Pertuzumab

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Pertuzumab
Pertuzumab-HER2 complex 1S78.png
The structure of HER2 and pertuzumab
Monoclonal antibody
Type Whole antibody
Source Humanized (from mouse)
Target HER2
Clinical data
Trade names Perjeta
Other names2C4
License data
Pregnancy
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Routes of
administration 		Intravenous
ATC code
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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. [4]

Contents

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. [6]

It was discovered and developed by Genentech and was first approved in 2012. [7] [8]

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. [4] [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. [4]

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. [9]

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. [6]

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. [6] [10] Trastuzumab is another monoclonal antibody against HER2; its epitope is the domain where HER2 binds to another HER2 protein. [6] The two mAbs together prevent HER2 from functioning. [6]

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. [11]

It is manufactured recombinantly in CHO cells. [4]

History

The monoclonal antibody 2C4 appears to have first been published in 1990 by scientists from Genentech, [12] the same year that F. Hoffmann-La Roche AG acquired a majority stake in Genentech. [13]

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. [14]

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. [15] [16]

In 2007, Genentech dropped the trade name Omnitarg. [17] [18]

In March 2009, Roche acquired Genentech. [19] [20]

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. [21] Pertuzumab received US FDA approval for the treatment of HER2-positive metastatic breast cancer later that year. [8] Results of a Phase II trial in the neoadjuvant setting, NeoSphere, published in 2012, [22] and results of a Phase II cardiac safety study in the same population, Tryphaena, published in 2013. [23] The FDA approved the neoadjuvant indication in 2013. [24]

Pertuzumab was approved for medical use in the European Union in 2013. [2] [5]

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. [25]

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. [26] [27] [28] 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. [29]

Related Research Articles

Genentech, Inc. is an American biotechnology corporation headquartered in South San Francisco, California. It became an independent subsidiary of Roche in 2009. Genentech Research and Early Development operates as an independent center within Roche. Historically, the company is regarded as the world's first biotechnology company.

<span class="mw-page-title-main">Trastuzumab</span> Medication

Trastuzumab, sold under the brand name Herceptin among others, is a monoclonal antibody used to treat breast cancer and stomach cancer. It is specifically used for cancer that is HER2 receptor positive. It may be used by itself or together with other chemotherapy medication. Trastuzumab is given by slow injection into a vein and injection just under the skin.

<span class="mw-page-title-main">HER2</span> Mammalian protein found in humans

Receptor tyrosine-protein kinase erbB-2 is a protein that normally resides in the membranes of cells and is encoded by the ERBB2 gene. ERBB is abbreviated from erythroblastic oncogene B, a gene originally isolated from the avian genome. The human protein is also frequently referred to as HER2 or CD340.

<span class="mw-page-title-main">Targeted therapy</span> Type of therapy

Targeted therapy or molecularly targeted therapy is one of the major modalities of medical treatment (pharmacotherapy) for cancer, others being hormonal therapy and cytotoxic chemotherapy. As a form of molecular medicine, targeted therapy blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth, rather than by simply interfering with all rapidly dividing cells. Because most agents for targeted therapy are biopharmaceuticals, the term biologic therapy is sometimes synonymous with targeted therapy when used in the context of cancer therapy. However, the modalities can be combined; antibody-drug conjugates combine biologic and cytotoxic mechanisms into one targeted therapy.

<span class="mw-page-title-main">Lapatinib</span> Cancer medication

Lapatinib (INN), used in the form of lapatinib ditosylate (USAN) is an orally active drug for breast cancer and other solid tumours. It is a dual tyrosine kinase inhibitor which interrupts the HER2/neu and epidermal growth factor receptor (EGFR) pathways. It is used in combination therapy for HER2-positive breast cancer. It is used for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 (ErbB2).

Triple-negative breast cancer (TNBC) is any breast cancer that either lacks or shows low levels of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) overexpression and/or gene amplification. Triple-negative is sometimes used as a surrogate term for basal-like.

<span class="mw-page-title-main">Neratinib</span> Chemical compound

Neratinib (INN), sold under the brand name Nerlynx, is a tyrosine kinase inhibitor anti-cancer medication used for the treatment of breast cancer.

A CDK inhibitor is any chemical that inhibits the function of CDKs. They are used to treat cancers by preventing overproliferation of cancer cells. The US FDA approved the first drug of this type, palbociclib (Ibrance), a CDK4/6 inhibitor, in February 2015, for use in postmenopausal women with breast cancer that is estrogen receptor positive and HER2 negative. While there are multiple cyclin/CDK complexes regulating the cell cycle, CDK inhibitors targeting CDK4/6 have been the most successful, with 4 CDK4/6 inhibitors haven been FDA approved. No inhibitors targeting other CDKs have been FDA approved, but several compounds are in clinical trials.

<span class="mw-page-title-main">Antibody–drug conjugate</span> Class of biopharmaceutical drugs

Antibody–drug conjugates or ADCs are a class of biopharmaceutical drugs designed as a targeted therapy for treating cancer. Unlike chemotherapy, ADCs are intended to target and kill tumor cells while sparing healthy cells. As of 2019, some 56 pharmaceutical companies were developing ADCs.

