OSIMERTINIB MESYLATE

Indications

• Non-small cell lung cancer (NSCLC) with T790M mutation
• Locally advanced or metastatic NSCLC

Dosage

Children: Refer to the BNF for Children for appropriate dosing in pediatric patients.

Adults: Refer to the BNF for detailed dosing recommendations.

Mechanism of action

Osimertinib binds to specific mutant forms of EGFR, including T790M, L858R, and exon 19 deletions, which are prevalent in NSCLC tumors that have developed resistance to first-line EGFR-TKIs. It exhibits a significantly higher affinity for the T790M mutation compared to wild-type EGFR, thus inhibiting tumor growth driven by these mutations while sparing normal EGFR, which reduces toxicity.

Pharmacodynamics

Pharmacodynamic studies indicate that osimertinib can cause a concentration-dependent prolongation of the QTc interval, with an increase of approximately 14 msec observed at a dose of 80 mg. This underscores the importance of monitoring cardiac function in patients receiving this medication.

Pharmacokinetics

Osimertinib has a molecular formula of C28H33N7O2. It is absorbed after oral administration, with peak plasma concentrations typically occurring within 6 to 8 hours. It exhibits moderate protein binding and is metabolized primarily by the liver, with a significant portion of the drug undergoing hepatic metabolism. The elimination half-life allows for once-daily dosing, making it convenient for patient adherence.

Contra-indications

• Hypersensitivity to osimertinib or any of its components
• Severe pulmonary hypertension

Adverse effects

• Diarrhea
• Rash
• Nausea
• Fatigue
• Decreased appetite
• QTc interval prolongation
• Pneumonitis
• Hepatotoxicity

Interactions

• Mitotane (severe, decreases exposure)
• St. John's Wort (severe, decreases exposure)
• Dabrafenib (moderate, decreases exposure)
• Bosentan (moderate, decreases exposure)
• Modafinil (moderate, decreases exposure)
• Etravirine (moderate, decreases exposure)
• NNRTIs (moderate, decreases exposure)
• Aliskiren (unknown, increases exposure)
• Fexofenadine (unknown, increases exposure)
• Colchicine (unknown, increases exposure)

Precautions

• Monitor for QT prolongation
• Assess for signs of pneumonitis
• Evaluate hepatic function before and during therapy
• Caution in patients with a history of aortic aneurysm or dissection
• Careful monitoring in patients with stable brain metastases

Pregnancy

There is insufficient data on the use of osimertinib during pregnancy. It is advised to use effective contraception during treatment and for at least 6 weeks after the last dose.

Breast-feeding

It is not known whether osimertinib is excreted in human milk. The potential risk to the infant should be considered, and a decision should be made whether to discontinue breastfeeding or to discontinue the drug.

Storage

Store at room temperature (20-25°C) in a tightly closed container, protected from moisture and light.

Formulations

• Osimertinib 80 mg film-coated tablets
• Osimertinib 40 mg film-coated tablets

Mechanism of action

Osimertinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that binds to certain mutant forms of EGFR (T790M, L858R, and exon 19 deletion) that predominate in non-small cell lung cancer (NSCLC) tumours following treatment with first-line EGFR-TKIs. As a third-generation tyrosine kinase inhibitor, osimertinib is specific for the gate-keeper T790M mutation which increases ATP binding activity to EGFR and results in poor prognosis for late-stage disease. Furthermore, osimertinib has been shown to spare wild-type EGFR during therapy, thereby reducing non-specific binding and limiting toxicity. Compared to wild-type EGFR, osimertinib has 200 times higher affinity for EGFR molecules with the L858R/T790M mutation _in vitro_.

Pharmacodynamics

A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg.