What are the side effects of lorlatinib?

Side Effects of Lorlatinib

Lorlatinib's most common side effects include hyperlipidemia, edema, increased weight, peripheral neuropathy, and cognitive effects, with hyperlipidemia being the most frequent and potentially requiring aggressive management. 1

Common Side Effects

Metabolic Effects

• Hyperlipidemia:
  • Occurs in 82.4% of patients 2
  • Includes both hypercholesterolemia and hypertriglyceridemia (60.7%) 2
  • May require lipid-lowering agents (81% of patients need at least one) 2
  • Can lead to grade 3-4 adverse events 1
  • In rare cases, can contribute to carotid artery stenosis requiring monitoring 3

Neurological Effects

• Peripheral neuropathy: Affects 43.7% of patients 2
• Cognitive effects: Occurs in 39.7% of patients 2
  • Can include memory impairment, confusion, and difficulty concentrating
  • Serious cognitive effects are rare (1%) but may require discontinuation 1
• Mood effects: Including depression, anxiety, or irritability 4

Physical Effects

• Edema: Affects 51.2% of patients 2
• Weight gain: Common side effect requiring monitoring 4
• Fatigue: Frequently reported 4

Gastrointestinal Effects

• Diarrhea: Common but typically mild to moderate 4
• Dyspnea: Reported in clinical trials 4

Severity and Management

The safety profile of lorlatinib is distinct from other ALK TKIs, with most adverse events being mild to moderate in severity 5. In the CROWN trial comparing lorlatinib to crizotinib:

• More grade 3-4 adverse events occurred with lorlatinib (72%) than with crizotinib (56%), mainly due to altered lipid levels 6
• Despite higher rates of adverse events, discontinuation rates were similar (7% for lorlatinib vs. 9% for crizotinib) 6

Management Strategies

Hyperlipidemia

• Initiate lipid-lowering agents promptly upon detection 3
• Consider dose reduction if severe or persistent despite medication 3
• Monitor for cardiovascular complications, including carotid ultrasound in severe cases 3

Neurological Effects

• Cognitive effects may require dose modification in severe cases 5
• Peripheral neuropathy can be managed with standard supportive care and dose adjustments 2

Physical Effects

• Monitor weight regularly
• Manage edema with standard medical therapy as needed 5

Drug Interactions

• Lorlatinib is both a substrate and inducer of the CYP3A enzyme system 5
• Contraindicated with strong CYP3A inducers 5
• Consider potential drug-drug interactions when prescribing supportive therapy 2

Special Considerations

For patients with brain metastases, the benefits of lorlatinib may outweigh the risks of side effects:

• Lorlatinib shows high intracranial response rates (82% in patients with measurable brain metastases) 6
• Complete intracranial response achieved in 71% of patients 1

Monitoring Recommendations

• Regular lipid panel monitoring
• Weight monitoring at each visit
• Neurological assessment for cognitive effects and peripheral neuropathy
• For patients with severe hyperlipidemia, consider cardiovascular risk assessment 3

Most side effects can be effectively managed with dose modification and/or standard supportive medical therapy, resulting in low rates of permanent discontinuation 2.