6 ADVERSE REACTIONS

The following adverse drug reactions are described elsewhere in the labeling:

•: Interstitial Lung Disease [see Warnings and Precautions (5.1)]
•: Diarrhea [see Warnings and Precautions (5.2)]
•: Dermatologic Adverse Reactions [see Warnings and Precautions (5.3)]

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 VIZIMPRO in 394 patients with first-line or previously treated NSCLC with EGFR exon 19 deletion or exon 21 L858R substitution mutations who received VIZIMPRO at the recommended dose of 45 mg once daily in 4 randomized, active-controlled trials [ARCHER 1050 (N=227), Study A7471009 (N=38), Study A7471011 (N=83), and Study A7471028 (N=16)] and one single-arm trial [Study A7471017 (N=30)]. The median duration of exposure to VIZIMPRO was 10.8 months (range 0.07–68) [see Warnings and Precautions (5)].

The data described below reflect exposure to VIZIMPRO in 227 patients with EGFR mutation-positive, metastatic NSCLC enrolled in a randomized, active-controlled trial (ARCHER 1050); 224 patients received gefitinib 250 mg orally once daily in the active control arm [see Clinical Studies (14)]. Patients were excluded if they had a history of ILD, interstitial pneumonitis, or brain metastases. The median duration of exposure to VIZIMPRO was 15 months (range 0.07–37).

The most common (>20%) adverse reactions in patients treated with VIZIMPRO were diarrhea (87%), rash (69%), paronychia (64%), stomatitis (45%), decreased appetite (31%), dry skin (30%), decreased weight (26%), alopecia (23%), cough (21%), and pruritus (21%).

Serious adverse reactions occurred in 27% of patients treated with VIZIMPRO. The most common (≥1%) serious adverse reactions were diarrhea (2.2%) and interstitial lung disease (1.3%). Dose interruptions occurred in 57% of patients treated with VIZIMPRO. The most frequent (>5%) adverse reactions leading to dose interruptions were rash (23%), paronychia (13%), and diarrhea (10%). Dose reductions occurred in 66% of patients treated with VIZIMPRO. The most frequent (>5%) adverse reactions leading to dose reductions were rash (29%), paronychia (17%), and diarrhea (8%).

Adverse reactions leading to permanent discontinuation of VIZIMPRO occurred in 18% of patients. The most common (>0.5%) adverse reactions leading to permanent discontinuation of VIZIMPRO were: rash (2.6%), interstitial lung disease (1.8%), stomatitis (0.9%), and diarrhea (0.9%).

Tables 3 and 4 summarize the most common adverse reactions and laboratory abnormalities, respectively, in ARCHER 1050. ARCHER 1050 was not designed to demonstrate a statistically significant difference in adverse reaction rates for VIZIMPRO or for gefitinib for any adverse reaction or laboratory value listed in Table 3 or 4.

Table 3. Adverse Reactions Occurring in ≥10% of Patients Receiving VIZIMPRO in ARCHER 1050*
Adverse Reaction	VIZIMPRO (N=227)		Gefitinib (N=224)
	All Grades† %	Grades 3 and 4 %	All Grades %	Grades 3 and 4 %
* National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03. † Grades 1 through 5 are included in All Grades. ‡ One Grade 5 (fatal) event in the VIZIMPRO arm. § Stomatitis includes mucosal inflammation and stomatitis. ¶ Rash includes dermatitis acneiform, rash, and rash maculo-papular. # Paronychia includes nail infection, nail toxicity, onychoclasis, onycholysis, onychomadesis, paronychia. Þ Dry skin includes dry skin, xerosis. ß Pruritus includes pruritus, pruritus generalized, rash pruritic. à Nasal mucosal disorder includes epistaxis, nasal inflammation, nasal mucosal disorder, nasal mucosal ulcer, rhinitis.
Gastrointestinal
Diarrhea‡	87	8	56	0.9
Stomatitis§	45	4.4	19	0.4
Nausea	19	1.3	22	0.4
Constipation	13	0	14	0
Mouth ulceration	12	0	6	0
Skin and Subcutaneous Tissue
Rash¶	69	23	47	0.4
Paronychia#	64	8	21	1.3
Dry skinÞ	30	1.8	19	0.4
Alopecia	23	0.4	13	0
Pruritusß	21	0.9	15	1.3
Palmar-plantar erythrodysesthesia syndrome	15	0.9	3.1	0
Dermatitis	11	1.8	4	0.4
Metabolism and Nutrition
Decreased appetite	31	3.1	25	0.4
Decreased weight	26	2.2	17	0.4
Respiratory
Cough	21	0	19	0.4
Nasal mucosal disorderà	19	0	4.9	0
Dyspnea	13	2.2	13	1.8
Upper respiratory tract infection	12	1.3	13	0
Chest pain	10	0	14	0
Eye
Conjunctivitis	19	0	4	0
Musculoskeletal
Pain in extremity	14	0	12	0
Musculoskeletal pain	12	0.9	13	0
General
Asthenia	13	2.2	13	1.3
Psychiatric
Insomnia	11	0.4	15	0

Additional adverse reactions (All Grades) that were reported in <10% of patients who received VIZIMPRO in ARCHER 1050 include:

General: fatigue 9%

Skin and subcutaneous tissue: skin fissures 9%, hypertrichosis 1.3%, skin exfoliation/exfoliative skin reactions 3.5%

Gastrointestinal: vomiting 9%

Nervous system: dysgeusia 7%

Respiratory: interstitial lung disease 2.6%

Ocular: keratitis 1.8%

Metabolism and nutrition: dehydration 1.3%

Table 4. Laboratory Abnormalities Worsening from Baseline in >20% of Patients in ARCHER 1050*
Laboratory Test Abnormality†	VIZIMPRO		Gefitinib
Laboratory Test Abnormality†	Change from Baseline All Grades (%)	Change from Baseline to Grade 3 or Grade 4 (%)	Change from Baseline All Grades (%)	Change from Baseline to Grade 3 or Grade 4 (%)
ALT=alanine aminotransferase; AST=aspartate aminotransferase.
* NCI CTCAE v4.03, except for increased creatinine which only includes patients with creatinine increase based on upper limit of normal definition. † Based on the number of patients with available baseline and at least one on-treatment laboratory test.
Hematology
Anemia	44	0.9	26	2.7
Lymphopenia	42	6	35	2.7
Chemistry
Hypoalbuminemia	44	0	34	0
Increased ALT	40	1.4	63	13
Hyperglycemia	36	1.0	38	2.5
Increased AST	35	0.5	57	8
Hypocalcemia	33	1.4	28	2.0
Hypokalemia	29	7	18	2.0
Hyponatremia	26	2.9	20	1.5
Increased creatinine	24	0	16	0.5
Increased alkaline phosphatase	22	0.5	21	2.0
Hypomagnesemia	22	0.5	9	0
Hyperbilirubinemia	16	0.5	22	0.5