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

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Panelists highlighted that the HER2CLIMB study showed adding tucatinib to trastuzumab and capecitabine provides a meaningful progression-free survival benefit in HER2-positive metastatic breast cancer with brain metastases, balancing improved intracranial control against manageable toxicities like diarrhea and hand-foot syndrome, and underscored the importance of patient education and dose management to maintain adherence and quality of life.

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.

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