TAGRISSO

1 INDICATIONS AND USAGE TAGRISSO is a kinase inhibitor indicated for: • adjuvant therapy 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, as detected by an FDA-approved test. ( 1.1 , 2.2 ) • the 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. ( 1.2 , 2.2 ) • the first-line treatment of adult patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test. ( 1.3 , 2.2 ) • in combination with pemetrexed and platinum-based chemotherapy, the first-line treatment of adult patients with locally advanced or metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test. ( 1.4 , 2.2 ) • the 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 TKI therapy. ( 1.5 , 2.2 ) 1.1 Adjuvant Treatment of EGFR Mutation-Positive Non-Small Cell Lung Cancer (NSCLC) TAGRISSO is indicated as adjuvant therapy 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, as detected by an FDA-approved test [see Dosage and Administration (2.2) ] . 1.2 Locally Advanced, Unresectable (Stage III) EGFR Mutation-Positive NSCLC TAGRISSO is indicated for the 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 [see Dosage and Administration (2.2)]. 1.3 First-line Treatment of EGFR Mutation-Positive Metastatic NSCLC TAGRISSO is indicated for the first-line treatment of adult patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test [see Dosage and Administration (2.2) ]. 1.4 First-line Treatment of EGFR Mutation-Positive Locally Advanced or Metastatic NSCLC TAGRISSO in combination with pemetrexed and platinum-based chemotherapy is indicated for the first-line treatment of adult patients with locally advanced or metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test [see Dosage and Administration (2.2) ]. 1.5 Previously Treated EGFR T790M Mutation-Positive Metastatic NSCLC TAGRISSO is indicated for the 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 [see Dosage and Administration (2.2) ] .

2 DOSAGE AND ADMINISTRATION 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. ( 2.3 ) 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. ( 2.3 ) Metastatic NSCLC: 80 mg orally once daily, with or without food, until disease progression or unacceptable toxicity. ( 2.3 ) 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. ( 2.3 ) 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) [see Warnings and Precautions (5.3) ] . • Before initiating TAGRISSO, perform complete blood count with differential [see Warnings and Precautions (5.7) ] . 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) [see Warnings and Precautions (5.3) ] . • Before initiating TAGRISSO, perform complete blood count with differential [see Warnings and Precautions (5.7) ] . 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 [see Indications and Usage (1.1) ] TAGRISSO monotherapy EGFR exon 19 deletions or exon 21 L858R mutations Tumor Locally Advanced, Unresectable (Stage III) EGFR Mutation-Positive NSCLC [see Indications and Usage (1.2) ] 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 [see Indications and Usage (1.3) ] 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 [see Indications and Usage (1.4) ] 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 [see Indications and Usage (1.5) ] TAGRISSO monotherapy EGFR T790M Mutation Plasma or tumor Information on FDA-approved tests for the detection of EGFR mutations is available at http://www.fda.gov/companiondiagnostics . 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 withou…

