Neratinib

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Neratinib
Neratinib skeletal.svg
Clinical data
Trade names Nerlynx, Hernix
Other namesHKI-272
AHFS/Drugs.com Monograph
MedlinePlus a617034
License data
Pregnancy
category
  • AU:D
Routes of
administration 		By mouth
Drug class Antineoplastic agent
ATC code
Legal status
Legal status
Identifiers
  • (2E)-N-[4-[[3-Chloro-4-[(pyridin-2-yl)methoxy]phenyl]amino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.241.512 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C30H29ClN6O3
Molar mass 557.05 g·mol−1
3D model (JSmol)
  • CCOc1cc2ncc(C#N)c(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2cc1NC(=O)C=CCN(C)C
  • InChI=1S/C30H29ClN6O3/c1-4-39-28-16-25-23(15-26(28)36-29(38)9-7-13-37(2)3)30(20(17-32)18-34-25)35-21-10-11-27(24(31)14-21)40-19-22-8-5-6-12-33-22/h5-12,14-16,18H,4,13,19H2,1-3H3,(H,34,35)(H,36,38)/b9-7+ Yes check.svgY
  • Key:JWNPDZNEKVCWMY-VQHVLOKHSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Neratinib (INN), sold under the brand name Nerlynx, is a tyrosine kinase inhibitor anti-cancer medication used for the treatment of breast cancer. [3] [4]

Contents

The most common side effect is diarrhea, which affects nearly all patients. [4] Other common side effects include nausea (feeling sick), vomiting, tiredness, belly pain, rash, decreased appetite, stomatitis (sore, inflamed mouth), and muscle spasms. [4]

Medical uses

In the European Union and the United States, neratinib is indicated for the extended adjuvant treatment of adults with early stage hormone receptor positive HER2-overexpressed/amplified breast cancer and who are less than one year from the completion of prior adjuvant trastuzumab based therapy. [3] [4]

In the United States, it is also indicated, in combination with capecitabine, for the treatment of adults with advanced or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2 based regimens in the metastatic setting. [3]

Contraindications

Women who are pregnant should not take it, and women should not become pregnant while taking it, and women who are breast-feeding should not use it, as it can cause harm to the fetus and to the baby. [3]

Adverse effects

Neratinib can cause life-threatening diarrhea in some people and mild to moderate diarrhea in almost everyone; people who take it are also at risk for complications of diarrhea like dehydration and electrolyte imbalance. [3] Similarly, there is a risk of severe liver damage and many patients have some level of it; symptoms of liver damage include fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and high levels of eosinophils. [3]

In addition to the above, more than 10% of people taking it have nausea, abdominal pain, vomiting, sores on their lips, stomach upset, decreased appetite, rashes, and muscle spasms. [3]

Interactions

People taking neratinib should not also take gastric acid reducing agents including proton pump inhibitors and H2-receptor antagonists; antacids may be used three hours before of after taking it. [3]

Drugs that inhibit CYP3A4 increase the activity of neratinib and can make adverse effects worse, and drugs that induce CYP3A4 make neratinib less active and can reduce its efficacy. Neratinib also inhibits p-glycoprotein and effectively raises the dose of drugs like digoxin that depend on it for elimination. [3]

Pharmacology

Like lapatinib and afatinib, it is a dual inhibitor of the human epidermal growth factor receptor 2 (Her2) and epidermal growth factor receptor (EGFR) kinases. [5] [6] It inhibits them by covalently binding with a cysteine side chain in those proteins. [7] Unlike related noncovalent inhibitors, neratinib is effective against the T790M resistant variant of EGFR. [8]

Neratinib has an IC50 of 59 nM against HER2 and shows weak inhibition against KDR and Scr with IC50 values of 0.8 μM and 1.4 μM, respectively. In BT474 cells, neratinib reduces HER2 autophosphorylation, and inhibited cyclin D1 expression while reduced proliferation has been observed A431 cells when treated with neratinib at concentrations of 3 or 5 nM. [9] In xenograft models with 3T3/neu tumors oral administration of neratinib at 10, 20, 40 or 80 mg/kg was able to inhibit tumor growth while in SK-OV-3 models doses of 5 and 60 mg/kg significantly inhibited tumor growth. [10]

