Chemistry:Pertuzumab

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Short description: Pharmaceutical drug
Pertuzumab
Pertuzumab-HER2 complex 1S78.png
The structure of HER2 and pertuzumab
Monoclonal antibody
TypeWhole antibody
SourceHumanized (from mouse)
TargetHER2
Clinical data
Trade namesPerjeta
Other names2C4
License data
Pregnancy
category
Routes of
administration		Intravenous
ATC code
Legal status
Legal status
Identifiers
CAS Number
DrugBank
ChemSpider
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UNII
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Pertuzumab, sold under the brand name Perjeta, is a monoclonal antibody used in combination with trastuzumab and docetaxel for the treatment of metastatic HER2-positive breast cancer; it also used in the same combination as a neoadjuvant in early HER2-positive breast cancer.[3]

Side effects in more than half the people taking it include diarrhea, hair loss, and loss of neutrophils; more than 10% experience loss of red blood cells, hypersensitivity or allergic reaction, infusion reactions, decreased appetite, insomnia, distortions in the sense of taste, inflammation of the mouth or lips, constipation, rashes, nail disease, and muscle pain.[2] Women who are pregnant or planning on getting pregnant should not take it, it was not studied in people with certain heart conditions and should be used in caution in such people, and it should not be used with an anthracycline.[2] It is unknown if pertuzumab interacts with doxorubicin.[2]

It is the first-in-class of a kind of drug called a "HER dimerization inhibitor" — it inhibits the dimerization of HER2 with other HER receptors, which prevents them from signalling in ways that promote cell growth and proliferation.[5]

It was discovered and developed by Genentech and was first approved in 2012.[6][7]

Medical uses

Pertuzumab is administered as an intravenous infusion in combination with trastuzumab and docetaxel as a first line treatment for HER2-positive metastatic breast cancer.[3][2] It is also used in the same combination as a neoadjuvant (given to reduce the size of a tumor, prior to surgery or radiation) for HER2-positive early breast cancer; as of 2016 this use had not been shown to increase survival.[3]

(As of 2016), pertuzumab has not been studied in people with a left ventricular ejection fraction value of ≤ 50% normal, a prior history of congestive heart failure, or conditions that could impair left ventricular function like uncontrolled hypertension, recent heart attacks, or serious cardiac arrhythmia.[2] Caution should be used combining pertuzumab with an anthracycline.[2] There is also no safety data available for use of pertuzumab in combination with doxorubicin.[2]

Women of child-bearing age should use contraception while taking pertuzumab; it may damage the fetus in pregnant women, and it may be secreted in breast milk.[2]

Adverse effects

In clinical trials of the three-agent combination therapy in metastatic breast cancer, adverse effects occurring in more than half the people taking it included diarrhea, hair loss, and loss of neutrophils; more than 10% of people experienced loss of neutrophils with fever, and loss of leukocytes.[2] After docetaxel was dropped in some people, the most common adverse effects were diarrhea (28.1%), upper respiratory tract infection (18.3%), rash (18.3%), headache (17.0%), fatigue (13.4%), swelling of nasal passages and throat (often due to catching the common cold) (17.0%), weakness (13.4%), itchiness (13.7%), joint pain (11.4%), nausea (12.7%), pain in an extremity (13.4%), back pain (12.1%) and cough (12.1%).[2]

In clinical trials of the neoadjuvant use of the combination, more than 50% of people had hair loss and loss of neutrophils.[2]

In both uses, more than 10% of people additionally experienced: loss of red blood cells, hypersensitivity or allergic reaction, infusion reactions, decreased appetite, insomnia, distortions in the sense of taste, inflammation of the mouth or lips, constipation, rashes, nail disease, and muscle pain.[2]

Pharmacology

The metabolism of pertuzumab has not been directly studied; in general antibodies are cleared principally by catabolism. The median clearance of pertuzumab was 0.235 liters/day and the median half-life was 18 days.[2]

Mechanism of action

HER2 is an extracellular receptor—a receptor tyrosine kinase - that when activated, sets off signal transduction through several pathways that stimulate cell proliferation and cell growth; if overexpressed it can cause uncontrollable growth. HER2 positive breast cancer is caused by ERBB2 gene amplification that results in overexpression of HER2 in approximately 15-30% of breast cancer tumors.[8]

Like many receptors HER2 normally combines another protein in order to function (a process called dimerization); it can bind with a second HER2 receptor (acting as a homodimer) and it can heterodimerize with a different receptor of the HER family. The most potent dimer for activating signalling pathways is HER2/HER3.[5]

