CANCER THERAPEUTICS

NERATINIB

Irreversible pan-HER tyrosine kinase inhibitor

Neratinib, an oral HER2 targeted therapy, was approved by the U.S. Food and Drug Administration in 2017 and by the European Commission in 2018. It has been included as a recommended treatment option in the latest National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines for early and metastatic breast cancer.1) HER2 plays a role in the rapid development and metastases of breast cancer, thus being the main target. Approximately 20 to 25 percent of breast cancer tumors overexpress HER2.2) 3) HER2 targeted therapy began in 1998 and has been widely used since.4) However, existing therapies being large molecules have difficulty passing through the Blood Brain Barrier (BBB) and hence, there is a limitation in the treatment and prevention of brain metastases which occur in approximately 30 to 50% in patients with advanced HER2+ breast cancer.5) 6) Neratinib, as a small molecule, is a next generation therapy developed to overcome the limits of the existing options.7)
  1. Gradishar, William J., et al. "NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)." Journal of the National Comprehensive Cancer Network 18.4 (2020).
  2. Slamon, Dennis J., et al. "Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene." science 235.4785 (1987): 177-182. 
  3. Slamon, Dennis J., et al. "Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer." Science 244.4905 (1989): 707-712.
  4. Kourie, Hampig Raphael, et al. "Emerging treatments for HER2-positive early-stage breast cancer: focus on neratinib." OncoTargets and therapy 10 (2017): 3363.
  5. Mehta, Ankit I., Adam M. Brufsky, and John H. Sampson. "Therapeutic approaches for HER2-positive brain metastases: circumventing the blood–brain barrier." Cancer treatment reviews 39.3 (2013): 261-269.
  6. Duchnowska, Renata, Sibylle Loibl, and Jacek Jassem. "Tyrosine kinase inhibitors for brain metastases in HER2-positive breast cancer." Cancer treatment reviews 67 (2018): 71-77.
  7. Roskoski Jr, Robert. "Small molecule inhibitors targeting the EGFR/ErbB family of protein-tyrosine kinases in human cancers." Pharmacological research 139 (2019): 395-411. 

Regulatory Approval

Canada, USA, Argentina, Europe, Singapore, Hong Kong, China, Australia

FDA approval

· Early Breast Cancer : As a single agent, for the extended adjuvant treatment of adult patients with early stage HER2-positive breast cancer, to follow adjuvant trastuzumab-based therapy.


· Metastatic Breast Cancer : In combination with capecitabine, for the treatment of adult patients with advanced or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2 based regimens in the metastatic setting.


EMA approval

· Early Breast Cancer : As a single agent, for the extended adjuvant treatment of adult patients with early-stage hormone receptor positive HER2-overexpressed/amplified breast cancer and who completed adjuvant trastuzumab-based therapy less than one year ago.


Gobal treatment guideline

1.  NCCN guideline 2020, Breast Cancer (National Comprehensive Cancer Network)
  Early Breast Cancer  
Consider extended adjuvant neratinib following adjuvant trastuzumab containing therapy for patient with HR-positive disease with a perceived high risk of recurrence

 Metastatic or Recurrent Breast Cancer  
In combination with capecitabine, for the treatment of patients with metastatic or recurrent HER2 positive breast cancer

  Metastatic or Recurrent Breast Cancer – Brain Metastases  

In combination with capecitabine or paclitaxel, for the treatment of patients with metastatic or recurrent HER2-positive breast cancer with brain metastases


Gradishar, William J., et al. "NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)."

Journal of the National Comprehensive Cancer Network 18, 4 (2020). NCCN Guidelines v1. 2019. Central Nervous System Cancers




2. ESMO guideline 2019, Early breast cancer (European Society for Medical Oncology)

  Early Breast Cancer  

Extended anti-HER2 therapy with neratinib may be considered in selected high-risk patients, not previously treated with dual blockade, and with appropriate diarrhoea prophylaxis and management


Cardoso, F., et al. "Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up"
Annals of  Oncology 30, 8 (2019): 1194-1220.