TAGRISSO

Osimertinib is an oral, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) drug developed by AstraZeneca Pharmaceuticals. 1, 9 Its use is indicated for the treatment of metastatic non-small cell lung cancer (NSCLC) in cases where tumour EGFR expression is positive for the T790M mutation as detected by FDA-approved testing and which has progressed following therapy with a first-generation EGFR tyrosine kinase inhibitor.

Approximately 10% of patients with NSCLC have a rapid and clinically effective response to EGFR-TKIs due to the presence of specific activating EGFR mutations within the tumour cells.

More specifically, deletions around the LREA motif in exon and exon 21 L858R point mutations are correlated with response to therapy.

Development of third-generation

EGFR-TKIs, such as osimertinib, has been in response to altered tumour resistance patterns following treatment and toxic side effects that impact patient quality of life.

Treatment with first-generation

EGFR-TKIs (gefitinib and erlotinib) has been associated with the development of resistance through activating mutations in the EGFR gene.

EGFR-TKIs (afatinib and dacomitinib) were then developed to be more potent inhibitors, although their use is associated with increased toxicity through nonspecific targeting of wild-type EGFR.

In contrast, third-generation inhibitors are specific for the gate-keeper T790M mutations which increases ATP binding activity to EGFR and result 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. 1, 2, 6.

Osimertinib is indicated for the

Adjuvant treatment of non-small cell lung cancer (NSCLC) after tumour resection in adult patients whose tumours have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test.

First-line treatment of adult patients with metastatic NSCLC whose tumours have EGFR exon 19 deletions or exon 21 L858R mutations.

In combination with pemetrexed and platinum-based chemotherapy for the first-line treatment of adult patients with locally advanced or metastatic NSCLC whose tumours have EGFR exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test.

Treatment of adult patients with metastatic EGFR T790M mutation-positive NSCLC, as detected by an FDA-approved test, whose disease has progressed on or after EGFR tyrosine kinase inhibitor (TKI) therapy.

Treatment of adult patients with locally advanced, unresectable (stage III) NSCLC whose disease has not progressed during or following concurrent or sequential platinum-based chemoradiation therapy and whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test

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.

The median time to

Cmax was found to be 6 hours.

The mean volume of distribution at steady state is 918 L.

Osimertinib is metabolized to at least two pharmacologically active metabolites, AZ7550 and AZ5104, that circulate at approximately 10% of the concentration of the parent compound.

Biochemical assays have shown that

AZ7550 has similar potency and efficacy to osimertinib, while AZ5104 is more potent against mutant and wild-type EGFR.

The main metabolic pathways are oxidation (predominantly by CYP3A) and dealkylation.

Hover over products below to view reaction partners Osimertinib AZ-7550 AZ-5104.

Osimertinib is primarily eliminated through excretion in the feces (68%), to a lesser extent through urine (14%), while only 2% is excreted unchanged.

The population estimated mean half-life is 48 hours.

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Across clinical trials, interstitial lung disease (ILD)/pneumonitis occurred in 3.7% of treated patients with 0.3% of these being fatal.

There is also a change of

QTc interval prolongation; electrocardiogram and electrolytes should be monitored in patients with a history or predisposition for QTc prolongation.

Cardiomyopathy occurred in 3% of patients, therefore left ventricular ejection fraction (LVEF) should be measured at baseline and during treatment.

Osimertinib can cause embryo-fetal toxicity, requiring female patients to take effective birth control during therapy and for 6 weeks after final dose.

Adjuvant treatment of early-stage

NSCLC: 80 mg orally once daily, with or without food, until disease recurrence, or unacceptable toxicity, or for up to 3 years.

Locally advanced, unresectable (stage III) NSCLC: Following platinum-based chemoradiation therapy, 80 mg orally once daily, with or without food, until disease progression or unacceptable toxicity.

NSCLC: 80 mg orally once daily, with or without food, until disease progression or unacceptable toxicity.

Locally advanced or metastatic

NSCLC: 80 mg orally once daily administered in combination with pemetrexed and platinum-based chemotherapy, with or without food, until disease progression or unacceptable toxicity due to TAGRISSO. 2.1 Recommended Evaluation and Testing Before Initiating TAGRISSO TAGRISSO Monotherapy.

• Before initiating TAGRISSO monotherapy in patients with cardiac risk factors, conduct cardiac monitoring, including assessment of left ventricular ejection fraction (LVEF) .

• Before initiating TAGRISSO, perform complete blood count with differential.

TAGRISSO in Combination with Pemetrexed and Platinum-based Chemotherapy.

• Before initiating TAGRISSO in combination with pemetrexed and platinum-based chemotherapy, conduct cardiac monitoring in all patients, including assessment of left ventricular ejection fraction (LVEF) .

