On July 17, 2017, the U.S. Food and Drug Administration approved neratinib (Nerlynx, Puma Biotechnology, Inc.) for the extended adjuvant treatment of adult patients with early stage HER2-overexpressed/amplified breast cancer to follow adjuvant trastuzumab-based therapy.
Neratinib, also known as HKI-272 or PB272, is an orally available, 6,7-disubstituted-4-anilinoquinoline-3-carbonitrile irreversible inhibitor of the HER-2 receptor tyrosine kinase with potential antineoplastic activity. Neratinib binds to the HER-2 receptor irreversibly, thereby reducing autophosphorylation in cells, apparently by targeting a cysteine residue in the ATP-binding pocket of the receptor. Treatment of cells with this agent results in inhibition of downstream signal transduction events and cell cycle regulatory pathways; arrest at the G1-S (Gap 1/DNA synthesis)-phase transition of the cell division cycle; and ultimately decreased cellular proliferation. Neratinib also inhibits the epidermal growth factor receptor (EGFR) kinase and the proliferation of EGFR-dependent cells. Trastuzumab is a monoclonal humanized antibody that has revolutionized the treatment of patients with Her2-positive breast cancer. It is a rationally designed substance which binds to cancer cells expressing the targeted antigen and causes tumor cell degradation by different mechanisms.
Combination therapy is the mainstay of cancer treatment, and so the axiom is proved once again with these two examples. Trastuzumab (Herceptin) acts by binding to the HER2 extracellular domain and blocking HER-2’s ability to dimerize with other HER receptors, thereby blocking downstream signaling. Combining trastuzumab with tyrosine kinase inhibitors would ostensibly result in a more complete shut down of signaling from the HER-family tyrosine kinase receptors. Tyrosine kinase inhibitors binds of trastuzumab also induces ADCC (antibody-dependent cellular cytotoxicity).
Extended adjuvant therapy is a form of therapy that is taken after an initial treatment to further lower the risk of the cancer coming back. For patients with breast cancer, neratinib is the first extended adjuvant therapy. Neratinib is indicated for adult patients who have been previously treated with a regimen that includes the drug trastuzumab. The pivotal phase 3 randomized trial consisted of 2840 patients with early-stage HER2-positive breast cancer who previously had completed trastuzumab treatment. After 2 years, patients treated with 1 year of neratinib had a disease-free survival rate of 94.2% versus 91.9% of patients on placebo.
Common side effects of Nerlynx include diarrhea, nausea, abdominal pain, fatigue, vomiting, rash, swollen and sore mouth (stomatitis), decreased appetite, muscle spasms, indigestion (dyspepsia), liver damage (AST or ALT enzyme increase), nail disorder, dry skin, abdominal swelling (distention), weight loss and urinary tract infection.
HER2-positive breast cancer is more aggressive and more likely to recur than HER2-negative breast cancer. Recurrence can happen anytime. With this kind of treatment, it maybe help prevent the HER2-positive breast cancer recurrence.
|CAS Number||Product Name||Description|
|1018448-65-1||trastuzumab emtansine||trastuzumab emtansine is an antibody-drug conjugate (ADC) consisting of the recombinant anti-epidermal growth factor receptor 2 (HER2) monoclonal antibody trastuzumab conjugated to the maytansinoid DM1 via a nonreducible thioether linkage (MCC) with potential antineoplastic activity. The trastuzumab moiety of this ADC binds to HER2 on tumor cell surface surfaces; upon internalization, the DM1 moiety is released and binds to tubulin, thereby disrupting microtubule assembly/disassembly dynamics and inhibiting cell division and the proliferation of cancer cells that overexpress HER2. Linkage of antibody and drug through a nonreducible linker has been reported to contribute to the improved efficacy and reduced toxicity of this ADC compared to similar ADCs constructed with reducible linkers. Check for active clinical trials or closed clinical trials using this agent.|
|698387-09-6||Neratinib||Neratinib, also known as HKI-272 or PB272, is an orally available, 6,7-disubstituted-4-anilinoquinoline-3-carbonitrile irreversible inhibitor of the HER-2 receptor tyrosine kinase with potential antineoplastic activity.|