Tucatinib is an oral small molecule tyrosine kinase inhibitor (TKI) sold under the trade name Tukysa. It is highly selective for the HER2 kinase domain and was initially developed by Array BioPharma (a subsidiary of Pfizer) and subsequently by Seattle Genetics for the treatment of HER2-positive solid tumors, including breast and colorectal cancer. Tucatinib was approved in the United States in April 2020 and in Switzerland in May 2020 for the treatment of HER2-positive breast cancer. It was subsequently approved for the treatment of adult patients with advanced unresectable or metastatic HER2-positive breast cancer.

Indications

Metastatic Breast Cancer

Tucatinib, in combination with trastuzumab and capecitabine, has been approved by Health Canada for the treatment of patients with locally advanced or metastatic HER2-positive breast cancer, including those with brain metastases, who have been previously treated with trastuzumab, pertuzumab, and T-DM1, either alone or in combination.

Unresectable or metastatic colorectal cancer

Tucatinib is indicated in combination with trastuzumab for the treatment of adult patients with RAS wild-type, HER2-positive unresectable or metastatic colorectal cancer that has progressed following fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.

Mechanism of Action

Tucatinib is a human epidermal growth factor receptor 2 (HER2) inhibitor that selectively binds to and inhibits the HER2 receptor, blocking the action of the HER2 protein to help slow or stop cancer cell growth in patients with advanced breast or colorectal cancer. Tucatinib and T-DM1 have a synergistic cytotoxic response when used in combination and exhibit enhanced antitumor activity in vivo. Mechanistically, Tucatinib mediates an increase in inactive HER2 molecules on the cell surface by inhibiting HER2 ubiquitination, which results in increased internalization and catabolism of T-DM1. The combination is associated with enhanced HER2 pathway inhibition, decreased proliferation, and increased apoptosis.

Side effects

The most common side effects of Tucatinib are gastrointestinal reactions, mainly manifested as diarrhea, nausea, vomiting and constipation. Other side effects include: anxiety, nosebleeds, decreased vision, burning, numbness, tingling or pain; clay-colored stools, dark urine, decreased or loss of appetite, dizziness, fever, headache, mood or mental changes, rash, itching, slow or fast heartbeat; swelling of the feet or calves; back pain, stomach pain or tenderness; unusual tiredness or weakness; cough, difficulty breathing and anemia, etc.

References:

[1] LEE A. Tucatinib: First Approval.[J]. Drugs, 2020, 80 10: 1033-1038. DOI:10.1007/s40265-020-01340-w.

[2] TOPLETZ-ERICKSON A, LEE A, MAYOR J G, et al. Pharmacokinetics and Safety of Tucatinib in Healthy Japanese and Caucasian Volunteers: Results From a Phase Ⅰ Study[J]. JAPANESE JOURNAL OF CLINICAL PHARMACOLOGY AND THERAPEUTICS, 2023, 56 1: 0. DOI:10.3999/jscpt.54.5\_187.