6 ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the labeling:

•: Interstitial Lung Disease/Pneumonitis [see Error! Hyperlink reference not valid.]
•: QTc Interval Prolongation [see Error! Hyperlink reference not valid.]
•: Cardiomyopathy [see Error! Hyperlink reference not valid.]
•: Keratitis [see Error! Hyperlink reference not valid.]
•: Erythema multiforme, Stevens-Johnson syndrome, and Toxic epidermal necrolysis [see Error! Hyperlink reference not valid.]
•: Cutaneous Vasculitis [see Error! Hyperlink reference not valid.]
•: Aplastic Anemia [see Error! Hyperlink reference not valid.]

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 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 4 and 5 summarize common adverse reactions and laboratory abnormalities which occurred in ADAURA.

Table 4. Adverse Reactions Occurring in ≥10% of Patients Receiving TAGRISSO in ADAURA*
Adverse Reaction	TAGRISSO (N=337)		PLACEBO (N=343)
Adverse Reaction	All Grades (%)	Grade 3 or higher† (%)	All Grades (%)	Grade 3 or higher† (%)
* NCI CTCAE v4.0. † All events were grade 3. ‡ Includes diarrhea, colitis, enterocolitis, enteritis. § Includes aphthous ulcer, cheilitis, gingival ulceration, glossitis, tongue ulceration, stomatitis and mouth ulceration. ¶ Includes abdominal discomfort, abdominal pain, abdominal lower pain, abdominal upper pain, epigastric discomfort, hepatic pain. # Includes 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. Þ Includes 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. ß Includes dry skin, skin fissures, xerosis, eczema, xeroderma. à Includes pruritus, pruritus generalized, eyelid pruritus. è Includes cough, productive cough, upper-airway cough syndrome. ð Includes arthralgia, arthritis, back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, pain in extremity, and spinal pain. ø Includes cystitis, urinary tract infection, and urinary tract infection bacterial. ý Includes asthenia, fatigue. £ Includes dizziness, vertigo, and vertigo positional.
Gastrointestinal Disorders
Diarrhea‡	47	2.4	20	0.3
Stomatitis§	32	1.8	7	0
Abdominal Pain¶	12	0.3	7	0
Skin Disorders
Rash#	40	0.6	19	0
Nail toxicityÞ	37	0.9	3.8	0
Dry skinß	29	0.3	7	0
Pruritusà	19	0	9	0
Respiratory, Thoracic and Mediastinal Disorders
Coughè	19	0	19	0
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal Painð	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 Infectionø	10	0.3	7	0
General Disorders and Administration Site Conditions
Fatigueý	13	0.6	9	0.3
Metabolism and Nutrition Disorders
Decreased appetite	13	0.6	3.8	0
Nervous System Disorders
Dizziness£	10	0	9	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 5. Laboratory Abnormalities Worsening from Baseline in ≥20% of Patients in ADAURA
Laboratory Abnormality*†	TAGRISSO (N=337)		PLACEBO (N=343)
Laboratory Abnormality*†	All Grades (%)	Grade 3 or Grade 4 (%)	All Grades (%)	Grade 3 or Grade 4 (%)
* NCI CTCAE v4.0 † Based on the number of patients with available follow-up laboratory data.
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%).

Locally Advanced, Unresectable (Stage III) EGFR Mutation Positive NSCLC

The safety of TAGRISSO was evaluated in LAURA, a double blind, randomized (2:1), placebo controlled study conducted in 216 patients with EGFR exon 19 deletions or exon 21 L858R mutation positive, locally advanced, unresectable (stage III) NSCLC, who had not progressed during or following definitive platinum based chemoradiation therapy. Among patients who received TAGRISSO, 81% were exposed for 6 months or longer and 74% were exposed for one year or longer.

Serious adverse reactions were reported in 38% of patients treated with TAGRISSO. The most common serious adverse reactions (≥1%) included ILD/pneumonitis (13%), pneumonia (6%) and gastroenteritis (1.4%). Fatal adverse reactions occurred in 1.4% of patients who received TAGRISSO due to pneumonia (0.7%) and ILD/pneumonitis (0.7%).

Permanent discontinuation of TAGRISSO due to an adverse reaction occurred in 13% of patients. The adverse reactions resulting in permanent discontinuation of TAGRISSO in > 1 patient were ILD/pneumonitis (7%) and pneumonia (1.4%).

