Side Effects of Osimertinib in NSCLC Treatment
Osimertinib demonstrates a favorable safety profile with grade 3 or higher adverse events occurring in only 34% of patients as monotherapy, significantly better than older-generation EGFR TKIs (45%) and substantially superior to platinum-based chemotherapy (47% vs 23%). 1, 2
Overall Adverse Event Profile
Common Side Effects (Any Grade)
Based on the FLAURA trial, the most frequent adverse events with osimertinib monotherapy include: 3
Dermatologic toxicities:
Gastrointestinal effects:
Hematologic abnormalities:
Constitutional symptoms:
- Fatigue: 21% (grade ≥3: 1.4%) 3
Serious and Life-Threatening Adverse Events
Interstitial Lung Disease/Pneumonitis
ILD/pneumonitis represents the most critical safety concern with osimertinib, occurring in 3.9-56% of patients depending on the clinical setting, with fatal outcomes reported. 2, 3
- In the FLAURA trial, ILD/pneumonitis occurred in 3.9% of patients, with 2 respiratory failure deaths and 1 pneumonitis death reported 2, 3
- In the LAURA trial (adjuvant setting), ILD/pneumonitis occurred in 56% of patients (grade 3-4: 3.5%) 3
- Patients must be monitored for new or worsening respiratory symptoms including dyspnea, cough, or fever 3
- Osimertinib must be permanently discontinued if ILD/pneumonitis is confirmed 3
Cardiac Toxicity
QTc Prolongation:
- Osimertinib increases QTc interval in a dose-dependent manner 1
- QTc prolongation occurred in 10% of patients in FLAURA (grade ≥3: 2.2%) 3
- Patients with baseline QTc >470 msec should not receive osimertinib 2
- Baseline and periodic ECG monitoring is required, especially in patients with cardiac risk factors 2
- Concomitant QT-prolonging medications must be discontinued or substituted before initiating therapy 2
Cardiomyopathy:
- Heart failure and cardiomyopathy can occur and may be fatal 3, 4
- Cardiac toxicity onset ranges from 1 to 28 months after initiation, with 70.59% occurring within the first 6 months 4
- Patients with pre-existing cardiac conditions (heart failure, hypertension) are at higher risk 4
- Symptoms include palpitations, shortness of breath, ankle swelling, dizziness, and lightheadedness 3
Severe Cutaneous Reactions
- Erythema multiforme major (EMM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) can occur 3
- Patients should immediately report target lesions or severe blistering/peeling of skin 3
Cutaneous Vasculitis
- Presents as multiple non-blanching red papules on forearms, lower legs, or buttocks 3
- May appear as large hives on trunk that persist >24 hours with bruised appearance 3
Aplastic Anemia
- Osimertinib can cause bone marrow failure leading to aplastic anemia, which may be fatal 3
- Monitor complete blood counts before and during treatment 3
- Patients should report new/persistent fevers, bruising, bleeding, pallor, infection, or weakness 3
Ocular Toxicity
- Keratitis can occur (0.4% in FLAURA) 3
- Patients should report eye inflammation, lacrimation, photophobia, eye pain, redness, or vision changes 3
- Ophthalmology referral is indicated if eye problems develop 3
Hematologic Management Considerations
For lymphopenia specifically: 5
- Continue osimertinib without dose modification for grades 1-3 lymphopenia (≥250/mm³) 5
- For grade 4 lymphopenia (<250/mm³), implement prophylaxis including MAC, PCP, CMV screening, and consider HIV/hepatitis screening 5
- Do not use G-CSF for isolated lymphopenia as it is ineffective for lymphocyte recovery 5
Comparative Safety Context
Osimertinib demonstrates superior tolerability compared to first/second-generation EGFR TKIs: 1
- Grade ≥3 adverse events: 34% with osimertinib vs 45% with erlotinib/gefitinib 1
- CNS progression events: 6% with osimertinib vs 15% with erlotinib/gefitinib 1
When combined with chemotherapy (FLAURA2 trial): 1
- Grade 3 adverse events increase but are primarily driven by chemotherapy-related toxicities 1