Osimertinib is used as a first-line treatment for patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have EGFR exon 19 deletion or exon 21 L858R mutation, confirmed by an FDA-approved test. It is also used for patients with metastatic EGFR T790M mutation-positive NSCLC whose disease has progressed during or after EGFR tyrosine kinase inhibitor (TKI) therapy.

Osimertinib is an epidermal growth factor receptor (EGFR) kinase inhibitor. It binds irreversibly to certain mutant forms of EGFR, including T790M, L858R, and exon 19 deletion, at much lower concentrations than required for wild-type EGFR. In laboratory studies and animal tumor models, Osimertinib showed anti-tumor activity against NSCLC cells carrying EGFR mutations such as T790M/L858R, L858R, T790M/exon 19 deletion, and exon 19 deletion. Its effect against wild-type EGFR amplification was less pronounced. After oral administration, two active metabolites, AZ7550 and AZ5104, were identified in plasma. These metabolites have inhibitory activity similar to Osimertinib. AZ7550 showed similar potency, while AZ5104 showed greater potency against exon 19 deletion and T790M mutant EGFR, as well as against wild-type EGFR. In vitro, Osimertinib also inhibited HER2, HER3, HER4, ACK1, and BLK at clinically relevant concentrations.

The area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax) of Osimertinib increase proportionally over the 20 to 240 mg dose range after oral administration and show linear pharmacokinetics. Once-daily oral use results in about 3-fold accumulation, with steady-state exposure reached after 15 days. At steady state, the Cmax to Cmin ratio is about 1.6-fold.

Absorption: The median time to reach Cmax is 6 hours, with a range of 3 to 24 hours. After administration of a 20 mg Osimertinib tablet with a high-fat, high-calorie meal, the Cmax and AUC were compared with fasting conditions.

Distribution: The mean volume of distribution at steady state (Vss/F) is 986 L. Osimertinib is approximately 95% bound to plasma proteins.

Elimination: Osimertinib plasma concentration declines over time. The population-estimated mean half-life is 48 hours, and oral clearance (CL/F) is 14.2 L/h.

Metabolism: Osimertinib is mainly metabolized through oxidation, primarily by CYP3A, and by dealkylation in vitro. Two active metabolites, AZ7550 and AZ5104, are found in plasma after oral dosing. At steady state, the geometric mean exposure (AUC) of each metabolite is about 10% of the Osimertinib exposure.

Excretion: Osimertinib is eliminated mainly through feces (68%) and to a lesser extent through urine (14%). Unchanged Osimertinib accounts for about 2% of total elimination.

The recommended dose of Osimertinib is 80 mg tablet once a day until disease progression or unacceptable toxicity. Osimertinib can be taken with or without food. If a dose of Osimertinib is missed, do not make up the missed dose and take the next dose as scheduled. Disperse tablet in 60 ml (2 ounces) of non-carbonated water only. Stir until tablet is dispersed into small pieces (the tablet will not completely dissolve) and swallow immediately. Do not crush, heat, or ultrasonicate during preparation. Rinse the container with 120 ml to 240 ml (4 to 8 ounces) of water and immediately drink. If administration via nasogastric tube is required, disperse the tablet as above in 15 ml of non-carbonated water, and then use an additional 15 ml of water to transfer any residues to the syringe. The resulting 30 ml liquid should be administered as per the nasogastric tube instructions with appropriate water flushes (approximately 30 ml).

Strong CYP3A Inhibitors: Avoid co-administration of Osimertinib with strong CYP3A inhibitors such as macrolide antibiotics (e.g., telithromycin), antifungal agents (e.g., itraconazole), antivirals (e.g., ritonavir), and nefazodone, as these may increase Osimertinib plasma levels. If no suitable alternative is available, patients should be closely monitored for potential adverse effects.

Strong CYP3A Inducers: Avoid concurrent use of Osimertinib with strong CYP3A inducers (e.g., phenytoin, rifampicin, carbamazepine, St. John’s Wort), as they may reduce Osimertinib plasma concentrations.

Effect on other drugs: Avoid co-administration of Osimertinib with medications that are sensitive substrates of CYP3A, breast cancer resistance protein (BCRP), or CYP1A2 with narrow therapeutic ranges. These include, but are not limited to, fentanyl, cyclosporine, quinidine, ergot alkaloids, phenytoin, and carbamazepine, as Osimertinib may alter their plasma concentrations.

The most commonly reported side effects of Osimertinib include diarrhea, rash, dry skin, nail toxicity, stomatitis, fatigue, and decreased appetite.

Osimertinib may cause fetal harm when administered to a pregnant woman. There are no adequate data on its use in pregnant women. It is also unknown whether Osimertinib is excreted in human milk or what effects it may have on a breastfed infant or milk production.

Contraception: Females of reproductive potential should use effective contraception during treatment with Osimertinib and for 6 weeks after the final dose. Male patients with female partners of reproductive potential should use effective contraception during treatment and for 4 months after the last dose of Osimertinib.

Infertility: Based on animal studies, Osimertinib may impair fertility in both females and males of reproductive potential. Effects on female fertility appear to be potentially reversible; however, it is unknown whether effects on male fertility are reversible.

Interstitial Lung Disease (ILD)/Pneumonitis: ILD/pneumonitis has been reported in 3.9% of patients treated with Osimertinib, with 0.4% of cases being fatal.

QTc Interval Prolongation: Monitor ECG and electrolyte levels in patients with a history of QTc prolongation or those receiving medications known to prolong QTc interval. Temporarily withhold, reduce dose, or permanently discontinue Osimertinib as appropriate.

Cardiomyopathy: Reported in 1.4% of patients. Evaluate left ventricular ejection fraction (LVEF) prior to treatment and reassess every 3 months during therapy.

Embryo-Fetal Toxicity: Osimertinib may cause fetal harm. Females should be counseled about potential risks to the fetus and advised to use effective contraception during treatment and for 6 weeks after the last dose. Males should use effective contraception during treatment and for 4 months after the final dose.

No clinically meaningful differences in the pharmacokinetics of osimertinib have been observed based on age, sex, ethnicity, body weight, baseline albumin, line of therapy, smoking status, or in patients with mild (ClCr 60–89 ml/min), moderate (ClCr 30–59 ml/min), or severe (ClCr 15–29 ml/min) renal impairment, as well as mild hepatic impairment (total bilirubin ≤ ULN with AST > ULN, or total bilirubin 1 to 1.5 × ULN with any AST) or moderate hepatic impairment (total bilirubin 1.5 to 3 × ULN with any AST). The pharmacokinetics of osimertinib in patients with end-stage renal disease (ClCr <15 ml/min) or severe hepatic impairment (total bilirubin 3 to 10 × ULN with any AST) remain unknown.

Pediatric Use: The safety and efficacy of Osimertinib in pediatric patients have not been established.

Geriatric Use: No overall differences in effectiveness were observed based on age. However, exploratory analyses indicate a higher incidence of Grade 3 and 4 adverse reactions (32% vs 25%) and more frequent dose modifications due to adverse reactions (13.4% vs 9.3% and 13.4% vs 7.6%) in patients aged 65 years or older compared to those younger than 65 years.

Renal Impairment: No dose adjustment is recommended for patients with mild, moderate, or severe renal impairment. There is no recommended dose of Osimertinib for patients with end-stage renal disease.

Hepatic Impairment: No recommended dose is available for patients with severe hepatic impairment.

Cytotoxic Chemotherapy

Store below 30°C. Protect from moisture and light. Dispose of expired or unused medicine safely. Keep Osimertinib and all other medicines out of the reach of children.