Ensacove Drug Information

is indicated for the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive locally advanced or metastatic non-small cell lung cancer (NSCLC)as detected by an FDA-approved test who have not previously received an ALK-inhibitor. ENSACOVE is a kinase inhibitor indicated for the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive locally advanced or metastatic non-small cell lung cancer (NSCLC) as detected by an FDA-approved test who have not previously received an ALK-inhibitor.

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 pooled safety population described in the WARNINGS AND PRECAUTIONS reflects exposure to ENSACOVE as a single agent in 458 patients with locally advanced or metastatic ALK-positive NSCLC in the following trials: eXALT3 Study (N=143), Study 101 (NCT01625234, N=98), Study BTP-28311 (NCT02959619, N=35), and Study BTP-42322 (NCT03215693, N=182). Patients received ENSACOVE 225 mg orally once daily, with or without food, until disease progression or unacceptable toxicity. Among 458 patients who received ENSACOVE, 63% were exposed for 6 months or longer and 47% were exposed for greater than one year.

In this pooled safety population, the most common adverse reactions (≥20%) were rash, musculoskeletal pain, constipation, pruritus, cough, nausea, edema, vomiting, fatigue, and pyrexia. The most frequent Grade 3 or 4 laboratory abnormalities (≥2%) were increased uric acid, decreased lymphocytes, increased alanine aminotransferase, decreased phosphate, increased gamma glutamyl transferase, increased magnesium, increased amylase, decreased sodium, increased glucose, decreased hemoglobin, increased bilirubin, decreased potassium, and increased creatine phosphokinase. TKI-naive ALK-Positive Locally Advanced or Metastatic NSCLC The safety of ENSACOVE was evaluated in the eXALT3 study.

Patients received ENSACOVE 225 mg orally once daily, with or without food, until disease progression or unacceptable toxicity. Among patients who received ENSACOVE, 78% were exposed for 6 months or longer and 66% were exposed for greater than one year. The median age of patients who received ENSACOVE was 54 years (range: 25-86); 50% male; 54% Asian, 43% White; 0.7% Black or African American; and 11% Hispanic or Latino.

Serious adverse reactions occurred in 23% of patients treated with ENSACOVE. Serious adverse reactions that occurred in ≥1% were pneumonia (4.9%), hemorrhage (2.1%), rash (2.1%) and cellulitis (1.4%). One fatal adverse reaction (0.7%) occurred due to bronchopneumonia. Permanent discontinuation of ENSACOVE due to an adverse reaction occurred in 12% of patients. Adverse reactions which resulted in permanent discontinuation of ENSACOVE (≥1%) included increased blood bilirubin (1.4%), increased conjugated bilirubin (1.4%), increased ALT (2.1%), increased AST (2.1%), and pneumonitis/ILD (2.1%). Dose interruptions of ENSACOVE due to an adverse reaction occurred in 41% of patients.

Adverse reactions which required dose interruptions (≥2%) included rash (13%), increased ALT (6%), edema (2.8%), pruritus (2.8%), pyrexia (2.8%), pneumonia (3.5%), increased AST (2.1%), hemorrhage (2.1%), and decreased appetite (2.1%). Dose reductions of ENSACOVE due to an adverse reaction occurred in 24% of patients. Adverse reactions which required dose reductions (≥2%) included rash (11%), increased ALT (4.2%), pruritus (2.8%), and edema (2.1%). Tables 3 and 4 summarize the most frequent adverse reactions and laboratory abnormalities, respectively. Table 3: Adverse Reactions ( ≥10%) in Patients with ALK-Positive Locally Advanced or Metastatic NSCLC Who Received ENSACOVE in eXALT3 Study ENSACOVE N = 143 Crizotinib N = 146 Adverse Reaction All Grades % Grade 3 or 4 % All Grades % Grade 3 or 4 % Skin and Subcutaneous Tissue Disorders Rash a 66 12 10 0 Pruritus b 30 2.1 4.1 0 Alopecia 11 0 4.8 0 Dry Skin 10 0.7 0.7 0 Musculoskeletal and Connective Tissue Disorders Musculoskeletal Pain c 36 1.4 20 0 Respiratory, Thoracic and Mediastinal Disorders Cough d 31 0.7 16 0 Gastrointestinal Disorders Constipation 31 0 26 0 Nausea 28 1.4 30

