Pharmacodynamics, pharmacokinetics and clinical efficacy of neratinib in HER2-positive breast cancer and breast cancer with HER2 mutations.
BACKGROUND
Despite the availability of several potent HER2-directed targeted agents, primary and acquired resistance continues to influence patient outcomes in HER2-positive breast cancer. Neratinib is an irreversible pan-HER tyrosine kinase inhibitor in late-phase clinical development.


METHODS
This review article focuses on neratinib in the treatment of HER2-positive breast cancer - early and metastatic stage - and HER2-mutant breast cancer, with particular emphasis on the pharmacokinetics and pharmacodynamics of the drug.


CONCLUSIONS
The phase III ExteNET trial shows that neratinib improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in early-stage HER2-positive breast cancer, and in particular HER2+/HR+ tumors. Survival data are awaited. The investigational role of neratinib in high-risk patients or conversely in de-escalation dual regimens with other anti-HER2 therapies and without chemotherapy are of interest. Phase II trials show that neratinib has efficacy, either as monotherapy or in combination with other chemotherapeutic or endocrine agents, in patients with HER2-positive metastatic breast cancer and in tumors harboring HER2 mutations. The role of neratinib in therapeutic algorithms of HER2-positive patients, as well as delaying CNS events, awaits the results of ongoing trials such as NALA. Diarrhea, the main toxicity of neratinib, can be effectively managed with early loperamide prophylaxis.
a Medical Oncology Clinic , Jules Bordet Institute, Free University of Brussels , Brussels , Belgium.
Hampig Raphael
HR
Kourie
a Medical Oncology Clinic , Jules Bordet Institute, Free University of Brussels , Brussels , Belgium.
Marie
M
Chaix
a Medical Oncology Clinic , Jules Bordet Institute, Free University of Brussels , Brussels , Belgium.
Andrea
A
Gombos
a Medical Oncology Clinic , Jules Bordet Institute, Free University of Brussels , Brussels , Belgium.
Phillippe
P
Aftimos
a Medical Oncology Clinic , Jules Bordet Institute, Free University of Brussels , Brussels , Belgium.
Ahmad
A
Awada
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D011804:Quinolines / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D000068878:Trastuzumab / Q000008:administration & dosage
D047428:Protein Kinase Inhibitors; D011804:Quinolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C487932:neratinib
Neratinib; adjuvant; brain metastases; breast cancer; efficacy HER2; metastatic; mutations; neoadjuvant; pharmacodynamics; pharmacokinetics; safety