6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

Diarrhea [see Warnings and Precautions (5.1)]
Bullous and Exfoliative Skin Disorders [see Warnings and Precautions (5.2)]
Interstitial Lung Disease [see Warnings and Precautions (5.3)]
Hepatic Toxicity [see Warnings and Precautions (5.4)]
Gastrointestinal Perforation [see Warnings and Precautions (5.5)]
Keratitis [see Warnings and Precautions (5.6)]

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 GILOTRIF for clinically significant adverse reactions in 4257 patients enrolled in LUX-Lung 3 (n=229) and LUX-Lung 8 (n=392), and 3636 patients with cancer enrolled in 42 studies of GILOTRIF administered alone or in combination with other anti-neoplastic drugs at GILOTRIF doses ranging from 10-70 mg daily or at doses 10-160 mg in other regimens. The mean exposure was 5.5 months. The population included patients with various cancers, the most common of which were NSCLC, breast, colorectal, brain, and head and neck.

The data described below reflect exposure to GILOTRIF as a single agent in LUX-Lung 3, a randomized, active-controlled trial conducted in patients with EGFR mutation-positive, metastatic NSCLC, and in LUX-Lung 8, a randomized, active-controlled trial in patients with metastatic squamous NSCLC progressing after platinum-based chemotherapy.

EGFR Mutation-Positive Metastatic NSCLC

The safety of GILOTRIF was evaluated in 229 EGFR-tyrosine kinase inhibitor-naïve patients with EGFR mutation-positive, metastatic non-squamous NSCLC enrolled in a randomized (2:1), multicenter, open-label trial (LUX-Lung 3). Patients received either GILOTRIF 40 mg daily until documented disease progression or intolerance to the therapy or pemetrexed 500 mg/m² followed after 30 minutes by cisplatin 75 mg/m² every three weeks for a maximum of six treatment courses. The median exposure was 11 months for patients treated with GILOTRIF and 3.4 months for patients treated with pemetrexed/cisplatin.

The overall trial population had a median age of 61 years; 61% of patients in the GILOTRIF arm and 60% of patients in the pemetrexed/cisplatin arm were younger than 65 years. A total of 64% of patients on GILOTRIF and 67% of pemetrexed/cisplatin patients were female. More than two-thirds of patients were from Asia (GILOTRIF 70%; pemetrexed/cisplatin 72%).

Serious adverse reactions were reported in 29% of patients treated with GILOTRIF. The most frequent serious adverse reactions reported in patients treated with GILOTRIF were diarrhea (6.6%); vomiting (4.8%); and dyspnea, fatigue, and hypokalemia (1.7% each). Fatal adverse reactions in GILOTRIF-treated patients in LUX-Lung 3 included pulmonary toxicity/ILD-like adverse reactions (1.3%), sepsis (0.43%), and pneumonia (0.43%).

Dose reductions due to adverse reactions were required in 57% of GILOTRIF-treated patients. The most frequent adverse reactions that led to dose reduction in the patients treated with GILOTRIF were diarrhea (20%), rash/acne (19%), paronychia (14%), and stomatitis (10%). Discontinuation of therapy in GILOTRIF-treated patients for adverse reactions was 14.0%. The most frequent adverse reactions that led to discontinuation in GILOTRIF-treated patients were diarrhea (1.3%), ILD (0.9%), and paronychia (0.9%).

Clinical trials of GILOTRIF excluded patients with an abnormal left ventricular ejection fraction (LVEF), i.e., below the institutional lower limit of normal. In LUX-Lung 3, all patients were evaluated for LVEF at screening and every 9 weeks thereafter in the GILOTRIF-treated group and as needed in the pemetrexed/cisplatin group. More GILOTRIF-treated patients (2.2%; n=5) experienced ventricular dysfunction (defined as diastolic dysfunction, left ventricular dysfunction, or ventricular dilation; all <Grade 3) compared to chemotherapy-treated patients (0.9%; n=1).

Tables 1 and 2 summarize common adverse reactions and laboratory abnormalities in LUX-Lung 3.

Table 1 Adverse Reactions Reported in ≥10% of GILOTRIF-Treated Patients in LUX-Lung 3*
Adverse Reaction	GILOTRIF n=229		Pemetrexed/Cisplatin n=111
Adverse Reaction	All Grades (%)	Grade 3† (%)	All Grades (%)	Grade 3† (%)
*NCI CTCAE v 3.0
†None of the adverse reactions in this table except stomatitis (one patient on GILOTRIF [0.4%]) were Grade 4 in severity.
1Includes stomatitis, aphthous stomatitis, mucosal inflammation, mouth ulceration, oral mucosa erosion, mucosal erosion, mucosal ulceration
2Includes acne, acne pustular, dermatitis, acneiform dermatitis, dermatosis, drug eruption, erythema, exfoliative rash, folliculitis, rash, rash erythematous, rash follicular, rash generalized, rash macular, rash maculo-papular, rash pruritic, rash pustular, skin disorder, skin erosion, skin exfoliation, skin fissures, skin lesion, skin reaction, skin toxicity, skin ulcer
3Includes paronychia, nail infection, nail bed infection
Gastrointestinal disorders
Diarrhea	96	15	23	2
Stomatitis1	71	9	15	1
Cheilitis	12	0	1	0
Skin and subcutaneous tissue disorders
Rash/acneiform dermatitis2	90	16	11	0
Pruritus	21	0	1	0
Dry skin	31	0	2	0
Infections
Paronychia3	58	11	0	0
Cystitis	13	1	5	0
Respiratory, thoracic and mediastinal disorders
Epistaxis	17	0	2	1
Rhinorrhea	11	0	6	0
Investigations
Weight decreased	17	1	14	1
General disorders and administration site conditions
Pyrexia	12	0	6	0
Eye disorders
Conjunctivitis	11	0	3	0

Other clinically important adverse reactions observed in patients treated with GILOTRIF but that occurred at a higher incidence in pemetrexed/cisplatin-treated patients and not listed elsewhere in section 6 include: decreased appetite (29% Grades 1-4, 4% Grade 3), nausea (25% Grades 1-4, 4% Grade 3), and vomiting (23% Grades 1-4, 4% Grade 3).

