Rozlytrek Drug Information

Clinical Trial 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. Data in WARNINGS AND PRECAUTIONS and below reflect exposure to ROZLYTREK in 355 patients, including 172 (48%) patients exposed for 6 months or longer and 84 (24%) patients exposed for 1 year or longer. ROZLYTREK was studied in one dose-finding trial in adults, one dose-finding and activity-estimating trial in adults, one dose-finding and activity-estimating trial in pediatric and adult patients, and one single arm, activity-estimating trial in adults.

The population characteristics were: median age 55 years (range: 4 to 86 years); 5% (n = 17) were less than 18 years of age; 55% were female; and 66% were White, 23% were Asian, and 5% were Black; 3% were Hispanic/Latino. The most common tumors (≥ 5%) were lung (56%), sarcoma (8%), and colon (5%). ROS1 gene fusions were present in 42% and NTRK gene fusions were present in 20%. Most adults (75%) received ROZLYTREK 600 mg orally once daily. The doses ranged from 100 mg/m 2 to 1600 mg/m 2 once daily in adults and 250 mg/m 2 to 750 mg/m 2 once daily in pediatric patients.

Serious adverse reactions occurred in 39% of patients. The most frequent serious adverse reactions (≥ 2%) were pneumonia (3.9%), dyspnea (3.7%), pleural effusion (3.4%), sepsis (2.5%), pulmonary embolism (2.3%), respiratory failure (2%), and pyrexia (2%). Grade 3 or 4 adverse reactions occurred in 60% of patients; the most common (≥ 2%) were lung infection (5%), increased weight (7%), dyspnea (6%), fatigue/asthenia (5%), cognitive disorders (4.5%), syncope (2.5%), pulmonary embolism (3.4%), hypoxia (3.4%), pleural effusion (3.1%), hypotension (2.8%), diarrhea (2%), and urinary tract infection (2.5%). Fatal events included dyspnea (0.6%), pneumonia (0.6%), sepsis (0.6%), completed suicide (0.3%), large intestine perforation (0.3%) and tumor lysis syndrome (0.3%). One patient developed Grade 4 myocarditis after one dose of ROZLYTREK which resolved after discontinuation of ROZLYTREK and administration of high-dose corticosteroids. Permanent discontinuation due to an adverse reaction occurred in 9% of patients who received ROZLYTREK. The most frequent adverse reactions (< 1% each) that resulted in permanent discontinuation were pneumonia, cardio-respiratory arrest, dyspnea, and fatigue.

Dose interruptions due to adverse reactions occurred in 46% of patients. The most frequent adverse reactions (≥ 2%) that resulted in interruption were increased blood creatinine (4%), fatigue (3.7%), anemia (3.1%), diarrhea (2.8%), pyrexia (2.8%), dizziness (2.5%), dyspnea (2.3%), nausea (2.3%), pneumonia (2.3%), cognitive disorder (2%) and neutropenia (2%). Dose reductions due to adverse reactions occurred in 29% of patients who received ROZLYTREK. The most frequent adverse reactions resulting in dose reductions (≥ 1%) were dizziness (3.9%), increased blood creatinine (3.1%), fatigue (2.3%), anemia (1.7%), and increased weight (1.4%). The most common adverse reactions (≥ 20%) were fatigue, constipation, dysgeusia, edema, dizziness, diarrhea, nausea, dysesthesia, dyspnea, myalgia, cognitive impairment, increased weight, cough, vomiting, pyrexia, arthralgia and vision disorders. Table 7 summarizes the adverse reactions observed in these 355 patients.

