Important Side Effects of ALK TKIs
Each ALK tyrosine kinase inhibitor has a distinct toxicity profile that should guide drug selection based on patient comorbidities and risk factors, with gastrointestinal toxicity predominating for ceritinib, pleural effusions for crizotinib, hepatotoxicity for brigatinib and ceritinib, and lipid abnormalities for lorlatinib. 1
Crizotinib
Common Side Effects
- Eye disorders (vision disturbances), edema, and transient changes in renal function are relatively common but generally manageable 2
- Gastrointestinal effects including nausea, vomiting, and diarrhea occur frequently but are typically well-tolerated 2
- Response rates exceed 60% in ALK-positive NSCLC, with rapid symptom improvement (cough, dyspnea, pain) 2
Serious Adverse Events
- Life-threatening pneumonitis can occur and requires immediate discontinuation of crizotinib 2
- Median time to progression is approximately 7 months to 1 year 2
- Grade ≥3 adverse events occur in 44.6% of patients 1
Ceritinib
Dose-Dependent Toxicity
- Ceritinib 750 mg has the highest rate of grade ≥3 adverse events (71.3%) among ALK TKIs, while the 450 mg dose shows 64.8% 1
- Gastrointestinal adverse events are most prominent with ceritinib 750 mg, including severe diarrhea and nausea 1
- Hepatic transaminase elevation is frequently observed with ceritinib 1
Management Considerations
- Ceritinib 750 mg has the highest rate of dose reduction among all ALK TKIs due to adverse events 1
- Treatment discontinuation rates remain relatively low (3.8-10.5%) despite high toxicity burden 1
Alectinib
Favorable Safety Profile
- Grade ≥3 adverse events occur in only 37.4% of patients, among the lowest rates of ALK TKIs 1
- Lowest rate of dose reduction due to adverse events compared to other ALK TKIs 1
- Generally well-tolerated with manageable toxicity spectrum 1, 3
Brigatinib
Hepatotoxicity Risk
- Hepatic transaminase elevation is a prominent concern with brigatinib 1
- Grade ≥3 adverse events occur in 72.8% of patients 1
- Second highest rate of dose reduction among ALK TKIs (after ceritinib 750 mg) 1
Lorlatinib
Unique Metabolic Effects
- Hypertriglyceridemia and hypercholesterolemia occur at high incidence with lorlatinib, which are rarely reported with other ALK inhibitors 1
- Grade ≥3 adverse events occur in 72.4% of patients 1
- Requires specific monitoring of lipid profiles not typically needed with other ALK TKIs 1
Ensartinib
Dermatologic Toxicity
- Rash occurs frequently with ensartinib compared to other ALK TKIs 1
- Grade ≥3 adverse events occur in 35.3% of patients 1
- Intermediate rate of dose reduction due to adverse events 1
General ALK TKI Considerations
Common Across All Agents
- Almost all patients receiving ALK inhibitor monotherapy experience at least one adverse event 1
- Treatment discontinuation rates due to adverse events remain low (3.8-10.5%) across all ALK TKIs despite high overall toxicity rates 1
- Frequency and severity of adverse effects vary significantly across different trials, making direct comparisons challenging 3
Clinical Practice Implications
- Drug selection should prioritize patient-specific risk factors: avoid ceritinib in patients with baseline gastrointestinal issues, consider alectinib for patients requiring better tolerability, and monitor lipids closely with lorlatinib 1
- Dose modifications are frequently required but rarely necessitate complete treatment discontinuation 1
- Sequential use of different ALK TKIs is common in clinical practice, with 95% of patients following guideline-concordant therapy sequences 4