PRINCIPAL DISPLAY PANEL - 50 mg Pellets Packet Carton

NDC 50242-623-42

Rozlytrek®
(entrectinib)
oral pellets

50 mg

42 packets

Rx only

Genentech

11006603

1 INDICATIONS AND USAGE

1.1 ROS1-Positive Non-Small Cell Lung Cancer

ROZLYTREK is indicated for the treatment of adult patients with ROS1-positive metastatic non-small cell lung cancer (NSCLC), as detected by an FDA-approved test.

1.2 NTRK Gene Fusion-Positive Solid Tumors

ROZLYTREK is indicated for the treatment of adult and pediatric patients older than 1 month of age with solid tumors that:

• have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion, as detected by an FDA-approved test without a known acquired resistance mutation,
• are metastatic or where surgical resection is likely to result in severe morbidity, and
• have progressed following treatment or have no satisfactory alternative therapy.

This indication is approved under accelerated approval based on tumor response rate and durability of response [see Clinical Studies (14.2)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

4 CONTRAINDICATIONS

None.

6 ADVERSE REACTIONS

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

• Congestive Heart Failure [see Warnings and Precautions (5.1)]
• Central Nervous System Effects [see Warnings and Precautions (5.2)]
• Skeletal Fractures [see Warnings and Precautions (5.3)]
• Hepatotoxicity [see Warnings and Precautions (5.4)]
• Hyperuricemia [see Warnings and Precautions (5.5)]
• QT Interval Prolongation [see Warnings and Precautions (5.6)]
• Vision Disorders [see Warnings and Precautions (5.7)]

6.1 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 [ALKA (n = 57)], one dose-finding and activity- estimating trial in adults [STARTRK-1 (n = 76)], one dose-finding and activity-estimating trial in pediatric and adult patients [STARTRK-NG (n = 16)], and one single arm, activity-estimating trial in adults [STARTRK-2 (n = 206)].

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/m2 to 1600 mg/m2 once daily in adults and 250 mg/m2 to 750 mg/m2 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.

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

Includes amnesia, aphasia, cognitive disorder, confusional state, delirium, disturbance in attention, hallucinations, visual hallucination, memory impairment, mental disorder, mental status changes

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

Includes ataxia, balance disorder, gait disturbances

Includes hypersomnia, insomnia, sleep disorder, somnolence

Includes anxiety, affect lability, affective disorder, agitation, depressed mood, euphoric mood, mood altered, mood swings, irritability, depression, persistent depressive disorder, psychomotor retardation

Includes musculoskeletal pain, musculoskeletal chest pain, myalgia, neck pain

Includes blindness, cataract, cortical cataract, corneal erosion, diplopia, eye disorder, photophobia, photopsia, retinal hemorrhage, vision blurred, visual impairment, vitreous adhesions, vitreous detachment, vitreous floaters

Includes lower respiratory tract infection, lung infection, pneumonia, respiratory tract infection

Includes hypotension, orthostatic hypotension 

Includes rash, rash maculopapular, rash pruritic, rash erythematous, rash papular 

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.

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).

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).

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

7 DRUG INTERACTIONS

7.1 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 [see Clinical Pharmacology (12.3)], 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 [see Dosage and Administration (2.8), Clinical Pharmacology (12.3)].

Pediatric Patients less than 2 Years

Avoid coadministration of ROZLYTREK with moderate or strong CYP3A inhibitors [see Clinical Pharmacology (12.3)].

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 [see Clinical Pharmacology (12.3)], which may reduce ROZLYTREK efficacy. Avoid coadministration of strong and moderate CYP3A inducers with ROZLYTREK.

7.2 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 [see Warnings and Precautions (5.6), Clinical Pharmacology (12.2)].

RECENT MAJOR CHANGES

3 DOSAGE FORMS AND STRENGTHS

Capsules:

• 100 mg: Size 2 yellow opaque body and cap, with "ENT 100" printed in blue ink on body.
• 200 mg: Size 0 orange opaque body and cap, with "ENT 200" printed in blue ink on body.

Pellets:

• 50 mg: Supplied as brownish orange or grayish orange pellets in packets.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

Congestive Heart Failure

• Inform patients of the risks of CHF and advise patients to contact their healthcare provider immediately for any new or worsening signs or symptoms of CHF [see Warnings and Precautions (5.1)].