Cell Biology

Neratinib is found to strongly reduce the amount of HER2 released by extracellular vescicles and to enhance the capacity of clathrin mediated endocytosis. However, despite HER2 mediated signaling downregulation, Neratinib exerts only a modest effect on HER2 trafficking at IC50 of 6nM in SKBR3 cells. [11]

Chemistry

Neratinib is a 4-anilino-3-cyano quinoline derivative. [3]

History

Neratinib was discovered and initially developed by Wyeth; Pfizer continued development up to Phase III in breast cancer, and licensed it to Puma Biotechnology in 2011. [12]

It was approved for medical use in the United States in July 2017, for the extended adjuvant treatment of adults with early stage HER2-overexpressed/amplified breast cancer, (after adjuvant trastuzumab-based therapy). [13] [14] [15] Approval was based on the ExteNET trial (NCT00878709), a multicenter, randomized, double-blind, placebo-controlled trial of neratinib following adjuvant trastuzumab treatment. [14] [15] [16]

Neratinib was approved for medical use in the European Union in August 2018. [4]

Brand names

In Bangladesh it is sold under the trade name Hernix. [17]

Related Research Articles

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

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">Gefitinib</span> Drug used in fighting breast, lung, and other cancers

Gefitinib, sold under the brand name Iressa, is a medication used for certain breast, lung and other cancers. Gefitinib is an EGFR inhibitor, like erlotinib, which interrupts signaling through the epidermal growth factor receptor (EGFR) in target cells. Therefore, it is only effective in cancers with mutated and overactive EGFR, but resistances to gefitinib can arise through other mutations. It is marketed by AstraZeneca and Teva.

<span class="mw-page-title-main">Erlotinib</span> EGFR inhibitor for treatment of non-small-cell lung cancer

Erlotinib, sold under the brand name Tarceva among others, is a medication used to treat non-small cell lung cancer (NSCLC) and pancreatic cancer. Specifically it is used for NSCLC with mutations in the epidermal growth factor receptor (EGFR) — either an exon 19 deletion (del19) or exon 21 (L858R) substitution mutation — which has spread to other parts of the body. It is taken by mouth.

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

Receptor tyrosine-protein kinase erbB-2 is a protein that in humans 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">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).

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

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.

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">Axitinib</span> Chemical compound

Axitinib, sold under the brand name Inlyta, is a small molecule tyrosine kinase inhibitor developed by Pfizer. It has been shown to significantly inhibit growth of breast cancer in animal (xenograft) models and has shown partial responses in clinical trials with renal cell carcinoma (RCC) and several other tumour types.

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

Afatinib, sold under the brand name Gilotrif among others, is a medication which is used to treat non-small cell lung carcinoma (NSCLC). It belongs to the tyrosine kinase inhibitor family of medications. It is taken by mouth.

<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.

<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 given by slow injection into a vein.

<span class="mw-page-title-main">Palbociclib</span> Medication for HR+ HER2− breast cancer

Palbociclib, sold under the brand name Ibrance among others, is a medication developed by Pfizer for the treatment of HR-positive and HER2-negative breast cancer. It is a selective inhibitor of the cyclin-dependent kinases CDK4 and CDK6. Palbociclib was the first CDK4/6 inhibitor to be approved as a cancer therapy.

<span class="mw-page-title-main">Targeted covalent inhibitors</span>

Targeted covalent inhibitors (TCIs) or Targeted covalent drugs are rationally designed inhibitors that bind and then bond to their target proteins. These inhibitors possess a bond-forming functional group of low chemical reactivity that, following binding to the target protein, is positioned to react rapidly with a proximate nucleophilic residue at the target site to form a bond.

<span class="mw-page-title-main">Osimertinib</span> Chemical compound, used as a medication to treat lung cancer

Osimertinib, sold under the brand name Tagrisso, is a medication used to treat non-small-cell lung carcinomas with specific mutations. It is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor.

T790M, also known as Thr790Met, is a gatekeeper mutation of the epidermal growth factor receptor (EGFR). The mutation substitutes a threonine (T) with a methionine (M) at position 790 of exon 20, affecting the ATP binding pocket of the EGFR kinase domain. Threonine is a small polar amino acid; methionine is a larger nonpolar amino acid. Rather than directly blocking inhibitor binding to the active site, T790M increases the affinity for ATP so that the inhibitors are outcompeted; irreversible covalent inhibitors such as neratinib can overcome this resistance.

<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.

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.