Table 7. Adverse Reactions (≥ 10%) in Patients Receiving ROZLYTREK in ALKA, STARTRK-1, STARTRK-2, and STARTRK-NG Adverse Reactions ROZLYTREK n = 355 All Grades (%) Grade ≥ 3 Grades 3 – 5, inclusive of fatal adverse reactions, including 2 events of pneumonia and 2 events of dyspnea. (%) General Fatigue Includes fatigue, asthenia 48 5 Edema Includes face edema, fluid retention, generalized edema, localized edema, edema, edema peripheral, peripheral swelling 40

Vomiting 24 0.8 Abdominal pain Includes abdominal pain upper, abdominal pain, lower

abdominal discomfort, abdominal tenderness 16

Dysesthesia Includes paresthesia, hyperesthesia, hypoesthesia, dysesthesia, oral hypoesthesia, palmar-plantar erythrodysesthesia, oral paresthesia

genital hypoesthesia 34

Cognitive impairment Includes amnesia, aphasia, cognitive disorder, confusional state, delirium, disturbance in

attention, hallucinations, visual hallucination, memory impairment, mental disorder, mental status changes 27

Peripheral sensory neuropathy Includes neuralgia, neuropathy peripheral, peripheral motor neuropathy, peripheral sensory

neuropathy 18

Headache 18 0.3 Ataxia Includes ataxia, balance disorder, gait disturbances 17 0.8

Sleep Includes hypersomnia, insomnia, sleep disorder, somnolence 14

Mood disorders Includes anxiety, affect lability, affective disorder, agitation, depressed mood, euphoric

mood, mood altered, mood swings, irritability, depression, persistent depressive disorder, psychomotor retardation 10

Respiratory, Thoracic and Mediastinal Dyspnea 30 6 Cough 24 0.3 Musculoskeletal and

Connective Tissue Myalgia Includes musculoskeletal pain, musculoskeletal chest pain, myalgia, neck pain 28

Arthralgia 21 0.6 Muscular weakness 12 0.8 Back pain 12 1 Pain

in extremity 11

Metabolism and Nutritional Increased weight 25 7 Decreased appetite 13 0.3 Dehydration

10

Eye Vision disorders Includes blindness, cataract, cortical cataract, corneal erosion, diplopia, eye

disorder, photophobia, photopsia, retinal hemorrhage, vision blurred, visual impairment, vitreous adhesions, vitreous detachment, vitreous floaters 21

Infections Urinary tract infection 13 2.3 Lung infection Includes lower respiratory tract

infection, lung infection, pneumonia, respiratory tract infection 10 6 Vascular Hypotension Includes hypotension, orthostatic hypotension 18

Skin and Subcutaneous Tissue Rash Includes rash, rash maculopapular, rash pruritic, rash

erythematous, rash papular 11

Clinically relevant adverse reactions occurring in ≤ 10% of patients include dysphagia

(10%), fall (8%), pleural effusion (8%), fractures (6%), hypoxia (4.2%), pulmonary embolism (3.9%), syncope (3.9%), congestive heart failure (3.4%), and QT prolongation (3.1%). Table 8 summarizes the laboratory abnormalities. Table 8. Laboratory Abnormalities (≥ 20%) Worsening from Baseline in Patients Receiving ROZLYTREK in ALKA, STARTRK-1, STARTRK-2, and STARTRK-NG Laboratory Abnormality ROZLYTREK NCI CTCAE Grade All Grades (%) Denominator for each laboratory parameter is based on the number of patients with a baseline and post-treatment laboratory value available which ranged from 111 to 346 patients. Grade 3 or 4 (%) AST: Aspartate Aminotransferase; ALT: Alanine Aminotransferase Chemistry Increased creatinine Based on NCI CTCAE v5.0 73

Hyperuricemia 52 10 Increased

AST 44

Increased

ALT 38

Hypernatremia 35 0.9 Hypocalcemia 34 1.8 Hypophosphatemia 30 7 Increased lipase 28

10 Hypoalbuminemia 28

Increased amylase 26 5.4 Hyperkalemia 25 1.5 Increased alkaline phosphatase 25 0.9

Hyperglycemia NE = Not evaluable. Grade 1 and 2 could not be determined per NCI CTCAE v5.0, as fasting glucose values were not collected NE

