine366(2), 109-119.

4. Gianni, L., Pienkowski, T., Im, Y. H., Roman, L., Tseng, L. M., Liu, M. C., ... & Valagussa, P. (2012). Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. The lancet oncology13(1), 25-32.

5. Schneeweiss, A., Chia, S., Hickish, T., Harvey, V., Eniu, A., Hegg, R., ... & Cortés, J. (2013). Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Annals of Oncology.

6. http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm307592.htm

7. http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm370449.htm

8. http://www.gene.com/download/pdf/perjeta_prescribing.pdf

 

 

9. http://www.pharmacytimes.com/publications/health-system-edition/2012/August2012/Pertuzumab--Perjeta