Central Nervous System Effects

• Advise patients to inform their healthcare provider if they experience new or worsening central nervous system symptoms. Instruct patients not to drive or operate hazardous machinery if they are experiencing CNS adverse reactions [see Warnings and Precautions (5.2)].

Skeletal Fractures

• Inform patients that bone fractures have been reported in patients taking ROZLYTREK. Advise patients to report symptoms such as pain, changes in mobility, or deformity to their healthcare provider [see Warnings and Precautions (5.3)].

Hepatotoxicity

• Advise patients that they will need to undergo laboratory tests to monitor liver function and to immediately report symptoms of hepatotoxicity [see Warnings and Precautions (5.4)].

Hyperuricemia

• Advise patients to inform their healthcare provider if they experience signs or symptoms associated with hyperuricemia [see Warnings and Precautions (5.5)].

QT Interval Prolongation

• Inform patients of the risks of QT interval prolongation and to advise patients to contact their healthcare provider immediately for any symptoms of QT interval prolongation [see Warnings and Precautions (5.6)].

Vision Disorders

• Advise patients to inform their healthcare provider if they experience visual changes [see Warnings and Precautions (5.7)].

Embryo-Fetal Toxicity

• Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.8), Use in Specific Populations (8.1, 8.3)].
• Advise females of reproductive potential to use effective contraception during treatment with ROZLYTREK and for 5 weeks after the last dose.
• Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose.

Lactation

• Advise females not to breastfeed during treatment with ROZLYTREK and for 1 week after the last dose [see Use in Specific Populations (8.2)].

Drug Interactions

• Advise patients to inform their healthcare providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products. Advise patients to avoid grapefruit juice while taking ROZLYTREK [see Drug Interactions (7)].

Administration

• Instruct patients and caregivers to read the Instructions for Use before the patient starts using ROZLYTREK, and each time the patient gets a refill as there may be new information they need to know.
• For capsules taken as an oral suspension or for administration by enteral tube: Provide patients and caregivers with a measuring device (e.g., oral syringe, measuring cup) to prepare and measure their prescribed dose if taking ROZLYTREK capsules as an oral suspension. Instruct patients and/or caregivers how to use the measuring device provided and inform patients they may need to measure out a portion of oral suspension prepared to receive the prescribed dosage. If not taken immediately after preparation, store no longer than 2 hours at room temperature below 30°C (86°F) [see Dosage and Administration (2.9)].
• For pellets: Instruct patients and caregivers that ROZLYTREK oral pellets should be sprinkled on one or more spoonfuls of a soft food (e.g., applesauce, yogurt, or pudding) and must be taken within 20 minutes of preparation. Oral pellets are not suitable for enteral administration due to potential for clogging in tubing [see Dosage and Administration (2.9)].
• Instruct patients if they miss a dose to make up that dose unless the next dose is due within 12 hours.
• Instruct patients if they vomit immediately after taking a dose of ROZLYTREK to take a dose as soon as possible [Dosage and Administration (2.4)].

ROZLYTREK (entrectinib)

Distributed by:
Genentech USA, Inc.
A Member of the Roche Group
1 DNA Way
South San Francisco, CA 94080-4990

ROZLYTREK® is a registered trademark of Genentech, Inc.

©2024 Genentech, Inc. All rights reserved.

INSTRUCTIONS FOR USE
ROZLYTREK**®**** [roz lye trek]**
(entrectinib)
oral pellets

This Instructions for Use contains information on how to prepare and take or give ROZLYTREK oral pellets.

Read this Instructions for Use before giving ROZLYTREK oral pellets for the first time and each time you get a refill. There may be new information.

Sprinkle ROZLYTREK oral pellets on 1 or more spoonfuls of a soft food before taking or giving**.**

Do not use ROZLYTREK oral pellets to prepare a suspension.

Do not give or take ROZYLTREK oral pellets through a gastrostomy tube (G Tube) or nasogastric tube (NG Tube) because the pellets may clog the feeding tube.

• Your healthcare provider should show you how to properly prepare and take or give a daily dose of ROZLYTREK oral pellets. Always take or give ROZLYTREK oral pellets exactly as your healthcare provider tells you. *Do not take ROZLYTREK oral pellets or give it to someone else until you have been shown how to properly prepare and take or give ROZLYTREK.
• Wash your hands before and after preparing, taking, or giving ROZLYTREK.
• Check the expiration date and check the product for damage before use.Do not use if expired or damaged.

