II. Indications
- Non-Small Cell Lung Cancer (ALK+ fusion, metastatic)
III. Mechanism
- Anaplastic Lymphoma Kinase (ALK Tyrosine Kinase)
- ALK Receptors are Insulin receptors key to Central Nervous System development
- Also found in the developing Small Intestine and Testes
- ALK receptors are not normally expressed in adults
- ALK receptors are expressed in certain cancers, associated with gene dysregulation
- Non-Small Cell Lung Cancer
- Anaplastic large cell Lymphoma
- ALK Receptors are Insulin receptors key to Central Nervous System development
- ALK Receptor Antagonists are small molecule, Tyrosine Kinase Inhibitors specific to ALK receptors
- Agents that block ALK, suppress specific tumor cell growth
IV. Medications
- Alectinib (Alecensa)
- Multi-kinase Inhibitor
- Adverse effects include hepatotoxicity, Interstitial Lung Disease (ILD), Bradycardia, CPK Increase
- No major Drug Interactions
- Brigatinib (Alunbrig)
- Adverse effects include ILD, Bradycardia, Hypertension, Vision change, CPK increase, Pancreatitis, Hyperglycemia
- Drug Interactions include strong CYP3A4 inhibitors and inducers (also may render OCPs ineffective)
- Ceritinib (Zykadia)
- Multi-kinase Inhibitor
- Adverse Effects include hepatotoxicity, Pancreatitis, ILD, Bradycardia, QT Prolongation, Hyperglycemia
- Increased absorption with fatty meal (and decreased with Proton Pump Inhibitors)
- Crizotinib (Xalkori)
- Also blocks c-Met/hepatocyte growth factor receptor (HGFR); aso blocks ROS1 (see ROS1 Inhibitor)
- Adverse Effects include ILD, hepatotoxicity, Bradycardia, QT Prolongation
- Lorlatinib (Lorbrena)
- Adverse Effects include hepatotoxicity, ILD, CNS effects, Hyperlipidemia, AV Block
- Drug Interactions include strong CYP3A4 inhibitors and inducers (also may render OCPs ineffective)
V. Adverse Effects
- Cardiovascular
- Bradycardia (all agents)
- QTc Prolongation (Ceritinib, Crizotinib)
- Hypertension (Brigatinib)
- AV Block (Lorlatinib)
- Hepatotoxicity
- Primarily occurs with Alectinib, Ceritinib, Crizotinib, Lorlatinib
- Monitor Liver Function Tests every 2 weeks during the first 3 months of therapy (esp. Alectinib)
-
Interstitial Lung Disease (ILD) or Pneumonitis
- Occurs with all agents: Brigatinib (9%), Alectinib (0.4%), Ceritinib, Crizotinib, Lorlatinib
-
Creatine Phosphokinase (CPK) Increased or severe myalgias
- Occurs with Alectinib (up to 4%) and Brigatinib
-
Lipase Elevation or Pancreatitis
- Occurs with Brigatinib and Ceritinib
-
Hyperglycemia
- Occurs with Brigatinib, Ceritinib
-
Hyperlipidemia
- Occurs with Lorlatinib
- Ocular Toxicity or visual disturbance
- Occurs with Brigatinib
- CNS Toxicity (Seizures, altered cognitive function, Hallucinations, altered speech)
- Occurs with Lorlatinib
- Nausea or Vomiting
VI. Safety
- Avoid in Lactation
- Avoid in pregnancy (all trimesters)
- Use reliable Contraception
- Use non-Hormonal Contraception with Brigatinib, Ceritinib, Lorlatinib (OCPs may fail)
VII. Efficacy
- Alectinib is highly effective in advanced ALK Lung Cancer
VIII. Drug Interactions
- Strong CYP3A4 inhibitors and inducers
- Brigatinib, Ceritinib, Lorlatinib
-
Proton Pump Inhibitors
- Ceritinib
IX. Resources
- Alectinib (DailyMed)
- Brigatinib (DailyMed)
- Ceritinib (DailyMed)
- Crizotinib (DailyMed)
- Lorlatinib (DailyMed)