Hematology Anemia 67 9 Lymphopenia 40 12 Neutropenia 28 7 Safety in

Pediatric Patients The safety of ROZLYTREK was evaluated was evaluated in pediatric patients with unresectable or metastatic solid tumors with a NTRK gene fusion enrolled in one of three multicenter, open-label clinical trials: STARTRK-NG (n=68), TAPISTRY (n=6) and STARTRK-2 (n=2). Patients received ROZLYTREK 20 mg to 600 mg based on body surface area (BSA) orally or via enteral feeding tube once daily in 4-week cycles until unacceptable toxicity or disease progression. Among patients who received ROZLYTREK, 58% were exposed for 6 months or longer and 38% were exposed for greater than one year. The median age of patients who received ROZLYTREK was 6 years (range: 0 to 17); 51% were females; 68% were White, 18% Asian, 7% Black or African American, and 7% were other races.

Serious adverse reactions occurred in 45% of patients who received ROZLYTREK. Serious adverse reactions in > 2% of patients included skeletal fractures (12%), pneumonia (5%), pyrexia (5%), hydrocephalus (5%), device related infection (4%), hypoxia (4%), dyspnea (3%), headache (3%), gait disturbance (3%), pain (3%), upper respiratory infection (3%), and sepsis (3%). Permanent discontinuation of ROZLYTREK due to an adverse reaction occurred in 13% of patients. Adverse reactions which resulted in permanent discontinuation of ROZLYTREK in > 2% of patients included skeletal fracture. Dosage interruptions of ROZLYTREK due to an adverse reaction occurred in 39% of patients.

Adverse reactions which required dosage interruption in > 5% of patients included decreased neutrophil count, pyrexia, vomiting, and diarrhea. Dose reductions of ROZLYTREK due to an adverse reaction occurred in 21% of patients. Adverse reactions which required dose reductions in > 2% of patients included increased blood creatinine and increased weight.

Table 9 summarizes the adverse reactions in STARTRK-NG (n=68), TAPISTRY (n=6) and STARTRK-2 (n=2). Table 9. Adverse Reactions (≥20%) in Pediatric Patients Who Received ROZLYTREK in STARTRK-NG, TAPISTRY and STARTRK-2 Adverse Reaction ROZLYTREK (n=76) All Grades (%) Grade 3 or 4 (%) General Disorders Pyrexia 43

Fatigue Includes fatigue, asthenia 30 2.6 Gastrointestinal Disorders Constipation 41 1.3 Vomiting

38 0 Diarrhea 37 0 Nausea 34 0 Abdominal Pain 20

Nasal Congestion 20 0 Musculoskeletal And Connective Tissue Disorders Pain in Extremity

26

Skeletal Fracture Includes clavicle fracture, tibia fracture, femur fracture, fibula fracture, foot

fracture, fracture, pathological fracture, limb fracture, lower limb fracture, pelvic fracture, spinal compression fracture, stress fracture, ulna fracture 25 11 Metabolism And Nutrition Disorders Decreased Appetite 24

Urinary Tract Infection 20 2.6 Clinically relevant adverse reactions in <20% of

patients who received ROZLYTREK included pruritus, rash, urinary incontinence, eye pain and photophobia. Tables 10 summarizes the laboratory abnormalities in STARTRK-NG (n=68), TAPISTRY (n=6) and STARTRK-2 (n=2). Table 10. Select Laboratory Abnormalities (≥20%) That Worsened from Baseline in Pediatric Patients Who Received ROZLYTREK in STARTRK-NG, TAPISTRY and STARTRK-2 Laboratory Abnormality ROZLYTREK The denominator used to calculate the rate varied from 67 to 76 based on the number of patients with a baseline value and at least one post-treatment value. All values based on NCI CTCAE v5.0 All Grades (%) Grade 3 or 4 (%) AST: Aspartate Aminotransferase; ALT: Alanine Aminotransferase Hematology Decreased Hemoglobin 53 7 Decreased Neutrophils 53 22 Decreased Leukocytes 46

Increased Lymphocytes 33 3 Chemistry Increased Creatinine 84 5 Increased

AST 61

Increased

ALT 53

Increased Sodium 38 1.4 Increased Magnesium 32 5 Increased Alkaline Phosphatase 25

0 Decreased Glucose 26 0 Increased Potassium 25

Decreased Albumin 24 9 Increased Calcium 21 8 Increased Bilirubin 20 8

Other clinically relevant laboratory abnormalities in patients who received ROZLYTREK included decreased phosphorous.

