Osimertinib

Usage

Osimertinib is prescribed for the treatment of non-small cell lung cancer (NSCLC) in adults. Specifically, it targets NSCLC with:

• Epidermal Growth Factor Receptor (EGFR) exon 19 deletions or exon 21 L858R substitution mutations. This includes first-line treatment of metastatic NSCLC and adjuvant therapy after complete tumor resection in stages IB-IIIA.
• EGFR T790M mutation-positive NSCLC, especially in cases where the disease has progressed after treatment with other EGFR tyrosine kinase inhibitors (TKIs).

Osimertinib’s pharmacological classification is as an antineoplastic agent, specifically an EGFR tyrosine kinase inhibitor.

It works by irreversibly binding to certain mutated forms of EGFR, blocking the signals that promote cancer cell growth and survival.

Alternate Names

The International Nonproprietary Name (INN) is osimertinib. The most widely recognized brand name is Tagrisso.

How It Works

Pharmacodynamics: Osimertinib selectively and irreversibly inhibits EGFR tyrosine kinase activity in cells with EGFR-sensitizing mutations (exon 19 deletions and L858R) and the T790M resistance mutation. It shows limited activity against wild-type EGFR. This targeted inhibition disrupts downstream signaling pathways involved in cell proliferation, survival, and angiogenesis, leading to tumor regression.

Pharmacokinetics:

• Absorption: Osimertinib is absorbed orally, reaching peak plasma concentrations in approximately 6 hours. Food does not significantly affect absorption.
• Metabolism: Primarily metabolized by CYP3A4 and CYP3A5 enzymes in the liver.
• Elimination: Primarily eliminated via hepatic metabolism and biliary excretion. Renal elimination plays a minor role. The terminal half-life is approximately 48 hours.

Mode of Action: Osimertinib covalently binds to cysteine residues in the ATP-binding pocket of the mutated EGFR tyrosine kinase domain, preventing its activation.

Receptor binding: Irreversible binding to mutated EGFR (exon 19 deletions, L858R, T790M).

Enzyme inhibition: Inhibits EGFR tyrosine kinase activity.

Elimination Pathways: Primarily hepatic metabolism (CYP3A4/5) and biliary excretion, with minimal renal excretion.

Dosage

Standard Dosage

Adults: 80 mg orally once daily, taken with or without food.

Children: Safety and efficacy not established in pediatric patients.

Special Cases:

• Elderly Patients: No dose adjustment is generally recommended. However, close monitoring for adverse events is advised.
• Patients with Renal Impairment: No dose adjustment necessary for mild to severe renal impairment. Use with caution in end-stage renal disease.
• Patients with Hepatic Dysfunction: No dose adjustment needed for mild hepatic impairment. No data available for moderate to severe impairment; use with caution.
• Patients with Comorbid Conditions: Caution is advised for patients with pre-existing cardiac conditions, especially long QT syndrome or congestive heart failure.

Clinical Use Cases

Osimertinib is primarily used for oral administration in outpatient settings for the treatment of NSCLC. Its use in settings like intubation, surgical procedures, mechanical ventilation, ICU use, and emergency situations is not established.

Dosage Adjustments

Dose reductions to 40 mg once daily may be necessary due to adverse events. Specific dose adjustments are based on the severity of the toxicity. (See FAQs for details)

Side Effects

Common Side Effects:

Diarrhea, rash, dry skin, nail changes (paronychia, onycholysis), fatigue, musculoskeletal pain, decreased appetite, stomatitis/mucositis.

Rare but Serious Side Effects:

Interstitial lung disease/pneumonitis, QTc prolongation, cardiomyopathy, keratitis, severe skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis).

Long-Term Effects:

Chronic lung damage from ILD/pneumonitis, cardiac dysfunction from cardiomyopathy.

Adverse Drug Reactions (ADR):

ILD/pneumonitis, QTc prolongation leading to torsades de pointes, severe skin reactions, keratitis, cardiomyopathy.

Contraindications

None listed in the current prescribing information. Concurrent use with St. John’s Wort.

Drug Interactions

• Strong CYP3A4 Inducers (e.g., rifampin, phenytoin, carbamazepine): Avoid if possible. If unavoidable, increase osimertinib dose to 160 mg daily and revert back to 80mg after 3 weeks of inducer discontinuation.
• Strong CYP3A4 Inhibitors (e.g., itraconazole, ketoconazole, clarithromycin): Avoid if possible. If unavoidable, closely monitor for adverse events.
• Medications that prolong the QTc interval (e.g., amiodarone, quinidine): Use with caution and monitor ECGs.
• St. John’s Wort.