<span class="mw-page-title-main">Mobocertinib</span> Small molecule tyrosine kinase inhibitor


Mobocertinib, sold under the brand name Exkivity, is used for the treatment of non-small cell lung cancer.

References

  1. ↑ "Summary Basis of Decision (SBD) for Nerlynx". Health Canada . 23 October 2014. Retrieved 29 May 2022.
  2. ↑ "Nerlynx 40 mg Film-coated Tablets - Summary of Product Characteristics (SmPC)". (emc). Retrieved 13 November 2020.
  3. 1 2 3 4 5 6 7 8 9 10 11 "Nerlynx- neratinib tablet". DailyMed. 6 August 2020. Retrieved 13 November 2020.
  4. 1 2 3 4 5 6 "Nerlynx EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 13 November 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  5. ↑ Baselga J, Coleman RE, Cortés J, Janni W (November 2017). "Advances in the management of HER2-positive early breast cancer". Critical Reviews in Oncology/Hematology. 119: 113–122. doi:10.1016/j.critrevonc.2017.10.001. PMC   5662944 . PMID   29042085.
  6. ↑ Minami Y, Shimamura T, Shah K, LaFramboise T, Glatt KA, Liniker E, et al. (July 2007). "The major lung cancer-derived mutants of ERBB2 are oncogenic and are associated with sensitivity to the irreversible EGFR/ERBB2 inhibitor HKI-272". Oncogene. 26 (34): 5023–5027. doi: 10.1038/sj.onc.1210292 . PMID   17311002.
  7. ↑ Singh J, Petter RC, Baillie TA, Whitty A (April 2011). "The resurgence of covalent drugs". Nature Reviews. Drug Discovery. 10 (4): 307–317. doi: 10.1038/nrd3410 . PMID   21455239. S2CID   5819338.
  8. ↑ Yun CH, Mengwasser KE, Toms AV, Woo MS, Greulich H, Wong KK, et al. (February 2008). "The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP". Proceedings of the National Academy of Sciences of the United States of America. 105 (6): 2070–2075. Bibcode:2008PNAS..105.2070Y. doi: 10.1073/pnas.0709662105 . PMC   2538882 . PMID   18227510.
  9. ↑ Schwab CL, English DP, Black J, Bellone S, Lopez S, Cocco E, et al. (October 2015). "Neratinib shows efficacy in the treatment of HER2 amplified carcinosarcoma in vitro and in vivo". Gynecologic Oncology. 139 (1): 112–117. doi:10.1016/j.ygyno.2015.08.002. PMC   4587290 . PMID   26260909.
  10. ↑ Ma Y, Lin Z, Fallon JK, Zhao Q, Liu D, Wang Y, Liu F (November 2015). "New mouse xenograft model modulated by tumor-associated fibroblasts for human multi-drug resistance in cancer". Oncology Reports. 34 (5): 2699–2705. doi:10.3892/or.2015.4265. PMC   4583831 . PMID   26352907.
  11. ↑ Santamaria S, Gagliani MC, Bellese G, Marconi S, Lechiara A, Dameri M, et al. (July 2021). "Imaging of Endocytic Trafficking and Extracellular Vesicles Released Under Neratinib Treatment in ERBB2+ Breast Cancer Cells". The Journal of Histochemistry and Cytochemistry. 69 (7): 461–473. doi: 10.1369/00221554211026297 . PMC   8246527 . PMID   34126793.
  12. ↑ "Puma Acquires Global Rights to Pfizer's Phase III Breast Cancer Drug Neratinib". GEN. 6 October 2011.
  13. ↑ "Nerlynx (neratinib maleate) Tablets". U.S. Food and Drug Administration (FDA). 21 August 2017. Retrieved 13 November 2020.
  14. 1 2 "FDA approves new treatment to reduce the risk of breast cancer returning". U.S. Food and Drug Administration (FDA) (Press release). 17 July 2017. Retrieved 13 November 2020.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  15. 1 2 "FDA approves neratinib for extended adjuvant treatment of early stage HER2-positive breast cancer". U.S. Food and Drug Administration (FDA). 17 July 2017. Retrieved 13 November 2020.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  16. ↑ "Drug Trials Snapshot: Nerlynx". U.S. Food and Drug Administration (FDA). 17 July 2017. Retrieved 13 November 2020.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  17. ↑ "Hernix". medex.com.bd. Retrieved 14 July 2021.
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