Tucatinib: A Breakthrough in Advanced Breast Cancer Therapy

Abstract

Tucatinib is a highly selective tyrosine kinase inhibitor targeting the HER2 protein, representing a significant advancement in treating HER2-positive metastatic breast cancer (MBC), including cases with brain metastases. This review assesses the efficacy and safety of tucatinib in combination with trastuzumab and capecitabine. Tucatinib inhibits HER2 signalling through its intracellular tyrosine kinase domain, disrupting critical pathways such as PI3K/AKT and MAPK. The HER2CLIMB trial (N=612) showed that combining tucatinib with trastuzumab and capecitabine significantly improved progression-free survival (PFS) (9.9 vs. 4.2 months, 95% CI) and overall survival (OS) (21.6 vs. 12.5 months, 95% CI) compared to placebo, with notable efficacy in reducing brain metastases. The most common adverse events associated with tucatinib were diarrhoea [331 (81.9%)], palmar-plantar erythrodysesthesia [264 (65.3%)], nausea [264 (65.3%)], and vomiting [152 (37.6%)]. Despite these, the overall safety profile was manageable and tolerable. Current NCCN, ASCO, and ESMO guidelines endorse tucatinib for patients with HER2-positive MBC who have progressed through prior HER2-targeted therapies. Ongoing clinical trials investigate tucatinib's efficacy with other agents to overcome resistance mechanisms and enhance treatment outcomes. Future research should optimise combination therapies, manage long-term side effects, and identify predictive biomarkers to refine patient selection and treatment strategies. This review underscores tucatinib's pivotal role in advancing the management of HER2-positive MBC and highlights the need for continued exploration in this therapeutic area.