Table 2 Laboratory Abnormalities Occurring in ≥10% of GILOTRIF Arm and at ≥2% Higher Incidence than in Chemotherapy Arm in LUX-Lung 3*
Laboratory Abnormality	GILOTRIF n=229		Pemetrexed/Cisplatin n=111
Laboratory Abnormality	All Grades (%)	Grades 3-4 (%)	All Grades (%)	Grades 3-4 (%)
*NCI CTCAE v 3.0
Increased alanine aminotransferase (ALT)	54	2	27	1
Increased alkaline phosphate	51	3	46	1
Decreased creatinine clearance	49	2	47	1
Increased aspartate aminotransferase (AST)	46	3	22	1
Decreased lymphocytes	38	9	32	14
Decreased potassium	30	8	11	3
Increased bilirubin	16	1	8	0

Previously Treated, Metastatic Squamous NSCLC

The safety of GILOTRIF was evaluated in 392 GILOTRIF-treated patients with metastatic squamous NSCLC enrolled in a randomized, multicenter, open-label trial (LUX-Lung 8). Patients were required to have received at least four cycles of platinum-based chemotherapy, ECOG Performance Status (PS) 0 or 1, and normal left ventricular ejection fraction (LVEF). Patients received GILOTRIF 40 mg once daily (n=392) or erlotinib 150 mg once daily (n=395). Treatment continued until documented disease progression or intolerance to the therapy. The median exposure was 2.1 months for patients treated with GILOTRIF, 15% were exposed for at least 6 months, and 5% were exposed for at least 12 months.

Among the 392 GILOTRIF-treated patients, the median age was 65 years, 53% were 65 years of age or older, 84% were male, 72% were White, 25% were Asian, ECOG PS 0 (32%) or 1 (68%).

Serious adverse reactions occurred in 44% of patients treated with GILOTRIF. The most frequent serious adverse reactions in patients treated with GILOTRIF were pneumonia (6.6%), diarrhea (4.6%), and dehydration and dyspnea (3.1% each). Fatal adverse reactions in GILOTRIF-treated patients included ILD (0.5%), pneumonia (0.3%), respiratory failure (0.3%), acute renal failure (0.3%), and general physical health deterioration (0.3%).

The most frequent adverse reactions that led to discontinuation in GILOTRIF-treated patients were diarrhea (4.1%) and rash/acne (2.6%).

Dose reductions due to adverse reactions were required in 27% of GILOTRIF-treated patients and discontinuation of GILOTRIF for adverse reactions was required for 20%. The most frequent adverse reactions that led to dose reduction in the patients treated with GILOTRIF were diarrhea (15%), rash/acne (5.9%), and stomatitis (3.1%).

Tables 3 and 4 summarize common adverse reactions and laboratory abnormalities in LUX-Lung 8.

Table 3 Adverse Reactions Reported in ≥10% of GILOTRIF-Treated Patients in LUX-Lung 8*
Adverse Reaction	GILOTRIF n=392		Erlotinib n=395
Adverse Reaction	All Grades (%)	Grade 3-4 (%)	All Grades (%)	Grade 3-4 (%)
*NCI CTCAE v 3.0
1Includes stomatitis, aphthous stomatitis, mucosal inflammation, mouth ulceration, oral mucosa erosion, mucosal erosion, mucosal ulceration
2Includes acne, dermatitis, acneiform dermatitis, eczema, erythema, exfoliative rash, folliculitis, rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, rash pustular, skin exfoliation, skin fissures, skin lesion, skin reaction, skin toxicity, skin ulcer
3Includes paronychia, nail infection, nail bed infection
Gastrointestinal disorders
Diarrhea	75	11	41	3
Stomatitis1	30	4	11	1
Nausea	21	2	16	1
Vomiting	13	1	10	1
Skin and subcutaneous tissue disorders
Rash/acneiform dermatitis2	70	7	70	11
Pruritus	10	0	13	0
Metabolism and nutrition disorders
Decreased appetite	25	3	26	2
Infections
Paronychia3	11	1	5	0

Table 4 Laboratory Abnormalities Occurring in ≥10% of GILOTRIF Arm and at ≥2% Higher Incidence than in Erlotinib Arm in LUX-Lung 8*
Laboratory Abnormality	GILOTRIF n=392		Erlotinib n=395
Laboratory Abnormality	All Grades (%)	Grades 3-4 (%)	All Grades (%)	Grades 3-4 (%)
*NCI CTCAE v 3.0
Increased alkaline phosphate	34	2	31	0
Decreased white blood cell count	12	1	8	1
Decreased potassium	11	1	8	1

Other clinically important laboratory abnormalities observed in patients treated with GILOTRIF that are not listed in Table 4 are: increased alanine aminotransferase (10% Grade 1-4; 1% Grade 3-4), increased aspartate aminotransferase (7% Grade 1-4; 1% Grade 3-4), and increased bilirubin (3% Grade 1-4; 0 Grade 3-4).

Less Common Adverse Reactions

Other adverse reactions reported in patients treated with GILOTRIF in LUX-Lung 3 and LUX-Lung 8 include:

Skin and subcutaneous disorders: nail disorders occurred in 9.2% and 2.8% of patients, respectively.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of GILOTRIF. 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.

Pancreatitis
Toxic epidermal necrolysis/Stevens Johnson syndrome