TAGRISSO (osimertinib 40 1) Dailymed

Recent Major Changes Section

•  Indications and Usage (1.3) 02/2024

Dosage and Administration, Patient Selection (2.2)                                    02/2024

Dosage and Administration, Recommended Dosage Regimen (2.3)           02/2024

Dosage and Administration, Dosage Modifications (2.5)                            02/2024

Warnings and Precautions, Interstitial Lung

Disease/Pneumonitis (5.1)                                                                            02/2024

Warnings and Precautions, QTc Interval Prolongation (5.2)                       02/2024

Warnings and Precautions, Cardiomyopathy (5.3)                                      02/2024

Warnings and Precautions, Keratitis (5.4)                                                   02/2024

Warnings and Precautions, Aplastic Anemia (5.7)                                      02/2024

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 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. (1.2, 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. (1.3, 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. (1.4, 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 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) ].

1.3 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)].

1.4 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)

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

Adjuvant Treatment of EGFR Mutation-Positive NSCLC

Select patients with resectable tumors for the adjuvant treatment of NSCLC with TAGRISSO based on the presence of EGFR exon 19 deletions or exon 21 L858R mutations in tumor specimens [see Clinical Studies (14.1) ].

First-line Treatment of EGFR Mutation-Positive Metastatic NSCLC

Select patients for the first-line treatment of locally advanced or metastatic EGFR-positive NSCLC with TAGRISSO based on the presence of EGFR exon 19 deletions or exon 21 L858R mutations in tumor or plasma specimens [see Clinical Studies (14.2)]. If these mutations are not detected in a plasma specimen, test tumor tissue if feasible.

First-line Treatment of EGFR Mutation-Positive Locally Advanced or Metastatic NSCLC

Select patients for the first-line treatment of locally advanced or metastatic EGFR-positive NSCLC with TAGRISSO in combination with pemetrexed and platinum-based chemotherapy, based on the presence of EGFR exon 19 deletions or exon 21 L858R mutations in tumor or plasma specimens [see Clinical Studies (14.3) ] . If these mutations are not detected in a plasma specimen, test tumor tissue if feasible.

Previously Treated EGFR T790M Mutation-Positive Metastatic NSCLC

Select patients for the treatment of metastatic EGFR T790M mutation-positive NSCLC with TAGRISSO following progression on or after EGFR TKI therapy based on the presence of an EGFR T790M mutation in tumor or plasma specimens [see Clinical Studies (14.4) ]. Testing for the presence of the T790M mutation in plasma specimens is recommended only in patients for whom a tumor biopsy cannot be obtained. If this mutation is not detected in a plasma specimen, re-evaluate the feasibility of biopsy for tumor tissue testing.

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 1 provides the recommended dosage of TAGRISSO by indication.

Table 1. 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
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 [see Dosage and Administration (2.4)].

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 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 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 2.

Table 2. 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).	Dosage Modification
Pulmonary [see Warnings and Precautions (5.1)]	Interstitial lung disease (ILD)/Pneumonitis	Permanently discontinue TAGRISSO.
Cardiac [see Warnings and Precautions (5.2, 5.3)]	QTcQTc = QT interval corrected for heart rate interval greater than 500 msec on at least 2 separate ECGsECGs = 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 TAGRISSO.
Cutaneous [see Warnings and Precautions (5.5)]	Erythema Multiforme Major (EMM), Stevens-Johnson syndrome (SJS), and Toxic Epidermal Necrolysis (TEN)	Withhold TAGRISSO if suspected and permanently discontinue if confirmed.
Blood and bone marrow [see Warnings and Precautions (5.7)]	Aplastic anemia	Withhold TAGRISSO if aplastic anemia is suspected and permanently discontinue if confirmed.
Other [see Adverse Reactions (6.1)]	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. For TAGRISSO dose modification instructions, see Table 2. Withhold, reduce the dose or permanently discontinue pemetrexed, cisplatin or carboplatin according to their respective Prescribing Information.

Drug Interactions

Strong 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. Resume TAGRISSO at 80 mg 3 weeks after discontinuation of the strong CYP3A4 inducer [see Drug Interactions (7) and Clinical Pharmacology (12.3)].