<span class="mw-page-title-main">Trastuzumab emtansine</span> Pharmaceutical drug

Trastuzumab emtansine, sold under the brand name Kadcyla, is an antibody-drug conjugate consisting of the humanized monoclonal antibody trastuzumab (Herceptin) covalently linked to the cytotoxic agent DM1. Trastuzumab alone stops growth of cancer cells by binding to the HER2 receptor, whereas trastuzumab emtansine undergoes receptor-mediated internalization into cells, is catabolized in lysosomes where DM1-containing catabolites are released and subsequently bind tubulin to cause mitotic arrest and cell death. Trastuzumab binding to HER2 prevents homodimerization or heterodimerization (HER2/HER3) of the receptor, ultimately inhibiting the activation of MAPK and PI3K/AKT cellular signalling pathways. Because the monoclonal antibody targets HER2, and HER2 is only over-expressed in cancer cells, the conjugate delivers the cytotoxic agent DM1 specifically to tumor cells. The conjugate is abbreviated T-DM1.

Margetuximab, sold under the brand name Margenza, is a chimeric IgG monoclonal antibody medication against HER2 used for the treatment of cancer.

<span class="mw-page-title-main">Pembrolizumab</span> Pharmaceutical drug used in cancer treatment

Pembrolizumab, sold under the brand name Keytruda, is a humanized antibody used in cancer immunotherapy that treats melanoma, lung cancer, head and neck cancer, Hodgkin lymphoma, stomach cancer, cervical cancer, and certain types of breast cancer. It is administered by slow intravenous injection.

ImmunoGen, Inc. was a biotechnology company focused on the development of antibody-drug conjugate (ADC) therapeutics for the treatment of cancer. ImmunoGen was founded in 1981 and was headquartered in Waltham, Massachusetts.

<span class="mw-page-title-main">Atezolizumab</span> Monoclonal anti-PD-L1 antibody

Atezolizumab, sold under the brand name Tecentriq, is a monoclonal antibody medication used to treat urothelial carcinoma, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), hepatocellular carcinoma and alveolar soft part sarcoma, but discontinued for use in triple-negative breast cancer (TNBC). It is a fully humanized, engineered monoclonal antibody of IgG1 isotype against the protein programmed cell death-ligand 1 (PD-L1).

<span class="mw-page-title-main">Sacituzumab govitecan</span> Antibody-drug conjugate

Sacituzumab govitecan, sold under the brand name Trodelvy, is a Trop-2-directed antibody and topoisomerase inhibitor drug conjugate used for the treatment of metastatic triple-negative breast cancer and metastatic urothelial cancer.

<span class="mw-page-title-main">Abemaciclib</span> Anti-breast cancer medication

Abemaciclib, sold under the brand name Verzenio among others, is a medication for the treatment of advanced or metastatic breast cancers. It was developed by Eli Lilly and it acts as a CDK inhibitor selective for CDK4 and CDK6.

<span class="mw-page-title-main">Tucatinib</span> Chemical compound

Tucatinib, sold under the brand name Tukysa, is an anticancer medication used for the treatment of HER2-positive breast cancer. It is a small molecule inhibitor of HER2. It was developed by Array BioPharma and licensed to Cascadian Therapeutics.

<span class="mw-page-title-main">Trastuzumab deruxtecan</span> Medication

Trastuzumab deruxtecan, sold under the brand name Enhertu, is an antibody-drug conjugate consisting of the humanized monoclonal antibody trastuzumab (Herceptin) covalently linked to the topoisomerase I inhibitor deruxtecan. It is licensed for the treatment of breast cancer or gastric or gastroesophageal adenocarcinoma. Trastuzumab binds to and blocks signaling through epidermal growth factor receptor 2 (HER2/neu) on cancers that rely on it for growth. Additionally, once bound to HER2 receptors, the antibody is internalized by the cell, carrying the bound deruxtecan along with it, where it interferes with the cell's ability to make DNA structural changes and replicate its DNA during cell division, leading to DNA damage when the cell attempts to replicate itself, destroying the cell.

Pertuzumab/trastuzumab/hyaluronidase, sold under the brand name Phesgo, is a fixed-dose combination medication to treat adults with HER2-positive breast cancer that has spread to other parts of the body, and for treatment of adults with early HER2-positive breast cancer. It contains pertuzumab, trastuzumab, and hyaluronidase–zzxf. It is injected under the skin via subcutaneous injection in the thigh. In the European Union, Phesgo contains the active ingredients pertuzumab and trastuzumab along with the enzyme vorhyaluronidase alfa.

Trastuzumab/hyaluronidase, sold under the brand name Herceptin SC among others, is a fixed-dose combination medication for the treatment of HER2-overexpressing breast cancer in adults. It is a combination of trastuzumab and hyaluronidase.

