From the Guidelines
Osimertinib can cause significant pulmonary toxicity, with an incidence of all-grade pneumonitis of 3.01% and high-grade pneumonitis of 0.56%, as reported in a recent meta-analysis 1.
Key Findings
- The incidence of pneumonitis associated with osimertinib therapy is a significant concern, with a reported overall incidence of 4% in a recent phase III first-line treatment of osimertinib for EGFR-mutant NSCLC 1.
- The radiologic patterns of osimertinib-related pneumonitis include organizing pneumonia, diffuse alveolar damage, hypersensitivity pneumonitis, and nonspecific interstitial pneumonia 1.
- Patients with a history of ILD, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active ILD should not receive osimertinib due to the increased risk of pulmonary toxicity.
Clinical Implications
- If a patient develops respiratory symptoms while on osimertinib, treatment should be interrupted immediately and a thorough evaluation including imaging (high-resolution CT scan) should be performed 1.
- If ILD is confirmed, osimertinib should be permanently discontinued, and corticosteroid treatment (prednisone 1-2 mg/kg/day or equivalent) should be initiated.
- Regular monitoring of pulmonary symptoms is essential throughout the treatment course, and patients should be educated about promptly reporting any respiratory changes.
Mechanism of Toxicity
- The mechanism behind osimertinib's pulmonary toxicity relates to its inhibition of EGFR signaling in lung tissue, which can disrupt normal repair processes and lead to inflammatory reactions 1.
From the FDA Drug Label
Interstitial lung disease (3.9%), interstitial lung disease (3.3%), interstitial lung disease (2.7%), interstitial lung disease (3%) The pulmonary toxicity of Osimertinib (Tagrisso, Azd9291) includes interstitial lung disease (ILD), which occurred in approximately 3-4% of patients in the clinical trials 2, 2.
- ILD was a serious adverse reaction that led to permanent discontinuation of TAGRISSO in some patients.
- The exact incidence of ILD may vary depending on the specific patient population and trial.
- Pulmonary embolism was also reported as a fatal adverse reaction in some patients 2.
- Other pulmonary-related adverse reactions included cough and dyspnea 2, 2.
From the Research
Pulmonary Toxicity of Osimertinib
The pulmonary toxicity of Osimertinib (Tagrisso, Azd9291) has been reported in several studies, with adverse pulmonary events being rare but potentially severe 3, 4, 5. The most common pulmonary toxicities associated with Osimertinib include:
- Interstitial lung disease (ILD) 3, 4, 6
- Interstitial pneumonia 3
- Diffuse alveolar damage 3
- Diffuse alveolar hemorrhage (DAH) 5
- Eosinophilic pneumonia 5
- Nonspecific interstitial pneumonia 5
- Organizing pneumonia 6
Risk Factors and Management
The risk of pulmonary toxicity with Osimertinib is higher in Japanese patients compared to the Caucasian population 3. The management of Osimertinib-induced pulmonary toxicity may involve discontinuation of the drug, dose reduction, or rechallenge with another EGFR tyrosine kinase inhibitor (TKI) 4, 6. Corticosteroid therapy may also be used to manage pulmonary toxicity 3, 4. A study found that a preventive dose reduction in patients with high Osimertinib exposure (>259 ng/mL) could reduce the risk of severe toxicity by 53% without affecting efficacy 7.
Rechallenge with Osimertinib or Other EGFR TKIs
Rechallenge with Osimertinib or other EGFR TKIs may be considered in patients who have experienced pulmonary toxicity, particularly those with grade 1 ILD 4. A study reported successful rechallenge with afatinib after Osimertinib-induced ILD 6. However, the decision to rechallenge with Osimertinib or another EGFR TKI should be made on a case-by-case basis, taking into account the severity of the pulmonary toxicity and the patient's overall clinical condition 4, 6.