• • Interstitial Lung Disease (ILD)/Pneumonitis: Occurred in 4% of patients. Permanently discontinue TAGRISSO in patients diagnosed with ILD/Pneumonitis. (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. (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 final 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

Interstitial lung disease (ILD)/pneumonitis occurred in 4% of the 1813 TAGRISSO-treated patients; 0.4% of cases were fatal.

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.

Withhold TAGRISSO and promptly investigate for ILD in patients who present with worsening of respiratory symptoms which may be indicative of ILD (e.g., dyspnea, cough and fever). Permanently discontinue TAGRISSO if ILD/pneumonitis is confirmed [see Dosage and Administration (2.5) and Adverse Reactions (6.1) ].

5.2 QTc Interval Prolongation

Heart rate-corrected QT (QTc) interval prolongation occurs in patients treated with TAGRISSO. Of the 1813 patients treated with TAGRISSO monotherapy in clinical trials, 1.1% were found to have a QTc >500 msec, and 4.3% of patients had an increase from baseline QTc >60 msec [see Clinical Pharmacology (12.2) ] .

Of the 276 patients treated with TAGRISSO in combination with pemetrexed and platinum-based chemotherapy in the FLAURA2 study, 1.8% were found to have a QTc >500 msec, and 10.5% of patients had an increase from baseline QTc >60 msec.

No QTc-related arrhythmias were reported.

Clinical trials of TAGRISSO did not enroll patients with baseline QTc of >470 msec. Conduct periodic monitoring with ECGs and electrolytes in patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval. Permanently discontinue TAGRISSO in patients who develop QTc interval prolongation with signs/symptoms of life-threatening arrhythmia [see Dosage and Administration (2.5) ].

5.3 Cardiomyopathy

Across clinical trials, cardiomyopathy (defined as cardiac failure, chronic cardiac failure, congestive heart failure, pulmonary edema or decreased ejection fraction) occurred in 3.8% of the 1813 TAGRISSO-treated patients; 0.1% of cardiomyopathy cases were fatal.

In the FLAURA2 study, cardiomyopathy occurred in 9% of the 276 patients who received TAGRISSO in combination with pemetrexed and platinum-based chemotherapy; 1.1% of cardiomyopathy cases were fatal.

A decline in left ventricular ejection fraction (LVEF) ≥10 percentage points from baseline and to less than 50% LVEF occurred in 4.2% of 1557 patients who had baseline and at least one follow-up LVEF assessment. In the ADAURA study, 1.5% (5/325) of patients treated with TAGRISSO experienced LVEF decreases greater than or equal to 10 percentage points and a drop to less than 50%. In the FLAURA2 study, 8% (21/262) of patients treated with TAGRISSO in combination with pemetrexed and platinum-based chemotherapy, who had baseline and at least one follow-up LVEF assessment, experienced LVEF decreases greater than or equal to 10 percentage points and a drop to less than 50%.

For patients who will be receiving TAGRISSO monotherapy, conduct cardiac monitoring, including assessment of LVEF at baseline and during treatment, in patients with cardiac risk factors.

For patients who will be receiving TAGRISSO in combination with pemetrexed and platinum-based chemotherapy, conduct cardiac monitoring, including assessment of LVEF at baseline and during treatment, in all patients.

Assess LVEF in patients who develop relevant cardiac signs or symptoms during treatment. For symptomatic congestive heart failure, permanently discontinue TAGRISSO [see Dosage and Administration (2.5)].

5.4 Keratitis

Keratitis was reported in 0.6% of 1813 patients treated with TAGRISSO monotherapy in clinical trials. Promptly refer patients with signs and symptoms suggestive of keratitis (such as eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye) to an ophthalmologist.

5.5 Erythema Multiforme Major, Stevens-Johnson Syndrome, and Toxic Epidermal Necrolysis

Postmarketing cases consistent with erythema multiforme major (EMM), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients receiving TAGRISSO [see Postmarketing (6.2)]. Withhold TAGRISSO if EMM, SJS, or TEN is suspected and permanently discontinue if confirmed.

