Instructions for Osimertinib

1. Generic name: Osimertinib

Product name:Tagrisso

All names: Osimertinib,Osimertinib, AZD9291, Tagrisso

2. Indications:

1. Adjuvant therapy for mutation-positive non-small cell lung cancer(NSCLC):

According to FDA-approved trials, Osimertinib (Osimertinib) is indicated for adjuvant treatment after tumor resection in adult patients with non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations.

2. First-line treatment of EGFR mutation-positive metastatic non-small cell lung cancer:

Osimertinib is indicated for the first-line treatment of adult patients with metastatic non-small cell lung cancer whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations as detected byFDA-approved trials.

3. Previously treatedEGFR T790M mutation-positive metastatic non-small cell lung cancer:

Osimertinib is indicated for the treatment of adult patients with metastatic EGFR T790M mutation-positive non-small cell lung cancer, as detected by an FDA-approved trial, whose disease has progressed during or after treatment with an EGFR tyrosine kinase inhibitor (TKI).

3. Usage and dosage:

1. Before treatment: Before patients are treated with osimertinib, doctors will determine whether there is EGFR exon 19 deletion, exon 21 L858R mutation, and T790M mutation in the tumor specimen. If these mutations are not detected in the plasma specimen, the tumor tissue will be detected if feasible.

2. Recommended dosage: The recommended dosage of osimertinib is 80 mg tablets, once a day, which can be taken with or without food. Patients are treated in the adjuvant setting and are taken until disease recurrence or unacceptable toxicity or for up to 3 years. Patients with metastatic lung cancer are treated until disease progression or toxicity is unacceptable.

3. Administer to patients who have difficulty swallowing solids:

Disperse tablets only in 60 mL (2 ounces) of non-carbonated water. Stir until the tablet is dispersed into small tablets (the tablet will not completely dissolve) and swallow immediately. Do not crush, heat or sonicate during preparation. Rinse container with 120-240mL (4 to 8 ounces) of water and drink immediately.

If administration by nasogastric tube is required, disperse the tablets in 15 mL of non-carbonated water as described above, then use an additional 15 mL of water to transfer any residue to a syringe. The resulting 30 mL of liquid should be flushed with appropriate water as directed for the nasogastric tube (approximately 30 mL).

4. Dosage adjustment:

Osimertinib should be discontinued if serious adverse reactions occur, such as interstitial lung disease(ILD)/pneumonitis, QTc interval prolongation with signs/symptoms of life-threatening arrhythmias, symptomatic congestive heart failure, great erythema multiforme (EMM) or other allergic reactions,aplastic anemia, etc.

5. Drug interactions: If patients use or unavoidable combination with strong CYP3A inducers, the patient should increase the dose of osimertinib to 160 mg daily. After discontinuing the strong CYP3A4 inducer for 3 weeks, resume osimertinib 80 mg.

4. Adverse reactions:

The most common adverse reactions reported in ≥20% of patients treated with osimertinib were diarrhea, rash, musculoskeletal pain, nail toxicity, dry skin, stomatitis, fatigue, and cough. The most common laboratory abnormalities were leukopenia, lymphopenia, thrombocytopenia, anemia, and neutropenia. Adverse reactions that have occurred after marketing include erythema multiforme(EMM), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), cutaneous vasculitis, and aplastic anemia.

5. Storage:

Store osimertinib bottles at25°C (77°F) with a tolerance of 15-30°C (59-86°F).

6. Specific groups of people:

1. Women: Osimertinib can cause malformations, embryonic death, and postnatal death. It is recommended that women of reproductive potential use osimertinib.Use effective contraception during treatment and for 6 weeks after the last dose. Women are advised not to breastfeed during osimertinib treatment and for 2 weeks after the last dose.

2. Men: It is recommended that male patients with female partners of reproductive potential use effective contraceptive measures during and for 4 months after taking the last dose of osimertinib.

3. Renal impairment: According to Cockcroft-Gault's estimate, dose adjustment is not recommended for patients with a creatinine clearance (CLcr) of 15-89 mL/min. There is no recommended dose of osimertinib for patients with end-stage renal disease (CLcr<15mL/min).

4. Liver function impairment: Dosage adjustment is not recommended for patients with mild to moderate hepatic impairment (Child-Pugh A and B or total bilirubin ≤ ULN and AST > ULN or total bilirubin 1-3 times ULN and any AST). There is no recommended dose of osimertinib for patients with severe hepatic impairment (total bilirubin between 3-10 times the ULN and any AST).

7. Mechanism of action:

Osimertinib is an epidermal growth factor receptor (EGFR) kinase inhibitor that irreversibly binds to certain mutant forms of EGFR (T790M, L858R, and exon 19 deletion) at concentrations approximately nine-fold lower than wild type. After oral administration of osimertinib, two pharmacologically active metabolites with similar inhibitory properties to osimertinib (AZ7550 and AZ5104, circulating in approximately 10% of the parent) were found in plasma. AZ7550 showed similar potency to osimertinib, while AZ5104 showed greater potency against exon 19 deletion and T790M mutant (approximately 8-fold) and wild-type (approximately 15-fold) EGFR. In vitro, osimertinib also inhibits the activities of HER2, HER3, HER4, ACK1 and BLK at clinically relevant concentrations.

8. Notes:

During the treatment of patients with Osimertinib, attention should be paid to the occurrence of interstitial lung disease/pneumonitis, QTc interval prolongation, cardiomyopathy, keratitis, severe erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis, cutaneous vasculitis, aplastic anemia and other events.