• Your healthcare provider will decide the right dose of ROZLYTREK for you or your child.
• ROZLYTREK oral pellets come in a carton with 42 packets. Each packet contains 50 mg of ROZLYTREK.
• Use the whole packet of pellets**. Do not** use part of the packet to try to prepare a dose.
• Sprinkle the prescribed number of packets on 1 or more spoonfuls of soft food and take or give within 20 minutes of sprinkling the pellets on the soft food. *Do not crush or chew the pellets to avoid a bitter taste.

Supplies needed to prepare and take or give ROZLYTREK oral pellets:

• the number of packets needed for your prescribed dose
• a clean spoon
• a paper towel or clean plate
• soft food like applesauce, yogurt, or pudding

Distributed by:
Genentech USA, Inc.
A Member of the Roche Group
1 DNA Way
South San Francisco, CA 94080-4990

ROZLYTREK® is a registered trademark of Genentech, Inc.

©2023 Genentech, Inc.

For more information, go to www.ROZLYTREK.com or call 1-877-436-3683.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

Issued: 10/2023

8 USE IN SPECIFIC POPULATIONS

8.1 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 [see Clinical Pharmacology (12.1)], 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 [resulting in exposures up to 2.7 times the human exposure (AUC) at the 600 mg dose] 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 [approximately 0.2 and 0.9 times the human exposure (AUC) at the 600 mg dose], respectively.

8.2 Lactation

Risk Summary

There are no data on the presence of entrectinib or its metabolites in human milk or their effects on either the breastfed child or on milk production. Because of the potential serious adverse reactions in breastfed children from ROZLYTREK, advise a lactating woman to discontinue breastfeeding during treatment with ROZLYTREK and for 7 days after the last dose.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating ROZLYTREK [see Use in Specific Populations (8.1)].

Contraception

ROZLYTREK can cause embryo-fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Females

Advise female patients of reproductive potential to use effective contraception during treatment with ROZLYTREK and for at least 5 weeks following the last dose [see Use in Specific Populations (8.1)].

Males

Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ROZLYTREK and for 3 months following the last dose [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

The safety and effectiveness of ROZLYTREK have been established in pediatric patients older than 1 month of age [Clinical Studies (14.2)]. 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).

8.5 Geriatric Use

Of the 355 patients who received ROZLYTREK across clinical trials, 25% were 65 years or older, and 5% were 75 years of age or older. Clinical studies of ROZLYTREK did not include sufficient numbers of geriatric patients to determine whether they respond differently from younger patients.

8.6 Renal Impairment

No dose adjustment is recommended for patients with mild or moderate renal impairment (CLcr 30 to < 90 mL/min calculated by Cockcroft-Gault equation). ROZLYTREK has not been studied in patients with severe renal impairment (CLcr < 30 mL/min) [see Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

The effect of moderate hepatic impairment (total bilirubin > 1.5 – 3.0 times ULN with any aspartate aminotransferase) or severe hepatic impairment (total bilirubin >3.0 times ULN with any aspartate aminotransferase) on the safety of ROZLYTREK at the recommended dosage is unknown. Consider the risk-benefit profile of ROZLYTREK prior to determining whether to administer ROZLYTREK to patients with moderate to severe hepatic impairment. Monitor for ROZLYTREK adverse reactions in patients with hepatic impairment more frequently since these patients may be at increased risk for adverse reactions [see Clinical Pharmacology (12.3)].

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Entrectinib is an inhibitor of the tropomyosin receptor tyrosine kinases (TRK) TRKA, TRKB, and TRKC (encoded by the neurotrophic tyrosine receptor kinase [NTRK] genes NTRK1, NTRK2, and NTRK3, respectively), proto-oncogene tyrosine- protein kinase ROS1 (ROS1), and anaplastic lymphoma kinase (ALK) with IC50 values of 0.1 to 2 nM. Entrectinib also inhibits JAK2 and TNK2 with IC50 values > 5 nM. The major active metabolite of entrectinib, M5, showed similar in vitro activity against TRK, ROS1, and ALK.