5.6 Cutaneous Vasculitis

Postmarketing cases of cutaneous vasculitis including leukocytoclastic vasculitis, urticarial vasculitis, and IgA vasculitis have been reported in patients receiving TAGRISSO [see Postmarketing (6.2)]. 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 of TAGRISSO based on severity.

5.7 Aplastic Anemia

Aplastic anemia has been reported in patients treated with TAGRISSO in clinical trials (0.06% of 1813) and postmarketing [see Postmarketing (6.2)]. Some cases had a fatal outcome. Inform patients of the signs and symptoms of aplastic anemia including but not limited to, new or persistent fevers, bruising, bleeding, and pallor. If aplastic anemia is suspected, withhold TAGRISSO and obtain a hematology consultation. If aplastic anemia is confirmed, permanently discontinue TAGRISSO [see Dosage and Administration (2.5) ].

Perform complete blood count with differential before starting TAGRISSO, periodically throughout treatment, and more frequently if indicated.

5.8 Embryo-Fetal Toxicity

Based on data from animal studies and its mechanism of action, TAGRISSO can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, osimertinib caused post-implantation fetal loss when administered during early development at a dose exposure 1.5 times the exposure at the recommended clinical dose. When males were treated prior to mating with untreated females, there was an increase in preimplantation embryonic loss at plasma exposures of approximately 0.5 times those observed at the recommended dose of 80 mg once daily. Verify pregnancy status of females of reproductive potential prior to initiating TAGRISSO. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TAGRISSO and for 6 weeks after the final dose. Advise males with female partners of reproductive potential to use effective contraception for 4 months after the final dose [see Use in Specific Populations (8.1 and 8.3)].

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 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 once daily in four randomized, controlled trials [ADAURA (n=337), FLAURA (n=338), FLAURA2 (monotherapy arm; n=275), and AURA3 (n=279)], two single arm trials [AURA Extension (n=201) and AURA2 (n=210)], and one dose-finding study, AURA1 (n=173) [see WARNINGS AND PRECAUTIONS (5)]. 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%).

The data described below reflect exposure to TAGRISSO (80 mg daily) in 337 patients with EGFR mutation-positive resectable NSCLC, and 833 patients with EGFR mutation-positive locally advanced or metastatic NSCLC in four randomized, controlled trials [ADAURA (n=337), 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 of interstitial lung disease, drug induced interstitial disease or radiation pneumonitis that required steroid treatment, serious arrhythmia or baseline QTc interval greater than 470 msec on electrocardiogram were excluded from enrollment in these studies.

Adjuvant Treatment of EGFR Mutation-Positive NSCLC - Monotherapy

The safety of TAGRISSO was evaluated in ADAURA, a randomized, double-blind, placebo-controlled trial for the adjuvant treatment of patients with EGFR exon 19 deletions or exon 21 L858R mutation-positive NSCLC who had complete tumor resection, with or without prior adjuvant chemotherapy. At time of DFS analysis, the median duration of exposure to TAGRISSO was 22.5 months.

Serious adverse reactions were reported in 16% of patients treated with TAGRISSO. The most common serious adverse reaction (≥1%) was pneumonia (1.5%). Adverse reactions leading to dose reductions occurred in 9% of patients treated with TAGRISSO. The most frequent adverse reactions leading to dose reductions or interruptions were diarrhea (4.5%), stomatitis (3.9%), nail toxicity (1.8%) and rash (1.8%). Adverse reactions leading to permanent discontinuation occurred in 11% of patients treated with TAGRISSO. The most frequent adverse reactions leading to discontinuation of TAGRISSO were interstitial lung disease (2.7%), and rash (1.2%).

Tables 3 and 4 summarize common adverse reactions and laboratory abnormalities which occurred in ADAURA.

Table 3. Adverse Reactions Occurring in ≥10% of Patients Receiving TAGRISSO in ADAURANCI CTCAE v4.0.

