Tucatinib/tucatinib are several generations of targeted drugs

Tucatinib/Tucatinib is a third-generation targeted drug. The development of targeted therapies has transformed the treatment of HER2-positive breast cancer. Dual blockade with the monoclonal antibodies trastuzumab and pertuzumab, coupled with first-line taxane chemotherapy and second-line treatment with the antibody drug conjugate T-DM1, is the internationally recognized standard of care for advanced HER2-positive breast cancer. However, until recently, options for patients receiving third-line and beyond therapies were ineffective or limited by toxicity. In 2019, trial results were presented for two exciting new drugs targeting this area.

Tucatinib is a highly selective, ATP-competitive small molecule TKI with nanomolar potency against the HER2 receptor. Cell-based analysis demonstrated that tucatinib is 1,000 times more specific for HER2 than EGFR. The third-generation HER2 tyrosine kinase inhibitor (TKI) tucatinib combines the efficacy of the second-generation drug neratinib with more manageable toxicity, and is used in combination with capecitabine and trastuzumab to become the new standard of treatment after T-DM1. The antibody-drug conjugate trastuzumab showed significant efficacy in a large number of pre-treated patients and received accelerated approval in the United States, while completing confirmatory Phase 3 trials.

In vitro models demonstrate that tucatinib strongly blocks the phosphorylation of HER2 and its downstream effector AKT3 in cell lines overexpressingHER2. In contrast, in EGFR-amplified cell lines, phosphorylation and proliferation were only weakly inhibited. Furthermore, tucatinib essentially inhibits the truncated form of HER2 in the setting of p95/p110 mutations, which are known to confer resistance to trastuzumab. In a HER2+ mouse xenograft model, tucatinib and its active metabolite showed better central nervous system penetration and intracranial tumor activity compared with neratinib or lapatinib. This resulted in prolonged survival of mice with intracranial HER2+ tumors treated with tucatinib monotherapy.