• Before initiating TAGRISSO, perform complete blood count with differential. 2.2 Patient Selection Table 1 below presents the patient selection criteria for treatment with TAGRISSO.

Table 1: Patient Selection Select patients for treatment with TAGRISSO based on the presence of a mutation as detected by an FDA-approved test.

Indication Treatment Regimen Required Mutation Source for Testing Adjuvant Treatment of EGFR Mutation-Positive NSCLC TAGRISSO monotherapy EGFR exon 19 deletions or exon 21 L858R mutations Tumor Locally Advanced, Unresectable (Stage III) EGFR Mutation-Positive NSCLC Following completion of platinum-based chemoradiation therapy, TAGRISSO monotherapy EGFR exon 19 deletions or exon 21 L858R mutations Tumor First-line Treatment of EGFR Mutation-Positive Metastatic NSCLC TAGRISSO monotherapy EGFR exon 19 deletions or exon 21 L858R mutations Plasma or tumor First-line Treatment of EGFR Mutation-Positive Locally Advanced or Metastatic NSCLC TAGRISSO in combination with pemetrexed and platinum-based chemotherapy EGFR exon 19 deletions or exon 21 L858R mutations Plasma or tumor Previously Treated EGFR T790M Mutation-Positive Metastatic NSCLC TAGRISSO monotherapy EGFR T790M Mutation Plasma or tumor Information on FDA-approved tests for the detection of EGFR mutations is available at. 2.3 Recommended Dosage and Administration Recommended Dosage Table 2 provides the recommended dosage of TAGRISSO by indication.

Table 2: Recommended Dosage of TAGRISSO Indication Recommended Dosage of TAGRISSO Duration of Treatment Adjuvant Treatment of EGFR Mutation-Positive NSCLC 80 mg tablet orally once daily with or without food For a total of 3 years or until disease recurrence or unacceptable toxicity Locally Advanced, Unresectable (Stage III) EGFR Mutation-Positive NSCLC Following platinum-based chemoradiation therapy, 80 mg tablet orally once daily with or without food Until disease progression or unacceptable toxicity First-line Treatment of EGFR Mutation-Positive Metastatic NSCLC 80 mg tablet orally once daily with or without food Until disease progression or unacceptable toxicity First-line Treatment of EGFR Mutation-Positive Locally Advanced or Metastatic NSCLC 80 mg tablet orally once daily with or without food in combination with pemetrexed and platinum-based chemotherapy Refer to the Prescribing Information for pemetrexed and cisplatin or carboplatin for the respective dosing information.

Until disease progression or unacceptable toxicity due to TAGRISSO Previously Treated EGFR T790M Mutation-Positive Metastatic NSCLC 80 mg tablet orally once daily with or without food Until disease progression or unacceptable toxicity Administration Administer TAGRISSO 80 mg tablet orally once daily with or without food.

Tablets may be dispersed in water for patients who have difficulty swallowing, or for nasogastric tube administration.

Missed Dose If a dose of

TAGRISSO is missed, do not make up the missed dose and take the next dose as scheduled. 2.4 Administration to Patients Who Have Difficulty Swallowing Solids Disperse TAGRISSO 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 TAGRISSO 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).

Repeat this step until no pieces remain in the syringe.

This will help to ensure that the full prescribed dose of the TAGRISSO is given.

The dispersion and residues should be administered within 30 minutes of the addition of the tablets to water. 2.5 Dosage Modifications for Adverse Reactions The recommended dose reductions for adverse reactions are provided in Table 3.

Table 3.

Recommended Dosage Modifications for TAGRISSO Target Organ Adverse Reaction Adverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE v5.0).

Pulmonary (Patients who have not received recent definitive platinum-based chemoradiation therapy) Any Grade Interstitial lung disease (ILD)/Pneumonitis Permanently discontinue TAGRISSO.

Pulmonary (Patients who have received recent definitive platinum-based chemoradiation therapy) Grade 1 ILD/Pneumonitis Withhold or continue TAGRISSO, as clinically indicated.

Grade ≥2 ILD/Pneumonitis Permanently discontinue TAGRISSO.

QTc = QT interval corrected for heart rate interval greater than 500 msec on at least 2 separate ECGs ECGs = Electrocardiograms Withhold TAGRISSO until QTc interval is less than 481 msec or recovery to baseline if baseline QTc is greater than or equal to 481 msec, then resume at 40 mg dose.

QTc interval prolongation with signs/symptoms of life-threatening arrhythmia Permanently discontinue TAGRISSO.

Symptomatic congestive heart failure Permanently discontinue

Major (EMM), Stevens-Johnson syndrome (SJS), and Toxic Epidermal Necrolysis (TEN) Withhold TAGRISSO if suspected and permanently discontinue if confirmed.

