Tucatinib

Class:

Selective HER2 Tyrosine Kinase Inhibitor (TKI)

Mechanism of Action:

• Inhibits the intracellular tyrosine kinase domain of HER2 with high selectivity.
• Blocks HER2 signaling pathways involved in tumor cell proliferation and survival.
• Minimal activity against EGFR, leading to fewer EGFR-related toxicities.

Indications:

• Treatment of adult patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, in combination with trastuzumab and capecitabine after one or more prior anti-HER2-based regimens in the metastatic setting.

Dosing & Administration:

• Dose: 300 mg orally twice daily (approximately 12 hours apart), continuously.
• Taken with or without food.
• Continue trastuzumab and capecitabine as per their prescribing information.

Pharmacokinetics:

• Absorption: Oral bioavailability not significantly affected by food.
• Metabolism: Primarily by CYP3A4 and minor by CYP2C8.
• Half-life: Approximately 19 hours.
• Elimination: Mainly fecal.

Common Adverse Effects:

• Diarrhea (often manageable, but can be severe)
• Palmar-plantar erythrodysesthesia (hand-foot syndrome)
• Fatigue
• Nausea, vomiting
• Hepatotoxicity (elevated AST, ALT)
• Stomatitis
• Anemia

Monitoring:

• Liver function tests (baseline, then periodically)
• Complete blood counts
• Monitor for diarrhea and manage promptly to prevent dehydration
• Assess skin for hand-foot syndrome and provide supportive care

Drug Interactions:

• Substrate of CYP3A4 → avoid strong CYP3A4 inhibitors or inducers.
• Potential interaction with P-gp substrates.
• Monitor and adjust co-administered drugs accordingly.

Practice Pearls:

• Tucatinib’s high HER2 selectivity offers efficacy with reduced EGFR-associated toxicities like rash and stomatitis compared to less selective TKIs.
• Especially valuable in patients with brain metastases due to CNS penetration.
• Educate patients to promptly report diarrhea and manage early with antidiarrheal agents.
• Regular liver monitoring is important due to risk of hepatotoxicity.

Key Takeaway:

Tucatinib is an effective, selective oral HER2 inhibitor for advanced HER2-positive breast cancer, particularly useful in heavily pretreated patients and those with brain metastases, with a manageable safety profile requiring proactive toxicity monitoring.