Tucatinib

Approved Indications:

• HER2-positive metastatic breast cancer:
  Tucatinib is indicated in combination with trastuzumab and capecitabine for the treatment of adult patients with advanced unresectable or metastatic HER2-positive breast cancer, including those with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting.

Off-Label or Clinically Accepted Uses:

• HER2-positive gastric and gastroesophageal junction (GEJ) cancers (investigational/early-phase clinical acceptance):
  In selected patients with HER2-positive metastatic gastric or GEJ adenocarcinoma, Tucatinib has shown benefit when combined with trastuzumab and chemotherapy.
• HER2-positive colorectal cancer (early-stage research and clinical trials):
  Tucatinib is being explored in combination therapy for HER2-amplified metastatic colorectal carcinoma in refractory settings.

Adults (including elderly):

• Standard dose: Tucatinib 300 mg orally twice daily (morning and evening, approximately 12 hours apart).
• In combination with:
• Trastuzumab (6 mg/kg IV every 3 weeks after an 8 mg/kg loading dose)
• Capecitabine (1000 mg/m² orally twice daily, Days 1–14 of a 21-day cycle)

Pediatric use:
Safety and efficacy in pediatric patients have not been established.

Renal impairment:

• Mild to moderate (eGFR ≥30 mL/min): No dose adjustment needed.
• Severe (eGFR <30 mL/min): Use with caution; clinical data are limited.

Hepatic impairment:

• Mild (Child-Pugh A): No dose adjustment required.
• Moderate (Child-Pugh B): Reduce dose to 200 mg twice daily.
• Severe (Child-Pugh C): Not recommended due to lack of data.

Administration Tips:

• Administer with or without food.
• Swallow tablets whole; do not crush, split, or chew.
• Continue treatment until disease progression or unacceptable toxicity.

Tucatinib is a potent and highly selective oral tyrosine kinase inhibitor (TKI) that specifically targets the HER2 (human epidermal growth factor receptor 2) intracellular kinase domain. By inhibiting HER2 phosphorylation, tucatinib blocks downstream signaling pathways, including PI3K/AKT and MAPK/ERK, which are responsible for cellular proliferation and survival in HER2-positive tumor cells. Its high selectivity for HER2 over EGFR minimizes off-target effects such as skin and gastrointestinal toxicity often seen with dual EGFR/HER2 inhibitors. This targeted mechanism allows tucatinib to enhance antitumor activity, particularly in HER2-driven metastatic cancers, including those with central nervous system involvement.

• Absorption:
  Oral bioavailability is high; Tmax is approximately 2 hours post-dose.
• Distribution:
  Volume of distribution: ~1670 L
  High plasma protein binding (>99.9%).
• Metabolism:
  Primarily metabolized by CYP2C8 and to a lesser extent by CYP3A4.
  Forms inactive oxidative metabolites.
• Elimination:
  Terminal half-life: ~8.5 hours
  Excretion: ~86% via feces (25% unchanged); ~4% via urine
• Steady-state: Achieved within 4–5 days of twice-daily dosing.

• Pregnancy:
  Based on animal studies and mechanism of action, tucatinib can cause fetal harm.
  Avoid use during pregnancy. Use effective contraception during and for at least 1 week after the last dose.
• Lactation:
  Unknown if excreted in human milk.
  Breastfeeding is not recommended during therapy and for 1 week after the last dose due to potential infant harm.

• Primary class: Antineoplastic Agent
• Subclass: Tyrosine Kinase Inhibitor (TKI), HER2-selective
• Generation: Selective next-generation HER2 TKI

• Known hypersensitivity to tucatinib or any of its excipients
• Severe hepatic impairment (Child-Pugh C)
• Concomitant use with strong CYP2C8 inhibitors or inducers, if alternative is unavailable

• Hepatotoxicity:
  Monitor liver enzymes (ALT, AST, bilirubin) at baseline and during treatment.
• Diarrhea:
  Common and can be severe; initiate antidiarrheals at first sign. Monitor hydration and electrolytes.
• Embryo-fetal toxicity:
  Can cause fetal harm. Confirm pregnancy status before initiating therapy.
• CNS metastases:
  Tucatinib crosses the blood-brain barrier; monitor for neurologic symptoms.
• Drug interactions:
  Caution with CYP2C8 inhibitors/inducers and P-gp substrates.
• QT prolongation:
  Monitor ECG in patients with cardiac risk or those on QT-prolonging drugs.

Common (≥10%):

• Gastrointestinal: Diarrhea, nausea, vomiting, decreased appetite
• General: Fatigue, hand-foot syndrome
• Laboratory: Elevated ALT/AST, increased bilirubin

Less Common (1–10%):

• Stomatitis, abdominal pain
• Headache, dizziness
• Anemia, neutropenia

Serious/Rare (<1%):

• Severe hepatotoxicity
• Severe diarrhea with dehydration or renal dysfunction
• QT interval prolongation
• Hypersensitivity reactions

• CYP2C8 inhibitors (e.g., gemfibrozil):
  May significantly increase tucatinib exposure → Avoid combination.
• CYP3A4 inducers (e.g., rifampin, phenytoin):
  May reduce efficacy by lowering tucatinib levels.
• P-glycoprotein substrates (e.g., digoxin):
  Tucatinib is a P-gp inhibitor, which may increase substrate levels → Monitor closely.
• Capecitabine & Trastuzumab:
  Safe and synergistic in combination when used in recommended regimens.
• Food/alcohol interactions:
  No major interactions known.

• FDA approval update (April 2020):
  Tucatinib was approved in combination with trastuzumab and capecitabine for HER2+ metastatic breast cancer including CNS metastases.
• NCCN guidelines (2024):
  Tucatinib triple combination is now preferred regimen for patients with progressive HER2+ brain metastases.
• Ongoing trials (HER2CLIMB-02, MOUNTAINEER):
  Expanding use in gastric and colorectal cancers; regulatory review pending.

• Temperature: Store below 30°C (86°F)
• Humidity & Light: Store in a dry place, protected from excessive moisture and light
• Container: Keep in original container with the lid tightly closed
• Handling: No refrigeration required; do not freeze
• Reconstitution: Not applicable; oral tablets only