Neratinib

In the European Union and the United States, neratinib is indicated for the extended adjuvant treatment of adults with early stage (human epidermal growth factor receptor 2) HER2-overexpressed/amplified breast cancer and who are less than one year from the completion of prior adjuvant trastuzumab based therapy.

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.{{cite web | title=Nerlynx- neratinib tablet | website=DailyMed | date=6 August 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d1e41dcf-e82a-47c2-a0ad-6c6eef621834 | access-date=13 November 2020}}

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.

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. 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.

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.

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.

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.

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.{{cite journal | vauthors = Baselga J, Coleman RE, Cortés J, Janni W | title = Advances in the management of HER2-positive early breast cancer | journal = Critical Reviews in Oncology/Hematology | volume = 119 | pages = 113–122 | date = November 2017 | pmid = 29042085 | pmc = 5662944 | doi = 10.1016/j.critrevonc.2017.10.001 }}{{cite journal | vauthors = Minami Y, Shimamura T, Shah K, LaFramboise T, Glatt KA, Liniker E, Borgman CL, Haringsma HJ, Feng W, Weir BA, Lowell AM, Lee JC, Wolf J, Shapiro GI, Wong KK, Meyerson M, Thomas RK | display-authors = 6 | title = The major lung cancer-derived mutants of ERBB2 are oncogenic and are associated with sensitivity to the irreversible EGFR/ERBB2 inhibitor HKI-272 | journal = Oncogene | volume = 26 | issue = 34 | pages = 5023–5027 | date = July 2007 | pmid = 17311002 | doi = 10.1038/sj.onc.1210292 | doi-access = free }} It inhibits them by covalently binding with a cysteine side chain in those proteins.{{cite journal | vauthors = Singh J, Petter RC, Baillie TA, Whitty A | title = The resurgence of covalent drugs | journal = Nature Reviews. Drug Discovery | volume = 10 | issue = 4 | pages = 307–317 | date = April 2011 | pmid = 21455239 | doi = 10.1038/nrd3410 | s2cid = 5819338 | doi-access = free }} Unlike related noncovalent inhibitors, neratinib is effective against the T790M resistant variant of EGFR.{{cite journal | vauthors = Yun CH, Mengwasser KE, Toms AV, Woo MS, Greulich H, Wong KK, Meyerson M, Eck MJ | display-authors = 6 | title = The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 6 | pages = 2070–2075 | date = February 2008 | pmid = 18227510 | pmc = 2538882 | doi = 10.1073/pnas.0709662105 | name-list-style = vanc | doi-access = free | bibcode = 2008PNAS..105.2070Y }}

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.{{cite journal | vauthors = Schwab CL, English DP, Black J, Bellone S, Lopez S, Cocco E, Bonazzoli E, Bussi B, Predolini F, Ferrari F, Ratner E, Silasi DA, Azodi M, Rutherford T, Schwartz PE, Santin AD | display-authors = 6 | title = Neratinib shows efficacy in the treatment of HER2 amplified carcinosarcoma in vitro and in vivo | journal = Gynecologic Oncology | volume = 139 | issue = 1 | pages = 112–117 | date = October 2015 | pmid = 26260909 | pmc = 4587290 | doi = 10.1016/j.ygyno.2015.08.002 }} 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.{{cite journal | vauthors = Ma Y, Lin Z, Fallon JK, Zhao Q, Liu D, Wang Y, Liu F | title = New mouse xenograft model modulated by tumor-associated fibroblasts for human multi-drug resistance in cancer | journal = Oncology Reports | volume = 34 | issue = 5 | pages = 2699–2705 | date = November 2015 | pmid = 26352907 | pmc = 4583831 | doi = 10.3892/or.2015.4265 }}

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. {{cite journal | vauthors = Santamaria S, Gagliani MC, Bellese G, Marconi S, Lechiara A, Dameri M, Aiello C, Tagliatti E, Castagnola P, Cortese K | display-authors = 6 | title = Imaging of Endocytic Trafficking and Extracellular Vesicles Released Under Neratinib Treatment in ERBB2⁺ Breast Cancer Cells | journal = The Journal of Histochemistry and Cytochemistry | volume = 69 | issue = 7 | pages = 461–473 | date = July 2021 | pmid = 34126793 | pmc = 8246527 | doi = 10.1369/00221554211026297 | doi-access = free }}

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

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.{{cite news|title=Puma Acquires Global Rights to Pfizer's Phase III Breast Cancer Drug Neratinib|url=https://www.genengnews.com/gen-news-highlights/puma-acquires-global-rights-to-pfizer-s-phase-iii-breast-cancer-drug-neratinib/81245787/|work=GEN|date=October 6, 2011}}

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).{{cite web | title=Nerlynx (neratinib maleate) Tablets | website=U.S. Food and Drug Administration (FDA) | date=21 August 2017 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208051Orig1s000TOC.cfm | access-date=13 November 2020}}{{cite press release | title=FDA approves new treatment to reduce the risk of breast cancer returning | website=U.S. Food and Drug Administration (FDA) | date=17 July 2017 | url=https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-reduce-risk-breast-cancer-returning | access-date=13 November 2020}} {{PD-notice}}{{cite web | title=FDA approves neratinib for extended adjuvant treatment of early stage HER2-positive breast cancer | website=U.S. Food and Drug Administration (FDA) | date=17 July 2017 | url=https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-neratinib-extended-adjuvant-treatment-early-stage-her2-positive-breast-cancer | access-date=13 November 2020}} {{PD-notice}} Approval was based on the ExteNET trial (NCT00878709), a multicenter, randomized, double-blind, placebo-controlled trial of neratinib following adjuvant trastuzumab treatment.{{cite web | title=Drug Trials Snapshot: Nerlynx | website=U.S. Food and Drug Administration (FDA) | date=17 July 2017 | url=https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshot-nerlynx | access-date=13 November 2020}} {{PD-notice}}

Neratinib was approved for medical use in the European Union in August 2018.{{cite web | title=Nerlynx EPAR | website=European Medicines Agency (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/nerlynx | access-date=13 November 2020}} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.

In Bangladesh it is sold under the trade name Hernix.{{cite web |title=Hernix |work=medex.com.bd |url=https://medex.com.bd/brands/27301/hernix-40mg |access-date=2021-07-14}}

{{Reflist}}

• {{cite web| url = https://druginfo.nlm.nih.gov/drugportal/name/neratinib | publisher = U.S. National Library of Medicine| work = Drug Information Portal| title = Neratinib }}
• {{cite web| url = https://druginfo.nlm.nih.gov/drugportal/name/neratinib%20maleate | publisher = U.S. National Library of Medicine| work = Drug Information Portal| title = Neratinib maleate}}
• {{cite web | title=Neratinib maleate | website=National Cancer Institute | date=27 July 2017 | url=https://www.cancer.gov/about-cancer/treatment/drugs/neratinibmaleate }}
• {{cite web | title=Neratinib maleate | work=NCI Drug Dictionary | publisher=National Cancer Institute | url=https://www.cancer.gov/publications/dictionaries/cancer-drug/def/neratinib }}
• {{ClinicalTrialsGov|NCT00878709|Study Evaluating The Effects Of Neratinib After Adjuvant Trastuzumab In Women With Early Stage Breast Cancer (ExteNET)}}

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