Pharm

ALK Inhibitor

ALK Inhibitor, ALK Tyrosine Kinase, Anaplastic Lymphoma Kinase Inhibitor, CD246, Alectinib, Alecensa, Brigatinib, Alunbrig, Ceritinib, Zykadia, Crizotinib, Xalkori, Lorlatinib, Lorbrena

See Also

Indications

Non-Small Cell Lung Cancer (ALK+ fusion, metastatic)

Mechanism

Anaplastic Lymphoma Kinase (ALK Tyrosine Kinase)
1. ALK Receptors are Insulin receptors key to Central Nervous System development
  1. Also found in the developing Small Intestine and Testes
2. ALK receptors are not normally expressed in adults
3. ALK receptors are expressed in certain cancers, associated with gene dysregulation
  1. Non-Small Cell Lung Cancer
  2. Anaplastic large cell Lymphoma
ALK Receptor Antagonists are small molecule, Tyrosine Kinase Inhibitors specific to ALK receptors
1. Agents that block ALK, suppress specific tumor cell growth

Medications

Alectinib (Alecensa)
1. Multi-kinase Inhibitor
2. Adverse effects include hepatotoxicity, Interstitial Lung Disease (ILD), Bradycardia, CPK Increase
3. No major Drug Interactions
Brigatinib (Alunbrig)
1. Adverse effects include ILD, Bradycardia, Hypertension, Vision change, CPK increase, Pancreatitis, Hyperglycemia
2. Drug Interactions include strong CYP3A4 inhibitors and inducers (also may render OCPs ineffective)
Ceritinib (Zykadia)
1. Multi-kinase Inhibitor
2. Adverse Effects include hepatotoxicity, Pancreatitis, ILD, Bradycardia, QT Prolongation, Hyperglycemia
3. Increased absorption with fatty meal (and decreased with Proton Pump Inhibitors)
Crizotinib (Xalkori)
1. Also blocks c-Met/hepatocyte growth factor receptor (HGFR); aso blocks ROS1 (see ROS1 Inhibitor)
2. Adverse Effects include ILD, hepatotoxicity, Bradycardia, QT Prolongation
Lorlatinib (Lorbrena)
1. Adverse Effects include hepatotoxicity, ILD, CNS effects, Hyperlipidemia, AV Block
2. Drug Interactions include strong CYP3A4 inhibitors and inducers (also may render OCPs ineffective)

Adverse Effects

Cardiovascular
1. Bradycardia (all agents)
2. QTc Prolongation (Ceritinib, Crizotinib)
3. Hypertension (Brigatinib)
4. AV Block (Lorlatinib)
Hepatotoxicity
1. Primarily occurs with Alectinib, Ceritinib, Crizotinib, Lorlatinib
2. Monitor Liver Function Tests every 2 weeks during the first 3 months of therapy (esp. Alectinib)
Interstitial Lung Disease (ILD) or Pneumonitis
1. Occurs with all agents: Brigatinib (9%), Alectinib (0.4%), Ceritinib, Crizotinib, Lorlatinib
Creatine Phosphokinase (CPK) Increased or severe myalgias
1. Occurs with Alectinib (up to 4%) and Brigatinib
Lipase Elevation or Pancreatitis
1. Occurs with Brigatinib and Ceritinib
Hyperglycemia
1. Occurs with Brigatinib, Ceritinib
Hyperlipidemia
1. Occurs with Lorlatinib
Ocular Toxicity or visual disturbance
1. Occurs with Brigatinib
CNS Toxicity (Seizures, altered cognitive function, Hallucinations, altered speech)
1. Occurs with Lorlatinib
Nausea or Vomiting

Safety

Avoid in Lactation
Avoid in pregnancy (all trimesters)
1. Use reliable Contraception
2. Use non-Hormonal Contraception with Brigatinib, Ceritinib, Lorlatinib (OCPs may fail)

Efficacy

Alectinib is highly effective in advanced ALK Lung Cancer

Drug Interactions

Strong CYP3A4 inhibitors and inducers
1. Brigatinib, Ceritinib, Lorlatinib
Proton Pump Inhibitors
1. Ceritinib

Resources

Alectinib (DailyMed)
1. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=42c49deb-713b-427a-9670-08af08adcffb
Brigatinib (DailyMed)
1. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0fe9ff20-d402-41f3-bc1e-7002ea7007db
Ceritinib (DailyMed)
1. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=fff5d805-4ffd-4e8e-8e63-6f129697563e
Crizotinib (DailyMed)
1. https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=2a51b0de-47d6-455e-a94c-d2c737b04ff7
Lorlatinib (DailyMed)
1. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2b34d62d-e02a-4af3-bc0d-1571dd4ee76d

References