Effect of Other Drugs on

ROZLYTREK Moderate and Strong CYP3A Inhibitors Adults and Pediatric Patients 2 Years and Older Coadministration of ROZLYTREK with a strong or moderate CYP3A inhibitor increases entrectinib plasma concentrations, which could increase the frequency or severity of adverse reactions. Avoid coadministration of strong or moderate CYP3A inhibitors with ROZLYTREK. If coadministration is unavoidable, reduce the ROZLYTREK dose. Pediatric Patients less than 2 Years Avoid coadministration of ROZLYTREK with moderate or strong CYP3A inhibitors . Avoid grapefruit products during treatment with ROZLYTREK, as they contain inhibitors of CYP3A. Moderate and Strong CYP3A Inducers Coadministration of ROZLYTREK with a strong or moderate CYP3A inducer decreases entrectinib plasma concentrations, which may reduce ROZLYTREK efficacy.

Avoid coadministration of strong and moderate CYP3A inducers with ROZLYTREK.

Drugs That Prolong QTc Interval QTc interval prolongation can occur with

ROZLYTREK. Avoid coadministration of ROZLYTREK with other products with a known potential to prolong QT/QTc interval .

Pregnancy Risk Summary Based on literature reports in humans with congenital mutations leading to changes in TRK signaling, findings from animal studies, and its mechanism of action , ROZLYTREK can cause fetal harm when administered to a pregnant woman. There are no available data on ROZLYTREK use in pregnant women. Administration of entrectinib to pregnant rats during the period of organogenesis resulted in malformations at maternal exposures approximately 2.7 times the human exposure at the 600 mg dose (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 Human Data Published reports of individuals with congenital mutations in TRK pathway proteins suggest that decreases in TRK-mediated signaling are correlated with obesity, developmental delays, cognitive impairment, insensitivity to pain, and anhidrosis. Animal Data Entrectinib administration to pregnant rats during the period of organogenesis at a dose of 200 mg/kg resulted in maternal toxicity and fetal malformations including body closure defects (omphalocele and gastroschisis) and malformations of the vertebrae, ribs, and limbs (micromelia and adactyly), but not embryolethality.

Lower fetal weights and reduced skeletal ossification occurred at doses ≥ 12.5 and 50 mg/kg, respectively.

Pediatric Use The safety and effectiveness of ROZLYTREK have been established in pediatric patients older than 1 month of age. Use of ROZLYTREK in these age groups is supported by evidence from adequate and well-controlled studies of ROZLYTREK in adults and pediatric patients with additional population pharmacokinetic data demonstrating that the exposure of drug substance in pediatric patients greater than 1 month of age is expected to be in the adult range, and that the course of disease is sufficiently similar in adult and pediatric patients to allow extrapolation of data in adults to pediatric patients. The safety and effectiveness of ROZLYTREK have not been established in pediatric patients with ROS1 -positive NSCLC. Juvenile Animal Toxicity Data In a 13-week juvenile rat toxicology study, animals were dosed daily from post-natal day 7 to day 97 (approximately equivalent to neonate to adulthood). Entrectinib resulted in: decreased body weight gain and delayed sexual maturation at doses ≥ 4 mg/kg/day (approximately 0.06 times the human exposure (AUC) at the 600 mg dose), deficits in neurobehavioral assessments including functional observational battery and learning and memory (at doses ≥ 8 mg/kg/day, approximately 0.14 times the human exposure at the 600 mg dose), and decreased femur length at doses ≥ 16 mg/kg/day (approximately 0.18 times the human exposure at the 600 mg dose).