Dosage interruptions of TAGRISSO due to an adverse reaction occurred in 56% of patients. The adverse reactions requiring dosage interruption in ≥2% of patients were ILD/pneumonitis (35%), pneumonia (6%), COVID-19 (4.2%), neutropenia (2.1%), and QTc interval prolongation (2.1%).

Dose reductions of TAGRISSO due to an adverse reaction occurred in 8% of patients.

The most common adverse reactions, including laboratory abnormalities worsening from baseline, were lymphopenia, leukopenia, ILD/pneumonitis, thrombocytopenia, neutropenia, rash, diarrhea, nail toxicity, musculoskeletal pain, cough, and COVID-19.

Tables 6 and 7 summarize common adverse reactions and laboratory abnormalities which occurred in LAURA.

Table 6. Adverse Reactions in ≥10% of Patients Receiving TAGRISSO in LAURA*
Adverse Reaction	TAGRISSO (N=143)		Placebo (N=73)
Adverse Reaction	Any Grade (%)	Grade 3 or 4(%)	Any Grade (%)	Grade 3 or 4 (%)
* NCI CTCAE v5.0 † Includes radiation pneumonitis, radiation lung fibrosis, pneumonitis, interstitial lung disease (ILD), pulmonary fibrosis. ‡ Includes cough, productive cough. § Includes rash, maculo-papular rash, pustular rash, pruritic rash, folliculitis, papule, dermatitis, acneiform dermatitis, atopic dermatitis, eczema, asteatotic eczema, acne, urticaria. ¶ Includes nail bed disorder, nail disorder, nail discoloration, nail infection, onychoclasis, paronychia. # Includes dry skin, skin fissures, senile xerosis, xeroderma. Þ Includes diarrhea, enteritis. ß Includes stomatitis, aphthous ulceration, mouth ulceration. à Includes musculoskeletal chest pain, myalgia, arthritis, arthralgia, back pain, bone pain, musculoskeletal pain, neck pain, pain in extremity, spinal osteoarthritis. è Includes COVID-19 and COVID-19 pneumonia. ð Includes pneumonia, aspiration pneumonia, viral pneumonia, Pneumocystis jiroveci pneumonia, Haemophilus pneumonia, lower respiratory tract infection.
Respiratory, Thoracic and Mediastinal Disorders
ILD/pneumonitis†	56	3.5	38	0
Cough‡	20	0	15	0
Skin Disorders
Rash§	39	0.7	19	0
Nail toxicity¶	23	0	1.4	0
Dry skin#	17	0.7	5	0
Pruritus	13	0	7	0
Gastrointestinal Disorders
DiarrheaÞ	36	2.1	14	0
Stomatitisß	15	0	5	0
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal painà	20	0.7	26	0
Infection and Infestation Disorders
COVID-19è	20	0.7	10	0
Pneumoniað	15	3.5	10	5
Metabolism and Nutrition Disorders
Decreased appetite	15	0.7	5	0

Clinically relevant adverse reactions in LAURA in <10% of patients receiving TAGRISSO were dyspnea (8%), urinary tract infection (8%), alopecia (1.4%), urticaria (1.4%), epistaxis (0.7%), keratitis (0.7%), and QTc interval prolongation (0.7%). QTc interval prolongation represents the incidence of patients who had a QTc prolongation >500 msec.

Table 7. Laboratory Abnormalities Worsening from Baseline in ≥20% of Patients in LAURA
Laboratory Abnormality*†	TAGRISSO (N=143)		Placebo (N=73)
Laboratory Abnormality*†	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
* NCI CTCAE v5.0 † Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available (TAGRISSO arm: 142 and placebo arm: 72).
Hematology
Lymphopenia	70	3.5	40	1.4
Leukopenia	66	2.8	24	0
Thrombocytopenia	51	1.4	8	1.4
Neutropenia	42	2.1	15	1.4

A clinically relevant laboratory abnormality in LAURA that occurred in <20% of patients receiving TAGRISSO was increased blood creatinine (19%).

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 8 and 9 summarize common adverse reactions and laboratory abnormalities which occurred in FLAURA.

