Introduction
Osimertinib (Tagrisso®) is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor specifically designed to target both EGFR-sensitizing mutations and the T790M resistance mutation. Approved by the FDA in 2015, it represents a significant advancement in the treatment of non-small cell lung cancer (NSCLC) with specific EGFR mutations.
Mechanism of Action
Osimertinib is an irreversible EGFR tyrosine kinase inhibitor that selectively targets both EGFR tyrosine kinase inhibitor-sensitizing mutations (exon 19 deletion and L858R) and the T790M resistance mutation. It forms covalent bonds with cysteine-797 in the ATP-binding site of EGFR, thereby inhibiting EGFR-mediated signaling pathways that promote tumor cell proliferation and survival. Osimertinib demonstrates significantly less activity against wild-type EGFR compared to first-generation EGFR TKIs, potentially reducing skin and gastrointestinal toxicities.
Indications
- First-line treatment of metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R mutations
- Treatment of metastatic EGFR T790M mutation-positive NSCLC in patients who have progressed on or after EGFR TKI therapy
- Adjuvant treatment following tumor resection in NSCLC patients with EGFR exon 19 deletions or exon 21 L858R mutations
Dosage and Administration
Standard dosing: 80 mg orally once daily Administration: With or without food. Tablets should be swallowed whole with water. Dose modification: Recommended for certain adverse reactions (see package insert for specific guidance) Special populations:- Renal impairment: No dose adjustment needed for mild to moderate impairment
- Hepatic impairment: No dose adjustment needed for mild to moderate impairment
- Elderly: No dose adjustment required
- Pediatric: Safety and effectiveness not established
Pharmacokinetics
Absorption: Median Tmax is 6 hours (range 3-24 hours). Food does not significantly affect exposure. Distribution: Mean apparent volume of distribution is 918 L. Plasma protein binding is 95%. Metabolism: Primarily metabolized by CYP3A4 and CYP3A5 via oxidation and dealkylation pathways. Elimination: Mean elimination half-life is 48 hours. Excretion is primarily fecal (68%) with renal elimination accounting for 14% of the dose.Contraindications
- Hypersensitivity to osimertinib or any component of the formulation
Warnings and Precautions
Interstitial Lung Disease (ILD): Occurred in 3.9% of patients, with 0.8% fatalities. Monitor for pulmonary symptoms and permanently discontinue if ILD is confirmed. QTc Interval Prolongation: Monitor ECG and electrolytes in patients with cardiac risk factors or those taking concomitant QT-prolonging drugs. Cardiomyopathy: Occurred in 3% of patients. Assess left ventricular ejection fraction at baseline and during treatment. Keratitis: Reported in 0.7% of patients. Promptly refer patients presenting with eye symptoms to ophthalmology. Skin Toxicity: Including erythema, acneiform rash, and dry skin. Manage with supportive care. Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of potential risk.Drug Interactions
Strong CYP3A Inducers: Avoid concomitant use (e.g., rifampin, carbamazepine, St. John's wort) as they may decrease osimertinib exposure. Strong CYP3A Inhibitors: Avoid concomitant use (e.g., ketoconazole, ritonavir) as they may increase osimertinib exposure. QTc-Prolonging Drugs: Use with caution when co-administered with other drugs known to prolong QTc interval.Adverse Effects
Most common (≥20%): Diarrhea (47%), rash (41%), dry skin (33%), nail toxicity (32%), fatigue (29%) Serious adverse reactions:- Interstitial lung disease/pneumonitis (3.9%)
- QTc interval prolongation (3.3%)
- Cardiomyopathy (3%)
- Keratitis (0.7%)
Monitoring Parameters
- Baseline and periodic assessment of cardiac function (ECG, echocardiogram)
- Respiratory symptoms suggestive of ILD
- Liver function tests
- Renal function
- Electrolytes (particularly potassium and magnesium)
- Ophthalmologic examinations if visual symptoms occur
- Skin and nail changes
- Pregnancy status in women of reproductive potential
Patient Education
- Take exactly as prescribed; do not stop or change dose without consulting your healthcare provider
- Report any new or worsening respiratory symptoms immediately
- Inform all healthcare providers about all medications you are taking
- Use effective contraception during treatment and for 6 weeks after final dose
- Report eye pain, redness, or vision changes promptly
- Maintain adequate hydration if experiencing diarrhea
- Use sunscreen and moisturizers as skin may become more sensitive
- Do not crush or chew tablets
- Keep all follow-up appointments for monitoring
References
1. Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018;378(2):113-125. 2. Mok TS, Wu YL, Ahn MJ, et al. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med. 2017;376(7):629-640. 3. Tagrisso® (osimertinib) prescribing information. AstraZeneca Pharmaceuticals LP; 2020. 4. Ramalingam SS, Vansteenkiste J, Planchard D, et al. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med. 2020;382(1):41-50. 5. US Food and Drug Administration. Tagrisso label. Accessed January 2023. 6. NCCN Guidelines® Version 3.2023 Non-Small Cell Lung Cancer.