Fusion proteins that include TRK, ROS1, or ALK kinase domains can drive tumorigenic potential through hyperactivation of downstream signaling pathways leading to unconstrained cell proliferation. Entrectinib demonstrated in vitro and in vivo inhibition of cancer cell lines derived from multiple tumor types harboring NTRK, ROS1, and ALK fusion genes.

Entrectinib demonstrated steady-state brain-to-plasma concentration ratios of 0.4 – 2.2 in multiple animal species (mice, rats, and dogs) and demonstrated in vivo anti-tumor activity in mice with intracranial implantation of TRKA- and ALK-driven tumor cell lines.

12.2 Pharmacodynamics

Entrectinib exposure-response relationships and the time course of pharmacodynamic responses are unknown.

Cardiac Electrophysiology

Across clinical trials, 3.1% of 355 patients, who received ROZLYTREK at doses ranging from 100 mg to 2600 mg daily under fasting or fed conditions (75% received 600 mg orally once daily) and had at least one post-baseline ECG assessment, experienced QTcF interval prolongation of > 60 ms after starting ROZLYTREK and 0.6% had a QTc interval > 500 ms [see Warnings and Precautions (5.6)].

12.3 Pharmacokinetics

The pharmacokinetics for entrectinib and its pharmacologically active major circulating metabolite M5 were characterized in adult patients with ROS1-positive NSCLC, NTRK gene fusion-positive solid tumors, and healthy subjects. The pharmacokinetics of entrectinib and M5 are linear and are not dose-dependent or time-dependent. Steady state is achieved within one week for entrectinib and two weeks for M5 following daily administration of ROZLYTREK. The pharmacokinetic parameters for entrectinib and M5 are described in Table 11.

Absorption

The maximum entrectinib plasma concentration was reached 4 – 6 hours after oral administration of a 600 mg dose.

Entrectinib exposure following a single oral dose (600 mg) of ROZLYTREK oral pellets was not clinically significant compared to ROZLYTREK capsule administered with a light meal (250 calories: 25% fat) in healthy subjects. In STARTRK-2, STARTRK-NG and TAPISTRY studies, ROZLYTREK was administered without regard to food in patients.

Entrectinib exposure of a single dose (600 mg) of ROZLYTREK capsules as a suspension with water or milk, administered orally or through a nasogastric or gastric tube, was not clinically significant compared to administration of intact ROZLYTREK capsules in healthy subjects under fasted conditions.

Effect of Food

A high-fat (approximately 50% of total caloric content), high-calorie (approximately 800 to 1000 calories) meal did not have a significant effect on entrectinib exposure of ROZLYTREK capsules.

Distribution

Entrectinib and its active major metabolite M5 are both > 99% bound to human plasma proteins in vitro.

The estimated apparent volume of distribution (V/F) was 551 L and 81.1 L for entrectinib and M5, respectively.

Elimination

The estimated apparent clearance (CL/F) was 19.6 L/h and 52.4 L/h for entrectinib and M5, respectively. The elimination half-lives of entrectinib and M5 were estimated to be 20 and 40 hours, respectively.

Metabolism

Entrectinib is metabolized primarily by CYP3A4 (~76%). The active metabolite M5 (formed by CYP3A4) is the only major active circulating metabolite identified. M5 has similar pharmacological potency to entrectinib in vitro and circulating M5 exposures at steady-state in patients were 40% of the corresponding entrectinib exposure.

Excretion

Following oral administration of a single oral dose of [14C]-labeled entrectinib, 83% of radioactivity was excreted in feces (36% of the dose as unchanged entrectinib and 22% as M5) with minimal excretion in urine (3%).

Specific Populations

No clinically significant differences in the pharmacokinetics of entrectinib were observed based on sex, race (White, Asian and Black), mild to moderate renal impairment (CLcr 30 to < 90 mL/min) and mild hepatic impairment (total bilirubin ≤ ULN with aspartate aminotransferase > ULN or total bilirubin > 1.0 – 1.5 times ULN with any aspartate aminotransferase). The impact of severe renal impairment on the pharmacokinetics of entrectinib is unknown.

Hepatic Impairment

Following administration of a single oral dose of ROZLYTREK 100 mg (1/6 of the recommended dose), the entrectinib AUCINF was increased by 39% for the mild, 39% for the moderate, and 23% for the severe hepatic impairment groups compared to the normal hepatic function group. The combined AUClast of entrectinib and M5 was increased by 16% for the mild, 16% for the moderate, and 4% for the severe hepatic impairment groups compared to the normal hepatic function group. Large variability in systemic exposure of entrectinib was observed in the hepatic impairment groups.

