Tucatinib Triplet Therapy: Efficacy, Safety and Clinical Decision-Making

EP: 1.Current Treatment Approaches in HER2+ Metastatic Breast Cancer

EP: 2.Optimizing Maintenance Therapy After First-Line Treatment in HER2+ Metastatic Breast Cancer

EP: 3.The Evolving Role of T-DXd in HER2+ Metastatic Breast Cancer

EP: 4.Strategies for Monitoring and Managing T-DXd-Related Adverse Effects

EP: 5.Patient Case Presentation: A 47-Year-Old Woman With HER2+ mBC and CNS Progression

EP: 6.Strategic Sequencing in HER2+ Breast Cancer: Optimizing Treatment in the Third Line and Beyond

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EP: 7.Tucatinib Triplet Therapy: Efficacy, Safety and Clinical Decision-Making

EP: 8.Expert Insights: Later-Line Treatment Strategies for HER2+ Metastatic Breast Cancer

EP: 9.Looking Ahead in HER2+ mBC: Unmet Needs, Future Perspectives and Highlights From ASCO 2025

The HER2CLIMB study evaluated the combination of tucatinib, trastuzumab, and capecitabine (T-DM1 plus tucatinib) versus T-DM1 alone in patients with HER2-positive metastatic breast cancer, particularly those with active brain metastases. The trial demonstrated a statistically significant progression-free survival (PFS) benefit of approximately 2 months with the addition of tucatinib. However, this modest gain was balanced against increased toxicity, notably gastrointestinal adverse effects such as diarrhea, nausea, and fatigue, as well as elevated liver enzymes. Despite these toxicities, the PFS improvement is considered clinically meaningful, especially in difficult-to-treat HER2-positive disease, including patients with central nervous system (CNS) involvement.

Regarding capecitabine toxicity, it is generally manageable and well tolerated in both the curative and metastatic settings. Most adverse effects related to capecitabine—particularly hand-foot syndrome and diarrhea—are usually mild to moderate (grade 1 or 2). Patient education on symptom management, such as using topical treatments for hand-foot syndrome and early intervention for diarrhea, helps maintain treatment adherence and quality of life. Dose adjustments are often the first step in managing toxicity before considering treatment interruption or discontinuation. Overall, the combination regimen is feasible for many patients, though the pill burden can be substantial, which requires patient counseling and support.

Importantly, tucatinib’s approval marks a significant advance in treating patients with brain metastases, offering intracranial disease control alongside systemic efficacy. While tucatinib is not solely a brain-directed therapy, it demonstrates activity in both CNS and extracranial sites. These benefits, combined with manageable adverse effects, make tucatinib-based regimens a valuable option for patients facing limited treatment choices due to brain involvement in metastatic HER2-positive breast cancer.