Vomiting e 16 0.7 32 0 General Disorders and

Administration Site Conditions Edema f 27 2.1 28

Pyrexia g 22 0.7 10 0.7 Fatigue h 21 0.7 14 1.4

Metabolism and Nutrition Disorders Decreased appetite 15 0 12

Infection and Infestation Respiratory Tract Infection 13 0.7 10 0 Nervous System

Disorders Dizziness i 12 0.7 14

Dysgeusia 10 0 11 0 Vascular Disorders Hemorrhage j 10 1.4 4.8

0 Adverse reactions were graded using NCI CTCAE version 4.03. a Includes dermatitis, dermatitis acneiform, dermatitis bullous, drug eruption, eczema, exfoliative rash, palmar-plantar erythrodysaesthesia, rash, rash erythematous, rash generalized, rash macular, rash maculo-papular, rash morbilliform, rash papular, rash pruritic, rash pustular, skin exfoliation, and vulvovaginal rash b Includes ear pruritus, eye pruritus, eyelids pruritus, lip pruritus, pruritus, and pruritus generalized c Includes arthritis, spinal pain, myalgia, musculoskeletal pain, back pain, pain in extremity, neck pain, arthralgia, non-cardiac chest pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort d Includes cough, productive cough, upper-airway cough syndrome e Includes vomiting and retching f Includes eyelid edema, face edema, generalized edema, localized edema, edema, edema peripheral, gravitational edema, skin edema, eye edema, and periorbital edema g Includes pyrexia and hyperthermia h Includes fatigue and asthenia i Includes dizziness, vertigo, postural dizziness j Includes hemoptysis, intracranial hemorrhage, gastrointestinal hemorrhage, hematuria, upper gastrointestinal hemorrhage, vaginal hemorrhage, gingival bleeding, vitreous hemorrhage, epistaxis, rectal hemorrhage, anal hemorrhage Table 4: Select Laboratory Abnormalities (≥20%) That Worsened from Baseline in Patients with ALK-Positive Locally Advanced or Metastatic NSCLC Who Received ENSACOVE in eXALT3 Study ENSACOVE N = 143 Crizotinib N = 146 Lab Abnormality All Grades % Grade 3 or 4 % All Grades % Grade 3 or 4 % Chemistry Alanine aminotransferase increased 73 5 74 8 Alkaline phosphatase increased 64 2.2 50

Albumin decreased 46 0.7 56 1.4 Phosphate decreased 39 7 42 4.9

Urate increased 39 39 27 27 Creatinine increased 37 0 27 0 Calcium decreased 36 1.4 64

Sodium decreased 27 4.3 27 4.2 Hematology Lymphocytes decreased 57 7 47

5 Hemoglobin decreased 43 0.7 31

Adverse reactions were graded using

NCI CTCAE version 4.03. ALT = Alanine aminotransferase; AST = Aspartate aminotransferase Clinically relevant adverse reactions in <10% of patients who received ENSACOVE included interstitial lung disease, photosensitivity, increased creatinine phosphokinase, bradycardia, and visual disturbances.

Effect of Other Drugs on

ENSACOVE Table 5 describes drug interactions where concomitant use of another drug affects ENSACOVE. Table 5: Effect of Other Drugs on ENSACOVE Strong or Moderate CYP3A Inhibitors Prevention or Management Avoid concomitant use of strong or moderate CYP3A inhibitors with ENSACOVE. Mechanism and Clinical Effect(s) This recommendation is based upon a mechanistic understanding of ensartinib pharmacokinetics and it being a CYP3A4 substrate in vitro . Concomitant use with strong or moderate CYP3A inhibitors may increase ensartinib exposure; however, this has not been studied clinically. Strong or Moderate CYP3A Inducers Prevention or Management Avoid concomitant use of strong or moderate CYP3A inducers with ENSACOVE. Mechanism and Clinical Effect(s) This recommendation is based upon a mechanistic understanding of ensartinib pharmacokinetics and it being a CYP3A4 substrate in vitro . Concomitant use with strong or moderate CYP3A inducers may decrease ensartinib exposure; however, this has not been studied clinically. P-gp Inhibitors Prevention or Management Avoid concomitant use of P-gp inhibitors with ENSACOVE. Mechanism and Clinical Effect(s) This recommendation is based upon a mechanistic understanding of ensartinib pharmacokinetics and it being a P-gp substrate in vitro . Concomitant use with P-gp inhibitors may increase ensartinib exposure; however, this has not been studied clinically.

Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action , ENSACOVE can cause fetal harm when administered to a pregnant woman. There are no available data on the use of ENSACOVE in pregnant women to inform a drug-associated risk. Oral administration of ensartinib to pregnant rats during the period of organogenesis caused adverse developmental outcomes, including embryo-fetal mortality, alterations to growth, and structural abnormalities.

Adverse embryo-fetal findings were seen at maternal exposures approximately equivalent to the human exposure at the recommended dose of 225 mg/day based on AUC ( 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 In an embryo-fetal development study, pregnant rats received 20, 40, or 80 mg/kg/day of ensartinib during the period of organogenesis (gestation day 6 to 17). Ensartinib doses ≥40 mg/kg/day (approximately equivalent to the human exposure at the recommended dose of 225 mg/day based on AUC) resulted in an increase in the incidence of fetal malformations (aortic dislocation, ventricular septal defect, separated vertebrae) and dose-dependent delayed skeletal development, including decreased or delayed ossification of the vertebrae.

Ensartinib at 80 mg/kg (approximately 6.4 times the human exposure at the recommended dose of 225 mg/day based on AUC) resulted in maternal toxicity (reduced body weight and food consumption), decreased fetal body weight, increased pre- and post-implantation loss, decreases in the number of live fetuses, and visceral variations (missing renal papillae, pyelectasis).

Pediatric Use The safety and effectiveness of ENSACOVE in pediatric patients have not been established.

is contraindicated in patients who have experienced a severe hypersensitivity reaction to ENSACOVE, FD&C Yellow No. 5 (tartrazine), or to any of its components . Hypersensitivity reaction to ENSACOVE, FD&C Yellow No. 5 (tartrazine), or to any of its components.