Pediatric Patients > 6 months

In pediatric patients older than 6 months administered 300 mg/m2 (based on BSA) of ROZLYTREK once daily, systemic exposure of the sum of entrectinib and M5 in pediatric patients receiving 300 mg/m2 of ROZLYTREK once daily is within the range of the adults treated with 600 mg of ROZLYTREK once daily.

The available efficacy and safety data also confirm the adequacy of the recommended doses [see Use in Specific Populations (8.4)].

Pediatric Patients > 1 to ≤ 6 months

In pediatric patients > 1 to ≤ 6 months administered 250 mg/m2 (based on BSA) of ROZLYTREK once daily, systemic exposure of the sum of entrectinib and M5 in pediatric patients was at the lower range of the adults administered 600 mg of ROZLYTREK once daily.

The available efficacy and safety data also confirm the adequacy of the recommended doses [see Use in Specific Populations (8.4)].

Drug Interaction Studies

Clinical Studies

Effect of CYP3A Inhibitors on Entrectinib: Coadministration of itraconazole (a strong CYP3A inhibitor) with a single 100 mg dose of ROZLYTREK capsule increased entrectinib AUC0-INF by 6-fold and Cmax by 1.7-fold [see Drug Interactions (7.1)]. Coadministration of a moderate CYP3A inhibitor with ROZLYTREK capsule is predicted to increase entrectinib AUC0-Tau by 3-fold and Cmax by 2.9-fold. Based on physiologically based pharmacokinetic (PBPK) modelling, a similar magnitude of the effect is expected in children as young as 2 years old.

Effect of CYP3A Inducers on Entrectinib: Coadministration of rifampin (a strong CYP3A inducer) with a single 600 mg dose of ROZLYTREK capsule reduced entrectinib AUC0-INF by 77% and Cmax by 56% [see Drug Interactions (7.1)]. Coadministration of a moderate CYP3A inducer with ROZLYTREK capsule is predicted to reduce entrectinib AUC0-Tau by 56% and Cmax by 43%.

Effect of Gastric Acid Reducing Drugs on Entrectinib: Coadministration of a proton pump inhibitor (PPI), lansoprazole with a single 600 mg dose of ROZLYTREK capsule reduced entrectinib AUC by 25% and Cmax by 23%.

Coadministration of lansoprazole, with a single 600 mg dose of ROZLYTREK capsule as oral suspension in water increased entrectinib AUC by 25% and Cmax by 17%. These changes are not likely to be clinically significant.

Effect of Entrectinib on CYP Substrates: Coadministration of 600 mg dose of ROZLYTREK capsule once daily with oral midazolam (a sensitive CYP3A substrate) in patients increased the midazolam AUC by 50% but reduced midazolam Cmax by 21% [see Drug Interactions (7.1)].

Effect of Entrectinib on Transporters: Coadministration of a single 600 mg dose of ROZLYTREK capsule with digoxin [a sensitive P-glycoprotein (P-gp) substrate] increased digoxin Cmax by 28% and AUC by 18%.

In Vitro Studies

Entrectinib is not a substrate of P-gp or BCRP, but M5 is a substrate of P-gp and BCRP. Entrectinib and M5 are not substrates of OATP1B1 or OATP1B3.

11 DESCRIPTION

Entrectinib is a kinase inhibitor. The molecular formula for entrectinib is C31H34F2N6O2 and the molecular weight is 560.64 Daltons. The chemical name is N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methylpiperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino) benzamide. The chemical structure of entrectinib is as follows:

Entrectinib is white to pale pink powder.

Capsules:

ROZLYTREK (entrectinib) capsules for oral use are supplied as printed hard- shell capsules containing 100 mg (yellow opaque HPMC capsule) or 200 mg of entrectinib (orange opaque HPMC capsule). Inactive ingredients are tartaric acid, lactose anhydrous, hypromellose, crospovidone, microcrystalline cellulose, colloidal silicon dioxide, and magnesium stearate.