5 WARNINGS AND PRECAUTIONS • Interstitial Lung Disease (ILD)/Pneumonitis : Monitor for new or worsening pulmonary symptoms indicative of ILD/pneumonitis. For patients receiving TAGRISSO who have not received recent definite platinum-based chemoradiation therapy, permanently discontinue TAGRISSO in patients diagnosed with ILD/Pneumonitis. For patients who received recent definitive platinum-based chemoradiation therapy with Grade 1 ILD/pneumonitis continue TAGRISSO or interrupt and restart, as appropriate. Permanently discontinue TAGRISSO in patients diagnosed with Grade ≥2 ILD/pneumonitis. ( 2.5 , 5.1 ) • QTc Interval Prolongation : Monitor electrocardiograms and electrolytes in patients who have a history or predisposition for QTc prolongation, or those who are taking medications that are known to prolong the QTc interval. Withhold, then restart at a reduced dose or permanently discontinue TAGRISSO based on severity. ( 2.5 , 5.2 ) • Cardiomyopathy : Occurred in 3.8% of patients. Conduct cardiac monitoring, including left ventricular ejection fraction (LVEF) assessment in patients with cardiac risk factors. ( 2.5 , 5.3 ) • Keratitis : Promptly refer patients with signs and symptoms of keratitis to an ophthalmologist for evaluation. ( 5.4 ) • Erythema Multiforme Major, Stevens-Johnson Syndrome, and Toxic Epidermal Necrolysis : Withhold TAGRISSO if erythema multiforme major (EMM), Stevens-Johnson syndrome (SJS), or toxic epidermal necrolysis (TEN) is suspected and permanently discontinue if confirmed. ( 2.5 , 5.5 ) • Cutaneous Vasculitis : Withhold TAGRISSO if cutaneous vasculitis is suspected, evaluate for systemic involvement, and consider dermatology consultation. If no other etiology can be identified, consider permanent discontinuation based on severity. ( 5.6 ) • Aplastic Anemia : Withhold TAGRISSO if aplastic anemia is suspected and permanently discontinue TAGRISSO if confirmed. ( 2.5 , 5.7 ) • Embryo-Fetal Toxicity : TAGRISSO can cause fetal harm. Advise females of potential risk to the fetus and to use effective contraception during treatment with TAGRISSO and for 6 weeks after last dose. Advise males to use effective contraception for 4 months after the last dose of TAGRISSO. ( 5.8 , 8.1 , 8.3 ) 5.1 Interstitial Lung Disease/Pneumonitis TAGRISSO can cause severe and fatal ILD/pneumonitis. Across clinical trials, interstitial lung disease (ILD)/pneumonitis occurred in 4% of the 1813 patients treated with TAGRISSO monotherapy who had not received recent definitive chemoradiation therapy; 0.4% of cases were fatal. ILD/Pneumonitis with TAGRISSO in Combination with Pemetrexed and Platinum-based Chemotherapy In the FLAURA2 study, ILD/pneumonitis occurred in 3.3% of the 276 patients who received TAGRISSO in combination with pemetrexed and platinum-based chemotherapy; 0.4% of cases were fatal. ILD/Pneumonitis Following Definitive Platinum-based Chemoradiation Therapy In the LAURA study, following definitive platinum-based chemoradiation therapy, ILD/pneumonitis, including radiation pneumonitis, occurred in 80 of the 143 patients (56%) who received TAGRISSO monotherapy and 28 of the 73 patients (38%) who received placebo. There was one fatal case (0.7%), 3.5% Grade 3, 34% Grade 2, and 18% Grade 1 adverse reactions of ILD/pneumonitis in TAGRISSO-treated patients. For TAGRISSO-treated patients, ILD/pneumonitis led to permanent discontinuation of TAGRISSO in 7% of patients and dosage interruptions of TAGRISSO in 35% of patients. Among the 46 patients who were rechallenged with TAGRISSO, 11% had recurrence of ILD/pneumonitis. In the 80 TAGRISSO-treated patients, ILD/pneumonitis resolved in 40%, resolved with sequelae in 1.3%, were resolving in 16%, did not resolve in 41%, and resulted in death in 1.3%. For patients receiving TAGRISSO who have not received recent definitive platinum-based chemoradiation therapy, withhold TAGRISSO and promptly investigate for ILD in patients who present with worsening or respiratory symptoms which ma…

4 CONTRAINDICATIONS None. None. ( 4 )

7 DRUG INTERACTIONS Strong CYP3A Inducers : Avoid concomitant use. If not possible, increase TAGRISSO to 160 mg daily in patients receiving a strong CYP3A4 inducer. ( 2.5 , 7.1 ) 7.1 Effect of Other Drugs on Osimertinib Strong CYP3A Inducers Co-administering TAGRISSO with a strong CYP3A4 inducer decreased the exposure of osimertinib compared to administering TAGRISSO alone [see Clinical Pharmacology (12.3) ] . Decreased osimertinib exposure may lead to reduced efficacy. Avoid co-administering TAGRISSO with strong CYP3A inducers. Increase the TAGRISSO dosage when co-administering with a strong CYP3A4 inducer if concurrent use is unavoidable [see Dosage and Administration (2.5) ] . No dose adjustments are required when TAGRISSO is used with moderate and/or weak CYP3A inducers. 7.2 Effect of Osimertinib on Other Drugs Co-administering TAGRISSO with a breast cancer resistant protein (BCRP) or P-glycoprotein (P-gp) substrate increased the exposure of the substrate compared to administering it alone [see Clinical Pharmacology (12.3) ] . Increased BCRP or P-gp substrate exposure may increase the risk of exposure-related toxicity. Monitor for adverse reactions of the BCRP or P-gp substrate, unless otherwise instructed in its approved labeling, when co-administered with TAGRISSO. 7.3 Drugs That Prolong the QTc Interval The effect of co-administering medicinal products known to prolong the QTc interval with TAGRISSO is unknown. When feasible, avoid concomitant administration of drugs known to prolong the QTc interval with known risk of Torsades de pointes. If not feasible to avoid concomitant administration of such drugs, conduct periodic ECG monitoring [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.2) ].