Adverse Reaction	TAGRISSO(N=337)		PLACEBO(N=343)
	All Grades (%)	Grade 3 or higher All events were grade 3. (%)	All Grades (%)	Grade 3 or higher (%)
Gastrointestinal Disorders
DiarrheaIncludes diarrhea, colitis, enterocolitis, enteritis.	47	2.4	20	0.3
StomatitisIncludes aphthous ulcer, cheilitis, gingival ulceration, glossitis, tongue ulceration, stomatitis and mouth ulceration.	32	1.8	7	0
Abdominal PainIncludes abdominal discomfort, abdominal pain, abdominal lower pain, abdominal upper pain, epigastric discomfort, hepatic pain.	12	0.3	7	0
Skin Disorders
RashIncludes rash, rash generalized, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pustular, rash pruritic, rash vesicular, rash follicular, erythema, folliculitis, acne, dermatitis, dermatitis acneiform, dermatitis bullous, dermatitis exfoliative generalized, drug eruption, eczema, eczema asteatotic, lichen planus, skin erosion, pustule.	40	0.6	19	0
Nail toxicityIncludes nail bed disorder, nail bed inflammation, nail bed infection, nail discoloration, nail pigmentation, nail disorder, nail toxicity, nail dystrophy, nail infection, nail ridging, onychalgia, onychoclasis, onycholysis, onychomadesis, onychomalacia, paronychia.	37	0.9	3.8	0
Dry skinIncludes dry skin, skin fissures, xerosis, eczema, xeroderma.	29	0.3	7	0
PruritusIncludes pruritus, pruritus generalized, eyelid pruritus.	19	0	9	0
Respiratory, Thoracic and Mediastinal Disorders
CoughIncludes cough, productive cough, upper-airway cough syndrome.	19	0	19	0
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal PainIncludes arthralgia, arthritis, back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, pain in extremity, and spinal pain.	18	0.3	25	0.3
Infection and Infestation Disorders
Nasopharyngitis	14	0	10	0
Upper respiratory tract infection	13	0.6	10	0
Urinary Tract InfectionIncludes cystitis, urinary tract infection, and urinary tract infection bacterial.	10	0.3	7	0
General Disorders and Administration Site Conditions
FatigueIncludes asthenia, fatigue.	13	0.6	9	0.3
Nervous System Disorders
DizzinessIncludes dizziness, vertigo, and vertigo positional.	10	0	9	0
Metabolism and Nutrition Disorders
Decreased appetite	13	0.6	3.8	0

Clinically relevant adverse reactions in ADAURA in <10% of patients receiving TAGRISSO were alopecia (6%), epistaxis (6%), interstitial lung disease (3%), palmar-plantar erythrodysesthesia syndrome (1.8%), skin hyperpigmentation (1.8%), urticaria (1.5%), keratitis (0.6%), QTc interval prolongation (0.6%), and erythema multiforme (0.3%). QTc interval prolongation represents the incidence of patients who had a QTcF prolongation >500 msec.

Table 4. Laboratory Abnormalities Worsening from Baseline in ≥20% of Patients in ADAURA

Laboratory Abnormality NCI CTCAE v4.0 Based on the number of patients with available follow-up laboratory data.	TAGRISSO (N=337)		PLACEBO (N=343)
	All Grades (%)	Grade 3 or Grade 4 (%)	All Grades (%)	Grade 3 or Grade 4 (%)
Hematology
Leukopenia	54	0	25		0
Thrombocytopenia	47	0	7		0.3
Lymphopenia	44	3.4	14		0.9
Anemia	30	0	12		0.3
Neutropenia	26	0.6	10		0.3
Chemistry
Hyperglycemia	25	2.3	30		0.9
Hypermagnesemia	24	1.3	14		1.5
Hyponatremia	20	1.8	16		1.5

Laboratory abnormalities in ADAURA that occurred in <20% of patients receiving TAGRISSO was increased blood creatinine (10%).

Previously Untreated EGFR Mutation-Positive Metastatic Non-Small Cell Lung Cancer - Monotherapy

The safety of TAGRISSO was evaluated in FLAURA, a multicenter international double-blind randomized (1:1) active‑controlled trial conducted in 556 patients with EGFR exon 19 deletion or exon 21 L858R mutation-positive, unresectable or metastatic NSCLC who had not received previous systemic treatment for advanced disease. The median duration of exposure to TAGRISSO was 16.2 months.