The epitope for pertuzumab is the domain of HER2 where it binds to HER3, and pertuzumab prevents the HER2/HER3 dimer from forming, which blocks signalling by the dimer.[5][9] Trastuzumab is another monoclonal antibody against HER2; its epitope is the domain where HER2 binds to another HER2 protein.[5] The two mAbs together prevent HER2 from functioning.[5]

Chemistry and manufacturing

Pertuzumab is an immunoglobulin G1 with a variable region against the human HER2 protein, a human-mouse monoclonal 2C4 heavy chain, disulfide bound with a human-mouse monoclonal 2C4 κ-chain.[10]

It is manufactured recombinantly in CHO cells.[3]

History

The monoclonal antibody 2C4 appears to have first been published in 1990 by scientists from Genentech,[11] the same year that F. Hoffmann-La Roche AG acquired a majority stake in Genentech.[12]

By 2003, Genentech understood that 2C4 prevented HER2 dimerizing with other HER receptors and had begun Phase I trials, aiming for a broad range of cancers, not just ones overexpressing HER2. It was the first known HER dimerization inhibitor.[13]

In 2005, Genentech presented poor results of Phase II trials of pertuzumab as a single agent in prostate, breast, and ovarian cancers, and said that it intended to continue developing it in combination with other drugs for ovarian cancer.[14][15]

In 2007, Genentech dropped the trade name Omnitarg.[16][17]

In March 2009, Roche acquired Genentech.[18][19]

In 2012, the results were published of the CLEOPATRA trial, a randomized placebo-controlled Phase III trial of pertuzumab in combination with trastuzumab and docetaxel in HER2-positive metastatic breast cancer.[20] Pertuzumab received US FDA approval for the treatment of HER2-positive metastatic breast cancer later that year.[7] Results of a Phase II trial in the neoadjuvant setting, NeoSphere, published in 2012,[21] and results of a Phase II cardiac safety study in the same population, Tryphaena, published in 2013.[22] The FDA approved the neoadjuvant indication in 2013.[23]

Pertuzumab was approved for medical use in the European Union in 2013.[2][4]

Society and culture

Economics

(As of 2016), in the US each cycle of the three-drug combination given every three weeks costs around US$8,500, not including ancillary care costs.[24]

In the UK, a NICE evaluation in 2015, made a preliminary finding that the drug combination was not cost effective, and NICE rejected the drug in the neoadjuvant setting in May 2016, primarily because it was unknown if the drug combination provided a survival benefit.[25][26][27] This decision was subsequently reversed six months later and pertuzumab became the first new breast cancer drug to be approved by NICE for routine NHS funding in almost a decade after Roche pledged to provide the drug to the NHS at an undisclosed discount for patients in the neoadjuvant setting and to share the long–term financial risks.[28]