Blood and bone marrow Aplastic anemia Withhold TAGRISSO if aplastic anemia is suspected and permanently discontinue if confirmed.

Other Adverse reaction of

Grade 3 or greater severity Withhold TAGRISSO for up to 3 weeks.

If improvement to

Grade 0-2 within 3 weeks Resume at 80 mg or 40 mg daily.

If no improvement within 3 weeks Permanently discontinue TAGRISSO.

Dosage Modifications for Combination Therapy When

TAGRISSO is administered in combination with pemetrexed and platinum-based chemotherapy, modify the dose of any one of the treatments for the management of adverse reactions, as appropriate.

TAGRISSO dose modification instructions, see Table 3.

Withhold, reduce the dose or permanently discontinue pemetrexed, cisplatin or carboplatin according to their respective Prescribing Information.

CYP3A4 Inducers Avoid concomitant use of strong CYP3A4 inducers with TAGRISSO.

If concurrent use is unavoidable, increase TAGRISSO dosage to 160 mg daily when co-administering with a strong CYP3A inducer.

TAGRISSO at 80 mg 3 weeks after discontinuation of the strong CYP3A4 inducer.

mg tablets: beige, oval and biconvex tablet marked with “AZ 80” on one side and plain on the reverse and are available in bottles of 30 (NDC 0310-1350-30). 40 mg tablets: beige, round and biconvex tablet marked with “AZ 40” on one side and plain on the reverse and are available in bottles of 30 (NDC 0310-1349-30).

TAGRISSO bottles at 25°C (77°F).

Excursions permitted to 15-30°C (59-86°F) .

Based on data from animal studies and its mechanism of action, TAGRISSO can cause fetal harm when administered to a pregnant woman.

There are no available data on

TAGRISSO use in pregnant women.

Administration of osimertinib to pregnant rats was associated with embryolethality and reduced fetal growth at plasma exposures 1.5 times the exposure at the recommended clinical dose.

Advise pregnant women of the potential risk to a fetus.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

When administered to pregnant rats prior to embryonic implantation through the end of organogenesis (gestation days 2-20) at a dose of 20 mg/kg/day, which produced plasma exposures of approximately 1.5 times the clinical exposure, osimertinib caused post-implantation loss and early embryonic death.

When administered to pregnant rats from implantation through the closure of the hard palate (gestation days to 16) at doses of 1 mg/kg/day and above (0.1 times the AUC observed at the recommended clinical dose of 80 mg once daily), an equivocal increase in the rate of fetal malformations and variations was observed in treated litters relative to those of concurrent controls.

When administered to pregnant dams at doses of 30 mg/kg/day during organogenesis through lactation Day 6, osimertinib caused an increase in total litter loss and postnatal death.

At a dose of 20 mg/kg/day, osimertinib administration during the same period resulted in increased postnatal death as well as a slight reduction in mean pup weight at birth that increased in magnitude between lactation days and 6.

The safety and effectiveness of

TAGRISSO in pediatric patients have not been established.

Of the 1813 patients with EGFR exon 19 deletion or exon 21 L858R mutation-positive NSCLC who were treated with TAGRISSO monotherapy, 770 patients were ≥65 years and 207 patients were ≥75 years of age.

Exploratory analysis suggests a higher incidence of Grade 3 or higher adverse reactions (43% vs 33%) and more frequent dosage modifications for adverse reactions (34% vs 23%) in patients 65 years or older as compared to those younger than 65 years.

No overall differences in safety or effectiveness were observed between patients 65 years or older and younger patients.

TAGRISSO Following Definitive Platinum-based Chemoradiation Therapy

Of the 142 patients with EGFR exon 19 deletion or exon 21 L858R mutation-positive, locally advanced unresectable (Stage III) NSCLC treated with TAGRISSO following definitive platinum-based chemoradiation therapy, 62 patients were ≥65 years and 13 patients were ≥75 years of age.

TAGRISSO in Combination with Pemetrexed and Platinum-based Chemotherapy Of the 276 patients with EGFR exon 19 deletion or exon 21 L858R mutation-positive, locally advanced or metastatic NSCLC treated with TAGRISSO in combination with pemetrexed and platinum-based chemotherapy, 104 patients were ≥65 years and 23 patients were ≥75 years of age.

Exploratory analysis suggests a higher incidence of Grade 3 or higher adverse reactions (68% vs 61%) and more frequent dosage modifications for adverse reactions (55% vs 43%) in patients 65 years or older as compared to those younger than 65 years.

Clinical studies of

TAGRISSO in combination with pemetrexed and platinum-based chemotherapy did not include sufficient numbers of patients age and over to determine whether they respond differently from younger patients.