8.1 Pregnancy Risk Summary Based on data from animal studies and its mechanism of action [see Clinical Pharmacology (12.1) ] , 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 (see Data ) . 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. Data Animal Data 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 6 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 4 and 6.

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.1 )] • QTc Interval Prolongation [see Warnings and Precautions (5.2) ] • Cardiomyopathy [see Warnings and Precautions (5.3) ] • Keratitis [see Warnings and Precautions (5.4) ] • Erythema multiforme, Stevens-Johnson syndrome, and Toxic epidermal necrolysis [see Warnings and Precautions (5.5) ] • Cutaneous Vasculitis [see Warnings and Precautions (5.6) ] • Aplastic Anemia [see Warnings and Precautions (5.7) ] Most common (≥20%) adverse reactions, including laboratory abnormalities, were: • TAGRISSO monotherapy: leukopenia, lymphopenia, thrombocytopenia, anemia, diarrhea, rash, musculoskeletal pain, neutropenia, nail toxicity, dry skin, stomatitis, and fatigue. ( 6.1 ) • TAGRISSO monotherapy following platinum-based chemoradiation therapy: lymphopenia, leukopenia, ILD/pneumonitis, thrombocytopenia, neutropenia, rash, diarrhea, nail toxicity, musculoskeletal pain, cough and COVID-19. ( 6.1 ) • TAGRISSO in combination with pemetrexed and platinum-based chemotherapy: leukopenia, thrombocytopenia, neutropenia, lymphopenia, rash, diarrhea, stomatitis, nail toxicity, dry skin, and increased blood creatinine. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 or www.TAGRISSO.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data in the WARNINGS AND PRECAUTIONS section reflect exposure to TAGRISSO in 1813 patients with EGFR mutation-positive NSCLC who received TAGRISSO monotherapy at the recommended dose of 80 mg orally once daily until disease progression or unacceptable toxicity in four randomized, controlled trials [ADAURA (n=337), FLAURA (n=338), FLAURA2 (monotherapy arm; n=275), and AURA3 (n=279)] [see Clinical Studies (14) ] , two single arm trials [AURA Extension (n=201) {NCT01802632} and AURA2 (n=210)]{NCT02094261}, and one dose-finding study, AURA1 (n=173). Among 1813 patients who received TAGRISSO monotherapy, 82% were exposed for 6 months or longer and 67% were exposed for greater than one year. In this pooled safety population, the most common adverse reactions in ≥20% of 1813 patients who received TAGRISSO monotherapy were diarrhea (47%), rash (46%), musculoskeletal pain (38%), nail toxicity (34%), dry skin (32%), stomatitis (24%), and fatigue (21%). The most common laboratory abnormalities in ≥20% of 1813 patients who received TAGRISSO monotherapy were leukopenia (65%), lymphopenia (64%), thrombocytopenia (53%), anemia (52%), and neutropenia (36%). In addition to the 1813 patients, certain subsections in the WARNINGS AND PRECAUTIONS describe adverse reactions observed with exposure to TAGRISSO monotherapy (80 mg orally once daily until disease progression or unacceptable toxicity) following definitive platinum-based chemoradiation therapy (n=143) in the LAURA study. The data described below reflect exposure to TAGRISSO (80 mg daily) in 337 patients with EGFR mutation-positive resectable NSCLC, 143 patients with EGFR mutation-positive locally advanced, unresectable (stage III) NSCLC, and 833 patients with EGFR mutation-positive locally advanced or metastatic NSCLC in five randomized, controlled trials [ADAURA (n=337), LAURA (n=143), FLAURA (n=279), FLAURA2 (monotherapy arm; n=275), and AURA3 (n=279)]. The data also reflect exposure to TAGRISSO at the recommended dose of 80 mg daily given in combination with pemetrexed and platinum-based chemotherapy in 276 patients with EGFR mutation-positive locally advanced or metastatic NSCLC in one randomized controlled trial [FLAURA2 (n=276)]. Patients with a history …