References

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  2. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 "Perjeta 420 mg Concentrate for Solution for Infusion - Summary of Product Characteristics (SmPC)". (emc). 2 July 2021. Retrieved 3 January 2022.
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  5. 1 2 "Perjeta EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 3 January 2022.
  6. 1 2 3 4 5 Harbeck N, Beckmann MW, Rody A, Schneeweiss A, Müller V, Fehm T, et al. (March 2013). "HER2 Dimerization Inhibitor Pertuzumab - Mode of Action and Clinical Data in Breast Cancer". Breast Care. 8 (1): 49–55. doi:10.1159/000346837. PMC   3971793 . PMID   24715843.
  7. ↑ "Drug Approval Package: Perjeta (pertuzumab) Injection NDA #125409". U.S. Food and Drug Administration (FDA). 3 August 2012. Retrieved 3 January 2022.
  8. 1 2 "FDA approves Perjeta for type of late-stage breast cancer". U.S. Food and Drug Administration (FDA). 8 June 2012. Archived from the original on 1 November 2012. Retrieved 3 January 2022.
  9. ↑ Mitri Z, Constantine T, O'Regan R (2012). "The HER2 Receptor in Breast Cancer: Pathophysiology, Clinical Use, and New Advances in Therapy". Chemotherapy Research and Practice. 2012: 743193. doi: 10.1155/2012/743193 . PMC   3539433 . PMID   23320171.
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  11. ↑ "Proposed INN: List 89" (PDF). WHO Drug Information. 17 (3). 2003.
  12. ↑ Fendly BM, Winget M, Hudziak RM, Lipari MT, Napier MA, Ullrich A (March 1990). "Characterization of murine monoclonal antibodies reactive to either the human epidermal growth factor receptor or HER2/neu gene product" (PDF). Cancer Research. 50 (5): 1550–1558. PMID   1689212., referenced in Molina MA, Codony-Servat J, Albanell J, Rojo F, Arribas J, Baselga J (June 2001). "Trastuzumab (herceptin), a humanized anti-Her2 receptor monoclonal antibody, inhibits basal and activated Her2 ectodomain cleavage in breast cancer cells" (PDF). Cancer Research. 61 (12): 4744–4749. PMID   11406546.
  13. ↑ Fisher LM (1 October 2000). "Genentech: Survivor Strutting Its Stuff". The New York Times.
  14. ↑ Albanell J, Codony J, Rovira A, Mellado B, Gascón P (2003). "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. Vol. 532. pp. 253–68. doi:10.1007/978-1-4615-0081-0_21. ISBN   978-0-306-47762-1. PMID   12908564.
  15. ↑ "Press Release: Data From Omnitarg Clinical Program Presented at American Society of Clinical Oncology Meeting". Genentech. 15 May 2005. Archived from the original on 6 April 2017. Retrieved 2 November 2016.
  16. ↑ "Genentech's Omnitarg fails in Phase II". Pharma Times. 16 May 2005.
  17. ↑ "Correction: Letter from the Editor". Cancer Oncology News: 3. February 2012.
  18. ↑ "Press release: Roche in the first half of 2007". Roche. 19 July 2007.
  19. ↑ Morse A (10 May 2006). "Chugai Shares Post Healthy Gain On Prospects for Cancer Drug". The Wall Street Journal. Retrieved 26 September 2008.
  20. ↑ "Roche Makes $43.7B Bid for Genentech". Genetic Engineering & Biotechnology News . 21 July 2008. Archived from the original on 3 February 2009. Retrieved 26 September 2008.
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  22. ↑ Gianni L, Pienkowski T, Im YH, Roman L, Tseng LM, Liu MC, et al. (January 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. Oncology. 13 (1): 25–32. doi:10.1016/s1470-2045(11)70336-9. PMID   22153890. cited in Mates M, Fletcher GG, Freedman OC, Eisen A, Gandhi S, Trudeau ME, Dent SF (March 2015). "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. doi:10.3747/co.22.2322. PMC   4381787 . PMID   25848335.
  23. ↑ Schneeweiss A, Chia S, Hickish T, Harvey V, Eniu A, Hegg R, et al. (September 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. 24 (9): 2278–2284. doi: 10.1093/annonc/mdt182 . PMID   23704196.
  24. ↑ "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.
  25. ↑ Durkee BY, Qian Y, Pollom EL, King MT, Dudley SA, Shaffer JL, et al. (March 2016). "Cost-Effectiveness of Pertuzumab in Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer". Journal of Clinical Oncology. 34 (9): 902–909. doi:10.1200/jco.2015.62.9105. PMC   5070553 . PMID   26351332.
  26. ↑ Fleeman N, Bagust A, Beale S, Dwan K, Dickson R, Proudlove C, Dundar Y (January 2015). "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. doi:10.1007/s40273-014-0206-2. PMID   25138171. S2CID   8470253.
  27. ↑ "Breast cancer (HER2 positive, metastatic) - pertuzumab (with trastuzumab and docetaxel) [ID523]". NICE. 1 September 2016. Retrieved 2 November 2016.
  28. ↑ McKee S (20 May 2016). "NICE rejects Roche's breast cancer drug Perjeta". Pharma Times.
  29. ↑ Yip A (22 November 2016). "NICE U-Turns and Backs Approval of Roche's Perjeta for HER2-Positive Breast Cancer". Pharmalive.

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