Table 8. Adverse Reactions Occurring in ≥10% of Patients Receiving TAGRISSO in FLAURA*
* NCI CTCAE v4.0 † One grade 5 (fatal) event was reported (diarrhea) for EGFR TKI comparator. ‡ Includes stomatitis and mouth ulceration. § Includes 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. ¶ Includes dry skin, skin fissures, xerosis, eczema, xeroderma. # Includes 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. Þ Includes pruritus, pruritus generalized, eyelid pruritus. ß Includes fatigue, asthenia. à Includes prolonged QT interval reported as adverse reaction.
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
Diarrhea†	58	2.2	57	2.5
Stomatitis‡	32	0.7	22	1.1
Nausea	14	0	19	0
Constipation	15	0	13	0
Vomiting	11	0	11	1.4
Skin Disorders
Rash§	58	1.1	78	7
Dry skin¶	36	0.4	36	1.1
Nail toxicity#	35	0.4	33	0.7
PruritusÞ	17	0.4	17	0
General Disorders and Administration Site Conditions
Fatigueß	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 Intervalà	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 9. Laboratory Abnormalities Worsening from Baseline in ≥20% of Patients in FLAURA
* NCI 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). ‡ Hyperglycemia 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).
Laboratory Abnormality*†	TAGRISSO (N=279)		EGFR TKI comparator (gefitinib or erlotinib) (N=277)
Laboratory Abnormality*†	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
Hyperglycemia‡	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

A clinically relevant laboratory abnormality 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 10 and 11 summarize common adverse reactions and laboratory abnormalities which occurred in FLAURA2.

Table 10. Adverse Reactions Occurring in ≥10% of Patients Receiving TAGRISSO in FLAURA2*
Adverse Reaction	TAGRISSO with Pemetrexed and Platinum-based Chemotherapy (N=276)		TAGRISSO (N=275)
Adverse Reaction	Any Grade (%)	Grade 3 or higher (%)	Any Grade (%)	Grade 3 or higher (%)
* NCI CTCAE v5.0 † Includes 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. ‡ Includes 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. § Includes dry skin, skin fissures, xerosis, eczema, xeroderma. ¶ Includes pruritus, eyelid pruritus. # Includes stomatitis and mouth ulceration.
Skin Disorders
Rash†	49	2.5	44	1.5
Nail toxicity‡	27	0.7	32	0.4
Dry skin§	24	0	31	0
Pruritus¶	8	0	11	0
Gastrointestinal Disorders
Diarrhea	43	2.9	41	0.4
Stomatitis#	31	0.4	21	0.4

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 11. Laboratory Abnormalities Worsening from Baseline in ≥20% of Patients in FLAURA2*†
Laboratory Abnormality‡	TAGRISSO with Pemetrexed and Platinum-based Chemotherapy (N=276)		TAGRISSO (N=275)
Laboratory Abnormality‡	All Grades (%)	Grade 3 or Grade 4 (%)	All Grades (%)	Grade 3 or Grade 4 (%)
* NCI CTCAE v5.0 † Findings based on test results presented as CTCAE grade shifts. ‡ 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).
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 12 and 13 summarize common adverse reactions and laboratory abnormalities which occurred in TAGRISSO-treated patients in AURA3.

Table 12. Adverse Reactions Occurring in ≥10% of Patients Receiving TAGRISSO in AURA3*
* NCI CTCAE v4.0. † No grade 4 events were reported. ‡ Includes stomatitis and mouth ulceration. § Includes rash, rash generalized, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pustular, erythema, folliculitis, acne, dermatitis, acneiform dermatitis, pustule. ¶ Includes dry skin, eczema, skin fissures, xerosis. # Includes 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. Þ Includes pruritus, pruritus generalized, eyelid pruritus. ß Includes fatigue, asthenia.
Adverse Reaction	TAGRISSO (N=279)		Chemotherapy (Pemetrexed/Cisplatin or Pemetrexed/Carboplatin) (N=136)
Adverse Reaction	All Grades† (%)	Grade 3/4† (%)	All Grades† (%)	Grade 3/4† (%)
Gastrointestinal Disorders
Diarrhea	41	1.1	11	1.5
Nausea	16	0.7	49	3.7
Stomatitis‡	19	0	15	1.5
Constipation	14	0	35	0
Vomiting	11	0.4	20	2.2
Skin Disorders
Rash§	34	0.7	6	0
Dry skin¶	23	0	4.4	0
Nail toxicity#	22	0	1.5	0
PruritusÞ	13	0	5	0
General Disorders and Administration Site Conditions
Fatigueß	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 13. Laboratory Abnormalities Worsening from Baseline in ≥20% of Patients in AURA3
* NCI 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). ‡ Hyperglycemia 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).
Laboratory Abnormality*†	TAGRISSO (N=279)		Chemotherapy (Pemetrexed/Cisplatin or Pemetrexed/Carboplatin) (N=131)
Laboratory Abnormality*†	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
Hyperglycemia‡	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.

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