Pregnancy and Breastfeeding

Pregnancy Safety Category: D

Fetal Risks: Osimertinib can cause fetal harm based on animal studies. Use only if the potential benefit outweighs the risk. Effective contraception is required during treatment and for 2 months (females) or 4 months (males) after the last dose.

Breastfeeding: It is unknown if osimertinib is excreted in human milk. Due to potential risks to infants, breastfeeding is not recommended during treatment and for 2 weeks after the last dose.

Drug Profile Summary

• Mechanism of Action: Irreversible EGFR TKI targeting sensitizing and T790M resistance mutations.
• Side Effects: Diarrhea, rash, dry skin, nail changes, fatigue, ILD/pneumonitis, QTc prolongation.
• Contraindications: St. John’s Wort.
• Drug Interactions: Strong CYP3A4 inducers/inhibitors, drugs prolonging QTc interval.
• Pregnancy & Breastfeeding: Contraindicated/not recommended.
• Dosage: 80 mg orally once daily, adjustments for toxicity.
• Monitoring Parameters: ECG (QTc interval), pulmonary function tests, liver function tests, complete blood counts, eye exams if symptoms develop.

Popular Combinations

Osimertinib is used in combination with pemetrexed and platinum-based chemotherapy (cisplatin or carboplatin) as first-line treatment for patients with advanced NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R substitution mutations.

Precautions

• General Precautions: Monitor for pulmonary, cardiac, and dermatologic toxicities. Obtain baseline ECG and monitor electrolytes.
• Pregnant Women: Avoid use unless potential benefit outweighs risk. Effective contraception is required.
• Breastfeeding Mothers: Do not breastfeed.
• Children & Elderly: Safety and efficacy not established in children. Elderly patients should be closely monitored for adverse events.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Osimertinib?

A: The standard dose is 80 mg orally once daily for adults. The dose may be reduced to 40mg daily depending on the side effects. Pediatric use is not established.

Q2: What are the most common side effects of Osimertinib?

A: Diarrhea, rash, dry skin, nail changes, and fatigue are common side effects.

Q3: What are the serious side effects of Osimertinib that require attention?

A: Interstitial lung disease, QTc prolongation, cardiomyopathy, and severe skin reactions are serious side effects that require prompt medical attention.

Q4: Can Osimertinib be taken with food?

A: Yes, it can be taken with or without food.

Q5: What should be done if a dose of Osimertinib is missed?

A: If a dose is missed and the next dose is due within 12 hours, skip the missed dose. If it is more than 12 hours until the next dose, take the missed dose as soon as possible.

Q6: How does Osimertinib interact with other drugs?

A: Osimertinib’s metabolism is affected by strong CYP3A4 inducers and inhibitors. Concomitant use with drugs that prolong the QTc interval should be monitored closely. St. John’s Wort is contraindicated.

Q7: Can Osimertinib be used during pregnancy or breastfeeding?

A: Osimertinib is not recommended during pregnancy due to potential fetal harm. Breastfeeding is also not recommended.

Q8: How should patients be monitored while taking Osimertinib?

A: Patients should be monitored for pulmonary toxicity (ILD/pneumonitis), cardiac toxicity (QTc prolongation, cardiomyopathy), skin reactions, and other adverse effects. Regular monitoring may include ECGs, pulmonary function tests, liver function tests, and complete blood counts. Ophthalmologic assessment is recommended if eye symptoms occur.

Q9: What are the dose reduction guidelines for Osimertinib due to adverse events?

A: Dose reductions to 40 mg once daily may be necessary due to adverse events. Here are dose reduction guidelines for some toxicities:

• ILD/pneumonitis: Hold osimertinib and investigate. Permanently discontinue if confirmed.
• Asymptomatic LVEF < 50% and absolute decrease of 10% from baseline: Hold for up to 4 weeks. If recovers, restart. If no recovery, discontinue permanently.
• QTc interval > 500 msec on at least 2 separate ECGs: Hold until QTc interval is < 481 msec or recovery to baseline. Then restart at 40mg.
• QTc prolonged with signs/symptoms of serious arrhythmia or Symptomatic congestive heart failure: Discontinue permanently.
• Signs & symptoms suggestive of keratitis: Refer promptly to an ophthalmologist. For ≥ grade 3 toxicity, hold if suspected and discontinue if confirmed.
• Other ≥ grade 3 toxicity: Hold for up to 3 weeks. If recovery to ≤ grade 2, restart at the same dose or at 40mg. If no recovery, discontinue permanently.