References

  1. ↑ 1.0 1.1 https://www.guildlink.com.au/gc/ws/ro/pi.cfm?product=ropperje11013 [bare URL]
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 "Perjeta 420 mg Concentrate for Solution for Infusion - Summary of Product Characteristics (SmPC)". 2 July 2021. https://www.medicines.org.uk/emc/product/2993/smpc. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 "Perjeta- pertuzumab injection, solution, concentrate". https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=17f85d17-ab71-4f5b-9fe3-0b8c822f69ff. 
  4. ↑ 4.0 4.1 "Perjeta EPAR". 17 September 2018. https://www.ema.europa.eu/en/medicines/human/EPAR/perjeta. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 "HER2 Dimerization Inhibitor Pertuzumab - Mode of Action and Clinical Data in Breast Cancer". Breast Care 8 (1): 49–55. March 2013. doi:10.1159/000346837. PMID 24715843. 
  6. ↑ "Drug Approval Package: Perjeta (pertuzumab) Injection NDA #125409". 3 August 2012. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/125409Orig1s000TOC.cfm. 
  7. ↑ 7.0 7.1 "FDA approves Perjeta for type of late-stage breast cancer". 8 June 2012. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm307549.htm. 
  8. ↑ "The HER2 Receptor in Breast Cancer: Pathophysiology, Clinical Use, and New Advances in Therapy". Chemotherapy Research and Practice 2012: 743193. 2012. doi:10.1155/2012/743193. PMID 23320171. 
  9. ↑ "A new therapeutic antibody masks ErbB2 to its partners". Cancer Cell 5 (4): 299–301. April 2004. doi:10.1016/s1535-6108(04)00088-1. PMID 15093533. 
  10. ↑ "Proposed INN: List 89". WHO Drug Information 17 (3). 2003. https://www.who.int/medicines/publications/druginformation/innlists/PL89.pdf. 
  11. ↑ "Characterization of murine monoclonal antibodies reactive to either the human epidermal growth factor receptor or HER2/neu gene product". Cancer Research 50 (5): 1550–1558. March 1990. PMID 1689212. http://cancerres.aacrjournals.org/content/canres/50/5/1550.full.pdf. , referenced in "Trastuzumab (herceptin), a humanized anti-Her2 receptor monoclonal antibody, inhibits basal and activated Her2 ectodomain cleavage in breast cancer cells". Cancer Research 61 (12): 4744–4749. June 2001. PMID 11406546. http://cancerres.aacrjournals.org/content/canres/61/12/4744.full.pdf. 
  12. ↑ "Genentech: Survivor Strutting Its Stuff". The New York Times. 1 October 2000. https://www.nytimes.com/2000/10/01/business/genentech-survivor-strutting-its-stuff.html. 
  13. ↑ "Mechanism of Action of Anti-Her2 Monoclonal Antibodies: Scientific Update on Trastuzumab and 2c4". New Trends in Cancer for the 21stCentury. Advances in Experimental Medicine and Biology. 532. 2003. pp. 253–68. doi:10.1007/978-1-4615-0081-0_21. ISBN 978-0-306-47762-1. 
  14. ↑ "Press Release: Data From Omnitarg Clinical Program Presented at American Society of Clinical Oncology Meeting". Genentech. 15 May 2005. https://www.gene.com/media/press-releases/8431/2005-05-15/data-from-omnitarg-clinical-program-pres. 
  15. ↑ "Genentech's Omnitarg fails in Phase II". Pharma Times. 16 May 2005. http://www.pharmatimes.com/news/genentechs_omnitarg_fails_in_phase_ii_998265. 
  16. ↑ "Correction: Letter from the Editor". Cancer Oncology News: 3. February 2012. https://issuu.com/mcmahongroup/docs/con0212_de/3. 
  17. ↑ "Press release: Roche in the first half of 2007". Roche. 19 July 2007. http://www.roche.com/investors/updates/inv-update-2007-07-19.htm. 
  18. ↑ "Chugai Shares Post Healthy Gain On Prospects for Cancer Drug". The Wall Street Journal. 10 May 2006. https://www.wsj.com/articles/SB114720225204948046?mod=googlenews_wsj. 
  19. ↑ "Roche Makes $43.7B Bid for Genentech". Genetic Engineering & Biotechnology News. 21 July 2008. http://www.genengnews.com/news/bnitem.aspx?name=39080941. 
  20. ↑ "Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer". The New England Journal of Medicine 366 (2): 109–119. January 2012. doi:10.1056/nejmoa1113216. PMID 22149875. 
  21. ↑ "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. Oncology 13 (1): 25–32. January 2012. doi:10.1016/s1470-2045(11)70336-9. PMID 22153890.  cited in "Systemic targeted therapy for her2-positive early female breast cancer: a systematic review of the evidence for the 2014 Cancer Care Ontario systemic therapy guideline". Current Oncology 22 (Suppl 1): S114–S122. March 2015. doi:10.3747/co.22.2322. PMID 25848335. 
  22. ↑ "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 24 (9): 2278–2284. September 2013. doi:10.1093/annonc/mdt182. PMID 23704196. 
  23. ↑ "FDA approves Perjeta for neoadjuvant breast cancer treatment". U.S. Food and Drug Administration (FDA) (Press release). 30 September 2013. Archived from the original on 10 October 2013. Retrieved 3 January 2022.
  24. ↑ "Cost-Effectiveness of Pertuzumab in Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer". Journal of Clinical Oncology 34 (9): 902–909. March 2016. doi:10.1200/jco.2015.62.9105. PMID 26351332. 
  25. ↑ "Pertuzumab in combination with trastuzumab and docetaxel for the treatment of HER2-positive metastatic or locally recurrent unresectable breast cancer". PharmacoEconomics 33 (1): 13–23. January 2015. doi:10.1007/s40273-014-0206-2. PMID 25138171. 
  26. ↑ "Breast cancer (HER2 positive, metastatic) - pertuzumab (with trastuzumab and docetaxel) [ID523"]. NICE. 1 September 2016. https://www.nice.org.uk/guidance/indevelopment/gid-tag322. 
  27. ↑ "NICE rejects Roche's breast cancer drug Perjeta". Pharma Times. 20 May 2016. http://www.pharmatimes.com/news/nice_rejects_roches_breast_cancer_drug_perjeta_1026018. 
  28. ↑ "NICE U-Turns and Backs Approval of Roche's Perjeta for HER2-Positive Breast Cancer". Pharmalive. 22 November 2016. http://www.pharmalive.com/nice-u-turns-and-backs-approval-of-roche-s-perjeta-for-her2-positive-breast-cancer/. 

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