Serious adverse reactions were reported in 4% of patients treated with TAGRISSO; the most common serious adverse reactions (≥1%) were pneumonia (2.9%), ILD/pneumonitis (2.1%), and pulmonary embolism (1.8%). Dose reductions occurred in 2.9% of patients treated with TAGRISSO. The most frequent adverse reactions leading to dose reductions or interruptions were prolongation of the QT interval as assessed by ECG (4.3%), diarrhea (2.5%), and lymphopenia (1.1%). Adverse reactions leading to permanent discontinuation occurred in 13% of patients treated with TAGRISSO. The most frequent adverse reaction leading to discontinuation of TAGRISSO was ILD/pneumonitis (3.9%).

Tables 5 and 6 summarize common adverse reactions and laboratory abnormalities which occurred in FLAURA.

Table 5. Adverse Reactions Occurring in ≥10% of Patients Receiving TAGRISSO in FLAURANCI CTCAE v4.0

Adverse Reaction	TAGRISSO (N=279)		EGFR TKI comparator (gefitinib or erlotinib) (N=277)
	Any Grade (%)	Grade 3 or higher (%)	Any Grade (%)	Grade 3 or higher (%)
Gastrointestinal Disorders
DiarrheaOne grade 5 (fatal) event was reported (diarrhea) for EGFR TKI comparator.	58	2.2	57	2.5
StomatitisIncludes stomatitis and mouth ulceration.	32	0.7	22	1.1
Nausea	14	0	19	0
Constipation	15	0	13	0
Vomiting	11	0	11	1.4
Skin Disorders
RashIncludes rash, rash generalized, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pustular, rash pruritic, rash vesicular, rash follicular, erythema, folliculitis, acne, dermatitis, dermatitis acneiform, drug eruption, skin erosion, pustule.	58	1.1	78	7
Dry skinIncludes dry skin, skin fissures, xerosis, eczema, xeroderma.	36	0.4	36	1.1
Nail toxicityIncludes nail bed disorder, nail bed inflammation, nail bed infection, nail discoloration, nail pigmentation, nail disorder, nail toxicity, nail dystrophy, nail infection, nail ridging, onychalgia, onychoclasis, onycholysis, onychomadesis, onychomalacia, paronychia.	35	0.4	33	0.7
PruritusIncludes pruritus, pruritus generalized, eyelid pruritus.	17	0.4	17	0
General Disorders and Administration Site Conditions
FatigueIncludes fatigue, asthenia.	21	1.4	15	1.4
Pyrexia	10	0	4	0.4
Metabolism and Nutrition Disorders
Decreased appetite	20	2.5	19	1.8
Respiratory, Thoracic and Mediastinal Disorders
Cough	17	0	15	0.4
Dyspnea	13	0.4	7	1.4
Neurologic Disorders
Headache	12	0.4	7	0
Cardiac Disorders
Prolonged QT IntervalIncludes prolonged QT interval reported as adverse reaction.	10	2.2	4	0.7
Infection and Infestation Disorders
Upper Respiratory Tract Infection	10	0	7	0

Clinically relevant adverse reactions in FLAURA in <10% of patients receiving TAGRISSO were alopecia (7%), epistaxis (6%), interstitial lung disease (3.9%), urticaria (2.2%), palmar-plantar erythrodysesthesia syndrome (1.4%), QTc interval prolongation (1.1%), keratitis (0.4%), and skin hyperpigmentation (0.4)%. QTc interval prolongation represents the incidence of patients who had a QTcF prolongation >500 msec.

