ReviewNeratinib, A Novel HER2-Targeted Tyrosine Kinase Inhibitor
Introduction
HER2 gene amplification and receptor overexpression is identified in 20% to 25% of human breast cancers.1 HER2 overexpression results in activation of multiple signaling pathways including the phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathway. This leads to an aggressive clinical phenotype with increased growth rate, high-grade tumors, early systemic metastasis, and decreased rates of disease-free and overall survival.1, 2 HER2 results in cell signaling through homo- and heterodimerization of HER (ErbB) receptor tyrosine kinases (EGFR [HER1 or ErbB1], HER2 [ErbB2], HER3 [ErbB3], and HER4 [ErbB4]) and subsequent downstream signaling. Trastuzumab and pertuzumab are commercially available humanized monoclonal antibodies targeting HER2. Trastuzumab binds to the extracellular domain IV and pertuzumab binds subdomain II of HER2 receptor acting in a complementary fashion provides a more complete blockade of HER2-mediated signal transduction while also mediating antibody-dependent cell-mediated cytotoxicity.3, 4, 5
After the approval by the US Food and Drug Administration (FDA) of trastuzumab in 2006 for early breast cancer, the prognosis of patients with HER2-positive disease has significantly improved, however one-third of these patients still continue to have disease relapse after adjuvant treatment.6 Only approximately 30% of patients respond to trastuzumab monotherapy in the metastatic setting but even the responders eventually develop resistance.7 Because of significant improvement of median survival in patients with metastatic HER2-positive breast cancer, primary and secondary resistance to trastuzumab are significant clinical problems.8 Because of the presence of HER reprogramming and other resistance mechanisms in HER2-positive breast cancer, inhibition of more than 1 member of the ErbB family is expected to improve efficacy in this setting.
A number of tyrosine kinase inhibitors (TKIs) targeting this pathway have shown activity in trastuzumab-resistant breast cancer and serve as an alternative to block HER2 signaling.8, 9 Oral, small molecule, dual TKIs of HER2 and EGFR have shown noncross-resistance with trastuzumab in preclinical studies and also to have promising activity in heavily pretreated metastatic HER2-positive breast cancer patients.8, 9, 10, 11
Lapatinib, afatinib, and neratinib are the TKIs that are being evaluated in various phase I, II and III clinical trials. Lapatinib (Tykerb, GlaxoSmithKline, Brentford, London, United Kingdom) is a small molecule TKI that reversibly inhibits the tyrosine kinases of HER2 and EGFR type 1 and currently FDA-approved for patients in whom trastuzumab treatment for metastatic breast cancer has failed. Afatinib irreversibly and selectively targets the ErbB family of receptors: ErbB1 (HER1) and ErbB2 (HER2). Compared with lapatinib, neratinib (HKI-272; Puma Biotechnology Inc, Los Angeles, CA) is an irreversible inhibitor of EGFR and HER2.
Neratinib is an oral pan HER inhibitor that irreversibly inhibits the tyrosine kinase activity of epidermal growth factor receptors, EGFR (or HER1), HER2, and HER4, which leads to reduced phosphorylation and activation of downstream signaling pathways. Neratinib targets tyrosine kinase activity at the intracellular domain of the HER receptors (EGFR, HER2, and HER4) and trastuzumab binds to the extracellular domain of the HER2 receptor. This difference in mechanism of action would explain the improved response when both drugs are combined, because trastuzumab can induce ligand-dependent inhibition of HER receptors12 whereas neratinib inhibits the phosphorylation and activity of HER receptors. This was clearly shown in preclinical studies with a significantly greater growth inhibitory effect in HER2-positive cell lines treated with trastuzumab together with neratinib. This effect was also seen in trastuzumab-resistant HER2-positive cell lines.13, 14
In this report we discuss the available data for neratinib in the metastatic, adjuvant, neoadjuvant, and extended adjuvant settings along with the ongoing clinical trials in breast cancer.
Section snippets
Neratinib in the Metastatic Setting
The initial phase I trial of neratinib showed the maximum tolerated dose (MTD) to be 240 mg/d with the most common dose-limiting toxicities being diarrhea (84%), nausea (55%), asthenia (45%), anorexia (31%), vomiting (29%), chills (12%), and rash (10%).15 Neratinib in combination with weekly paclitaxel and trastuzumab was tested in a phase I trial (National Surgical Adjuvant Breast and Bowel Project FB8 [NSABP FB8]) with the MTD for neratinib determined as 200 mg/d. Of the 21 patients enrolled
Neratinib in the Adjuvant/Extended Adjuvant Setting
In HER2-positive early breast cancer, up to one-third of patients have relapse with invasive disease despite trastuzumab-containing adjuvant therapy.3 Neratinib was used in the extended adjuvant setting after completion of standard chemotherapy with adjuvant trastuzumab and the results of the primary analysis at 2 years of a phase III, randomized, placebo-controlled trial (ExteNET [A Randomized, Double-Blind, Placebo-Controlled Trial Of Neratinib After Trastuzumab In Women With Early-Stage
Neratinib in Neoadjuvant Treatment
The I-SPY-2 trial (Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging And moLecular Analysis 2), a phase II trial of neratinib with standard neoadjuvant therapy for high-risk breast cancer patients. This trial used adaptive randomization, which is an innovative accelerated effort for evaluating targeted therapies that allows researchers to analyze accumulating study data at prospective interim time points and to alter the course of the trial itself. The intent of
Ongoing Trials
For neratinib please refer to Table 2 for a complete list of ongoing clinical trials.
A number of clinical trials are ongoing that are investigating the combination of neratinib with chemotherapy in metastatic breast cancer patients. Neratinib in combination with paclitaxel showed an ORR of 73%, suggesting that inhibition of microtubules potentiates neratinib drug response.17 With this underlying hypothesis a phase I/II study (NSABP FB 10) investigating the combination of trastuzumab emtansine
Disclosure
The authors have stated that they have no conflicts of interest.
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