Tucatinib — Drug Monograph

Brand names: Tukysa

Drug class: Tyrosine Kinase Inhibitor

Mechanism of Action

Highly selective HER2 (ErbB2) tyrosine kinase inhibitor with minimal EGFR inhibition (unlike lapatinib or neratinib), reducing EGFR-mediated toxicities such as rash and mucositis. Inhibits HER2 kinase domain, blocking downstream PI3K/AKT and RAS/MAPK signaling. CNS-penetrant, with significant activity against brain metastases.

FDA Indications

• HER2-positive metastatic breast cancer in combination with trastuzumab and capecitabine after ≥1 prior anti-HER2 regimen (FDA approved April 2020; HER2CLIMB: OS HR 0.66; 49.9% reduction in brain progression risk)
• HER2-positive (IHC 3+ or ISH amplified) unresectable or metastatic colorectal cancer in combination with trastuzumab (FDA approved 2023; MOUNTAINEER: 38.1% ORR)

Common Side Effects

• Diarrhea (81% — most common)
• Palmar-plantar erythrodysesthesia (hand-foot syndrome, from capecitabine)
• Nausea (58%)
• Fatigue (45%)
• Hepatotoxicity (ALT/AST elevation)
• Vomiting (36%)
• Stomatitis
• Decreased appetite

Clinical Pearl

Tucatinib's high selectivity for HER2 over EGFR results in significantly less rash and mucositis compared to lapatinib/neratinib. It is the only HER2 TKI with demonstrated significant CNS activity in HER2CLIMB, reducing the risk of brain progression by ~50%. It is a potent CYP2C8 inhibitor, necessitating dose reductions for co-administered CYP2C8 substrates such as paclitaxel.

Related Therapies & Mechanisms

• Alpelisib (Piqray) — Tyrosine Kinase Inhibitor · Breast
• Encorafenib (Braftovi) — Tyrosine Kinase Inhibitor · CRC
• Fruquintinib (Fruzaqla) — Tyrosine Kinase Inhibitor · CRC
• Regorafenib (Stivarga) — Tyrosine Kinase Inhibitor · CRC