Table 6. Laboratory Abnormalities Worsening from Baseline in ≥20% of Patients in FLAURA

Laboratory AbnormalityNCI CTCAE v4.0 Each test incidence, except for hyperglycemia, is based on the number of patients who had both baseline and at least one on-study laboratory measurement available (TAGRISSO range: 267 - 273 and EGFR TKI comparator range: 256 - 268).	TAGRISSO (N=279)		EGFR TKI comparator (gefitinib or erlotinib) (N=277)
	All Grades (%)	Grade 3 or Grade 4 (%)	All Grades (%)	Grade 3 or Grade 4 (%)
Hematology
Lymphopenia	63	6	36	4.2
Anemia	59	0.7	47	0.4
Thrombocytopenia	51	0.7	12	0.4
Neutropenia	41	3	10	0
Chemistry
HyperglycemiaHyperglycemia is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: TAGRISSO (179) and EGFR comparator (191).	37	0	31	0.5
Hypermagnesemia	30	0.7	11	0.4
Hyponatremia	26	1.1	27	1.5
Increased AST	22	1.1	43	4.1
Increased ALT	21	0.7	52	8
Hypokalemia	16	0.4	22	1.1
Hyperbilirubinemia	14	0	29	1.1

Clinically relevant laboratory abnormalities in FLAURA that occurred in <20% of patients receiving TAGRISSO was increased blood creatinine (9%).

Previously Untreated EGFR Mutation-Positive Locally Advanced or Metastatic Non-Small Cell Lung Cancer – TAGRISSO in Combination with Pemetrexed and Platinum-based Chemotherapy

The safety of TAGRISSO in combination with pemetrexed and platinum-based chemotherapy was evaluated in FLAURA2, a multicenter international open-label, randomized (1:1), active-controlled trial conducted in 557 patients with EGFR exon 19 deletion or exon 21 L858R mutation-positive, locally advanced or metastatic NSCLC who had not received previous systemic treatment for advanced disease. The median duration of exposure to TAGRISSO in combination with pemetrexed and platinum-based chemotherapy was 22.3 months and the median duration of exposure to TAGRISSO monotherapy was 19.3 months.

Serious adverse reactions were reported in 38% of patients treated with TAGRISSO in combination with pemetrexed and platinum-based chemotherapy; the most frequently reported serious adverse reactions (≥2%) in the combination arm were anemia (3.3%), COVID-19 (2.5%), pneumonia (2.5%), febrile neutropenia (2.2%), thrombocytopenia (2.2%), and pulmonary embolism (2.2%). Fatal adverse reactions occurred in 7% of patients who received TAGRISSO in combination with pemetrexed and platinum-based chemotherapy including pulmonary embolism (1.1%), pneumonia (1.1%) and cardiomyopathy (1.1%).

Dosage interruptions of TAGRISSO, when given with pemetrexed and platinum-based chemotherapy, due to an adverse reaction occurred in 44% of patients. Adverse reactions which required dosage interruption in ≥ 2% of patients included anemia (4.7%), neutropenia (4.3%), diarrhea (3.6%), febrile neutropenia (3.3%) and thrombocytopenia (2.9%).

Permanent discontinuation of TAGRISSO when given in combination with pemetrexed and platinum-based chemotherapy due to an adverse reaction occurred in 11% of patients. Adverse reactions which resulted in permanent discontinuation of TAGRISSO in ≥1% of patients included ILD/pneumonitis (2.9%), pneumonia (1.4%), and decreased ejection fraction (1.1%).

Adverse reactions leading to dose reduction of TAGRISSO occurred in 10% of patients treated with TAGRISSO in combination with pemetrexed and platinum-based chemotherapy. The most frequently reported adverse reactions leading to dose reduction of TAGRISSO in the combination arm in ≥1% of patients were diarrhea (1.1%) and rash (1.1%).

Tables 7 and 8 summarize common adverse reactions and laboratory abnormalities which occurred in FLAURA2.

Table 7. Adverse Reactions Occurring in ≥10% of Patients Receiving TAGRISSO in FLAURA2NCI CTCAE v5.0

