Tucatinib – A Novel HER2 Inhibitor for Treatment of Breast Cancer

by Dr. C.H. Weaver M.D. updated 12/2019

Tucatinib in combination with Herceptin (trastuzumab) and Xeloda (capecitabine) improves outcomes for women with locally advanced unresectable or metastatic HER2-positive breast cancer compared to treatment with Herceptin and Xeloda alone.

“There is significant unmet medical need following treatment with Herceptin, pertuzumab and T-DM1 in patients with metastatic HER2-positive breast cancer,” said Roger Dansey, M.D., Chief Medical Officer at Seattle Genetics, We plan to submit a New Drug Application (NDA) to the FDA in the first quarter of 2020, with the goal of bringing a much-needed new medicine to patients.”

About HER2-Positive Breast Cancer

Patients with HER2-positive breast cancer have cancer with high levels of a protein called human epidermal growth factor receptor 2 (HER2) which promotes the aggressive spread of cancer cells. Between 15 and 20 percent of individuals with breast cancer are HER2-positive. There are several approved treatments for HER2-positive breast cancer but currently no approved therapies demonstrating progression-free survival or overall survival benefit for the treatment of patients with HER2-positive metastatic breast cancer after progression on T-DM1. (1,2,3)

About Tucatinib

Tucatinib is a tyrosine kinase inhibitor drug that is highly selective for HER2 without significant inhibition of EGFR. Inhibition of EGFR is associated with significant side effects including skin rash and diarrhea. HER2 is a growth factor receptor that is over expressed in multiple cancers, including breast, colorectal and gastric cancers. HER2 mediates cell growth, differentiation, and survival. Tucatinib has been granted orphan drug designation by the FDA for the treatment of breast cancer patients with brain metastases.

About HER2CLIMB

The HER2CLIMB clinical trial compared tucatinib in combination with Herceptin and Xeloda to treatment with Herceptin and Xeloda alone in patients with locally advanced or metastatic HER2-positive breast cancer who were previously treated with Herceptin, pertuzumab and T-DM1 in 612 patients.

Trial results were updated at the December 2019 San Antonio Breast Cancer Symposia. The addition of tucatinib to Herceptin and Xeloda significantly improved the outcomes of women with advanced HER2 + breast cancer including women with brain metastases. Compared to treatment with Herceptin and Xeloda, the addition of tucatinib

  • Resulted in a 46% reduction in the risk of disease progression or death.
  • Improved overall survival, with a 34% reduction in the risk of death compared to Herceptin and Xeloda. Estimated survival at two years was 45% with the addition of tucatinib compared to 27% for Herceptin + Xeloda. Median survival duration was improved to 22 months compared to 17 months.
  • Delayed cancer progression; 33% of tucatinib treated patients survived one year without cancer progression compared to only 12% for Herceptin + Xeloda.
  • Resulted in a 52 percent reduction in the risk of disease progression or death in patients with brain metastases compared to Herceptin and Xeloda.

Tucatinib in combination with Herceptin and Xeloda was generally well tolerated with a manageable safety profile. The most frequent side effects were diarrhea, palmar-plantar erythrodysaesthesia syndrome (PPE), nausea, fatigue, and vomiting. Tucatinib has the potential to improve the treatment of advanced HER2 + breast cancer and is undergoing evaluation in women with early stage disease.

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References:

  1. Verma S, Miles D, Gianni L, et al. (2012). Trastuzumab Emtansine for HER2-Positive Advanced Breast Cancer. New England Journal of Medicine 367(19): 1783-91.
  2. Meyer CE, Forster J, Lindquist D, et al. (2006). Lapatinib plus Xeloda for HER2-Positive Advanced Breast Cancer. New England Journal of Medicine 355(26): 2733-43.
  3. Blackwell KL, Burstein HJ, Storniolo AM, et al. (2012). Overall Survival Benefit With Lapatinib in Combination With Trastuzumab for Patients With Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer: Final Results From the EGF104900 Study. Journal of Clinical Oncology 30(21): 2585-92.
  4. https://www.nejm.org/doi/full/10.1056/NEJMoa1914609?query=featured_home
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