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)
Images: Related links to external sites (from Bing)
Related Studies
Definition (NCI) | An orally available aminopyridine-based inhibitor of the receptor tyrosine kinase anaplastic lymphoma kinase (ALK) and the c-Met/hepatocyte growth factor receptor (HGFR) with antineoplastic activity. Crizotinib, in an ATP-competitive manner, binds to and inhibits ALK kinase and ALK fusion proteins. In addition, crizotinib inhibits c-Met kinase, and disrupts the c-Met signaling pathway. Altogether, this agent inhibits tumor cell growth. ALK belongs to the insulin receptor superfamily and plays an important role in nervous system development. ALK dysregulation and gene rearrangements are associated with a series of tumors. |
Definition (NCI_NCI-GLOSS) | A substance being studied in the treatment of some types of cancer. It blocks enzymes that cancer cells need to grow and spread. It may also prevent the growth of new blood vessels that tumors need to grow. It is a type of tyrosine kinase inhibitor and a type of antiangiogenesis agent. |
Concepts | Organic Chemical (T109) , Pharmacologic Substance (T121) |
MSH | C551994 |
SnomedCT | 703637000, 703638005 |
English | (R)-3-(1-(2,6-Dichloro-3-Fluorophenyl)Ethoxy)-5-(1-(Piperidin-4-Yl)-1h-Pyrazol-4-Yl)Pyridin-2-Amine, crizotinib, CRIZOTINIB, 2-Pyridinamine, 3-((1R)-1-(2,6-Dichloro-3-Fluorophenyl)Ethoxy)-5-(1-(4-Piperidinyl)-1H-Pyrazol-4-yl)-, Crizotinib (substance), Crizotinib, Crizotinib (product) |
Ontology: ceritinib (C3818721)
Concepts | Pharmacologic Substance (T121) |
MSH | C586847 |
SnomedCT | 703146007 |
English | CERITINIB, Ceritinib, Ceritinib (substance), 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine, ceritinib |