Adverse Reaction	TAGRISSO with Pemetrexed and Platinum-based Chemotherapy (N=276)		TAGRISSO (N=275)
	Any Grade (%)	Grade 3 or higher (%)	Any Grade (%)	Grade 3 or higher (%)
Gastrointestinal Disorders
Diarrhea	43	2.9	41	0.4
StomatitisIncludes stomatitis and mouth ulceration.	31	0.4	21	0.4
Skin Disorders
RashIncludes rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pustular, rash pruritic, rash vesicular, rash follicular, erythema, folliculitis, acne, dermatitis, dermatitis acneiform, drug eruption, skin erosion, pustule.	49	2.5	44	1.5
Nail toxicityIncludes nail bed disorder, nail bed inflammation, nail bed infection, nail discoloration, nail pigmentation, nail disorder, nail toxicity, nail dystrophy, nail infection, nail ridging, onychalgia, onychoclasis, onycholysis, onychomadesis, onychomalacia, paronychia.	27	0.7	32	0.4
Dry skinIncludes dry skin, skin fissures, xerosis, eczema, xeroderma.	24	0	31	0
PruritusIncludes pruritus, eyelid pruritus.	8	0	11	0

Clinically relevant adverse reactions in FLAURA2 in <10% of patients receiving TAGRISSO in combination with pemetrexed and platinum-based chemotherapy were alopecia (9%), epistaxis (7%), palmar-plantar erythrodysesthesia syndrome (5%), interstitial lung disease (3.3%), skin hyperpigmentation (2.5%), QTc interval prolongation (1.8%), erythema multiforme (1.4%), urticaria (1.4%), and keratitis (0.7%). QTc interval prolongation represents the incidence of patients who had a QTcF prolongation >500 msec.

Table 8. Laboratory Abnormalities Worsening from Baseline in ≥20% of Patients in FLAURA2NCI CTCAE v5.0 Findings based on test results presented as CTCAE grade shifts.

Laboratory Abnormality Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available (TAGRISSO with pemetrexed and platinum-based chemotherapy arm: 275 and TAGRISSO monotherapy arm: 275).	TAGRISSO with Pemetrexed and Platinum-based Chemotherapy (N=276)		TAGRISSO (N=275)
	All Grades (%)	Grade 3 or Grade 4 (%)	All Grades (%)	Grade 3 or Grade 4 (%)
Hematology
Leukopenia	88	20	53	3.3
Thrombocytopenia	85	16	44	1.8
Neutropenia	85	36	40	4.7
Lymphopenia	78	16	55	7
Chemistry
Blood creatinine increased	22	0.4	8	0

Previously Treated EGFR T790M Mutation-Positive Metastatic Non-Small Cell Lung Cancer – Monotherapy

The safety of TAGRISSO was evaluated in AURA3, a multicenter international open label randomized (2:1) controlled trial conducted in 419 patients with unresectable or metastatic EGFR T790M mutation-positive NSCLC who had progressive disease following first line EGFR TKI treatment. A total of 279 patients received TAGRISSO 80 mg orally once daily until intolerance to therapy, disease progression, or investigator determination that the patient was no longer benefiting from treatment. A total of 136 patients received pemetrexed plus either carboplatin or cisplatin every three weeks for up to 6 cycles; patients without disease progression after 4 cycles of chemotherapy could continue maintenance pemetrexed until disease progression, unacceptable toxicity, or investigator determination that the patient was no longer benefiting from treatment. Left Ventricular Ejection Fraction (LVEF) was evaluated at screening and every 12 weeks. The median duration of treatment was 8.1 months for patients treated with TAGRISSO and 4.2 months for chemotherapy-treated patients. The trial population characteristics were: median age 62 years, age less than 65 (58%), female (64%), Asian (65%), never smokers (68%), and ECOG PS 0 or 1 (100%).

Serious adverse reactions were reported in 18% of patients treated with TAGRISSO and 26% in the chemotherapy group. No single serious adverse reaction was reported in 2% or more patients treated with TAGRISSO. One patient (0.4%) treated with TAGRISSO experienced a fatal adverse reaction (ILD/pneumonitis).

Dose reductions occurred in 2.9% of patients treated with TAGRISSO. The most frequent adverse reactions leading to dose reductions or interruptions were prolongation of the QT interval as assessed by ECG (1.8%), neutropenia (1.1%), and diarrhea (1.1%). Adverse reactions resulting in permanent discontinuation of TAGRISSO occurred in 7% of patients treated with TAGRISSO. The most frequent adverse reaction leading to discontinuation of TAGRISSO was ILD/pneumonitis (3%).

Tables 9 and 10 summarize common adverse reactions and laboratory abnormalities which occurred in TAGRISSO-treated patients in AURA3.

