Common Specific Side Effects of EGFR TKIs
All EGFR TKIs share common cutaneous and gastrointestinal adverse events, but each agent has distinct toxicity profiles that should guide selection and monitoring strategies. 1
Shared Class Effects Across All EGFR TKIs
Cutaneous Toxicities
- Rash occurs in 54-89% of patients across all EGFR TKIs, with Grade ≥3 severity in 0-16.2% 1
- Dry skin, pruritus, and paronychia are common cutaneous manifestations requiring prophylactic emollient use 1
- Cutaneous adverse events typically onset during the first month of treatment and can be prevented with regular emollient application 1
Gastrointestinal Toxicities
- Diarrhea is experienced by the majority of patients, managed with loperamide and dietary modifications (low-fat, low-fiber diet; minimizing fruit, red meat, alcohol, spicy food, and caffeine) 1
- Stomatitis and mucositis occur commonly across the class 1
Agent-Specific Toxicity Profiles
Osimertinib (Third-Generation)
- Superior safety profile with Grade ≥3 adverse events in only 34% versus 45% with first-generation TKIs 1, 2
- Improved toxicity compared to gefitinib/erlotinib, with lower rates of serious adverse events 1, 2
- Median time to rash onset: not specifically reported but generally better tolerated 2
Gefitinib (First-Generation)
- Rash incidence: 85% (all grades), 14% Grade 3-4 3
- Diarrhea incidence: 62% (all grades), 5% Grade 3-4 3
- Hepatotoxicity: Grade 3-4 liver test abnormalities can occur, including rare fatal hepatic failure 4, 3
- Skin reactions: redness, rash, itching, and acne are common; severe reactions including peeling or blistering require immediate medical attention 4
- Ocular problems: watery eyes, sensitivity to light, blurred vision, eye pain, and redness 4
- Lower rates of dose reduction and treatment discontinuation compared to erlotinib 5
Erlotinib (First-Generation)
- Rash incidence: 60-85% (all grades), 9-14% Grade 3-4 3
- Diarrhea incidence: 20-62% (all grades), 2-5% Grade 3-4 3
- Higher rates of rash and diarrhea compared to gefitinib, with median time to rash onset of 10-15 days and diarrhea onset of 15-32 days 3
- Hepatotoxicity: ALT elevations Grade ≥2 in 3% of patients; bilirubin elevations Grade ≥2 in 5% 3
- Dose modifications: required in 37% of patients, with 5% needing reduction for rash and 3% for diarrhea 3
- Minimal neutropenia risk compared to chemotherapy, with no routine blood count monitoring required 6
Afatinib (Second-Generation)
- Higher incidence of Grade 3 skin and gastrointestinal toxicity compared to first-generation TKIs 1
- Significant proportion requires dose reduction due to toxicity 1
- Diarrhea: 13% Grade 3 versus 1% with gefitinib 1
- Liver enzyme elevations: 0% Grade 3 versus 9% with gefitinib 1
- More serious treatment-related side effects: 11% versus 4% with gefitinib 1
- Grade 3/4 adverse events rate comparable to erlotinib but higher than gefitinib 5
Dacomitinib (Second-Generation)
- Higher incidence of Grade 3 skin and gastrointestinal toxicity similar to afatinib 1
- Significant proportion requires dose reduction 1
- Specific toxicity data limited in provided evidence but follows second-generation TKI pattern 1
Critical Management Considerations
Monitoring Schedule
- Bi-weekly follow-up during first 6 weeks of treatment, then monthly thereafter 1
Dose Modification Triggers
- Grade 2 toxicity: dose reduction or interruption appropriate if prolonged or intolerable 1
- Diarrhea persisting >48 hours: discontinue drug and restart with dose reduction when toxicity returns to Grade 1 or baseline 1