Neratinib is used as an adjuvant therapy in people with: - early stage breast cancer in which HER2 is overexpressed, after the person receives treatment with trastuzumab. - metastatic HER2-positive breast cancer after 2 or more lines of anti-HER2 therapy. People should be given drugs to prevent diarrhea when they are given neratinib. 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 causes fetal harm. A clinical trial demonstrated that Neratinib and Temsirolimus in combination produced responses in 19% of patients ranging from 2 to 18+ months in patients with HER2-mutant lung cancers. A common toxicity, diarrhea was well-managed with loperamide prophylaxis.
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. 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.
Interactions
People taking neratinib should not also take gastric acidreducing 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.
Pharmacology
Like lapatinib and afatinib, it is a dual inhibitor of the human epidermal growth factor receptor 2 and epidermal growth factor receptor kinases. It inhibits them by covalently binding with a cysteine side chain in those proteins. Unlike related noncovalent inhibitors, neratinib is effective against the T790M resistant variant of EGFR. 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. 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.
Chemistry
Neratinib is a 4-anilino-3-cyano quinoline derivative.
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. In September 2016, Puma submitted a new drug application to the U.S. Food and Drug Administration for neratinib as a treatment for some people with HER-2 positive breast cancer. In July 2017, it was approved in the United States for adjuvant treatment of adult patients with early stage HER2-overexpressed/amplified breast cancer,. In January 2018, a European Medicines Agency committee gave a negative review to neratinib.