Table 9. Adverse Reactions Occurring in ≥10% of Patients Receiving TAGRISSO in AURA3NCI CTCAE v4.0.

Adverse Reaction	TAGRISSO (N=279)			Chemotherapy (Pemetrexed/Cisplatin or Pemetrexed/Carboplatin) (N=136)
	All Grades No grade 4 events were reported. (%)		Grade 3/4 (%)	All Grades (%)	Grade 3/4 (%)
Gastrointestinal Disorders
Diarrhea	41	1.1		11	1.5
Nausea	16	0.7		49	3.7
StomatitisIncludes stomatitis and mouth ulceration.	19	0		15	1.5
Constipation	14	0		35	0
Vomiting	11	0.4		20	2.2
Skin Disorders
RashIncludes rash, rash generalized, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pustular, erythema, folliculitis, acne, dermatitis, acneiform dermatitis, pustule.	34	0.7		6	0
Dry skinIncludes dry skin, eczema, skin fissures, xerosis.	23	0		4.4	0
Nail toxicityIncludes nail disorders, nail bed disorders, nail bed inflammation, nail bed tenderness, nail discoloration, nail disorder, nail dystrophy, nail infection, nail ridging, nail toxicity, onychalgia, onychoclasis, onycholysis, onychomadesis, paronychia.	22	0		1.5	0
PruritusIncludes pruritus, pruritus generalized, eyelid pruritus.	13	0		5	0
General Disorders and Administration Site Conditions
FatigueIncludes fatigue, asthenia.	22	1.8		40	5.1
Metabolism and Nutrition Disorders
Decreased appetite	18		1.1	36	2.9
Respiratory, Thoracic and Mediastinal Disorders
Cough	17		0	14	0
Musculoskeletal and Connective Tissue Disorders
Back pain	10		0.4	9	0.7

Clinically relevant adverse reactions in AURA3 in <10% of patients receiving TAGRISSO were epistaxis (5%), interstitial lung disease (3.9%), alopecia (3.6%), urticaria (2.9%), palmar-plantar erythrodysesthesia syndrome (1.8%), QTc interval prolongation (1.4%), keratitis (1.1%), and erythema multiforme (0.7%), and skin hyperpigmentation (0.4%). QTc interval prolongation represents the incidence of patients who had a QTcF prolongation >500 msec.

Table 10. Laboratory Abnormalities Worsening from Baseline in ≥20% of Patients in AURA3

Laboratory AbnormalityNCI CTCAE v4.0 Each test incidence, except for hyperglycemia, is based on the number of patients who had both baseline and at least one on-study laboratory measurement available (TAGRISSO 279, Chemotherapy comparator 131).	TAGRISSO (N=279)		Chemotherapy (Pemetrexed/Cisplatin or Pemetrexed/Carboplatin) (N=131)
	All Grades (%)	Grade 3 or Grade 4 (%)	All Grades (%)		Grade 3 or Grade 4 (%)
Hematology
Anemia	43	0		79	3.1
Lymphopenia	63	8		61	10
Thrombocytopenia	46	0.7		48	7
Neutropenia	27	2.2		49	12
Chemistry
Hypermagnesemia	27	1.8		9	1.5
Hyponatremia	26	2.2		36	1.5
HyperglycemiaHyperglycemia is based on the number of patients who had both baseline and at least one on-study laboratory measurement available (TAGRISSO 270, Chemotherapy 5; fasting glucose was not a protocol requirement for patients in the chemotherapy arm).	20	0		NA	NA
Hypokalemia	9	1.4		18	1.5
NA=Not Applicable

Clinically relevant laboratory abnormalities in AURA3 that occurred in <20% of patients receiving TAGRISSO included increased blood creatinine (7%).

Other Clinical Trials Experience

The following adverse reaction has been reported following administration of TAGRISSO: increased blood creatine phosphokinase.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of TAGRISSO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

•  
  • • Skin and subcutaneous tissue: Erythema multiforme major (EMM), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), cutaneous vasculitis, erythema dyschromicum perstans
  • • Blood and lymphatic system disorders: Aplastic anemia