The yellow opaque capsule shell contains hypromellose, titanium dioxide, and yellow iron oxide. The orange opaque capsule shell contains hypromellose, titanium dioxide, and FD&C yellow #6. The printing ink contains shellac, propylene glycol, strong ammonia solution, and FD&C blue #2 aluminum lake.

Pellets:

ROZLYTREK (entrectinib) oral pellets are supplied as brownish orange or grayish orange, round film-coated pellets in packets. Each packet contains 50 mg of entrectinib and the following inactive ingredients: tartaric acid, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, sodium stearyl fumarate, mannitol, and magnesium stearate.

The film-coating contains polyvinyl alcohol (partially hydrolyzed), titanium dioxide, polyethylene glycol 3350, talc, yellow iron oxide, red iron oxide, and ferrosoferric oxide.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies were not conducted with entrectinib. Entrectinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay; however, an in vitro assay in cultured human peripheral blood lymphocytes did demonstrate a potential for abnormal chromosome segregation (aneugenicity). Entrectinib was not clastogenic or aneugenic in the in vivo micronucleus assay in rats and did not induce DNA damage in a comet assay in rats.

Dedicated fertility studies were not conducted with entrectinib. With the exception of dose-dependent decreases in prostate weight in male dogs, there were no effects on male and female reproductive organs observed in general toxicology studies conducted in rats and dogs at doses resulting in exposures of up to approximately 3.2-fold the human exposure (AUC) at the 600 mg dose.

14 CLINICAL STUDIES

14.1 ROS1-Positive Non-Small Cell Lung Cancer

The efficacy of ROZLYTREK was evaluated in a pooled subgroup of patients with ROS1-positive metastatic NSCLC who received ROZLYTREK at various doses and schedules (90% received ROZLYTREK 600 mg orally once daily) and were enrolled in one of three multicenter, single-arm, open-label clinical trials: ALKA, STARTRK-1 (NCT02097810) and STARTRK-2 (NCT02568267). To be included in this pooled subgroup, patients were required to have histologically confirmed, recurrent or metastatic, ROS1-positive NSCLC, ECOG performance status ≤ 2, measurable disease per RECIST v 1.1, ≥ 18 months of follow-up from first post- treatment tumor assessment, and no prior therapy with a ROS1 inhibitor. Identification of ROS1 gene fusion in tumor specimens was prospectively determined in local laboratories using either a fluorescence in situ hybridization (FISH), next-generation sequencing (NGS), or polymerase chain reaction (PCR) laboratory-developed tests. All patients were assessed for CNS lesions at baseline. The major efficacy outcome measures were overall response rate (ORR) and duration of response (DOR) according to RECIST v1.1 as assessed by Blinded Independent Central Review (BICR). Intracranial response according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) was assessed by BICR. Tumor assessments with imaging were performed every 8 weeks.

Efficacy was assessed in 92 patients with ROS1-positive NSCLC. The median age was 53 years (range: 27 to 86); female (65%); White (48%), Asian (45%), and Black (5%); and Hispanic or Latino (2.4%); never smoked (59%); and ECOG performance status 0 or 1 (88%). Ninety-nine percent of patients had metastatic disease, including 42% with CNS metastases; 96% had adenocarcinoma; 65% received prior platinum-based chemotherapy for metastatic or recurrent disease and no patient had progressed in less than 6 months following platinum-based adjuvant or neoadjuvant therapy. ROS1 positivity was determined by NGS in 79%, FISH in 16%, and PCR in 4%. Twenty-five percent had central laboratory confirmation of ROS1 positivity using an analytically validated NGS test.

Efficacy results are summarized in Table 12.

Among the 92 patients, 10 had measurable CNS metastases at baseline as assessed by BICR and had not received radiation therapy to the brain within 2 months prior to study entry. Responses in intracranial lesions were observed in 7 of these 10 patients.

14.2 NTRK Gene Fusion-Positive Solid Tumors

Efficacy in Adult Patients

The efficacy of ROZLYTREK was evaluated in a pooled subgroup of adult patients with unresectable or metastatic solid tumors with a NTRK gene fusion enrolled in one of three multicenter, single-arm, open-label clinical trials: ALKA, STARTRK-1 (NCT02097810) and STARTRK-2 (NCT02568267). To be included in this pooled subgroup, patients were required to have progressed following systemic therapy for their disease, if available, or would have required surgery causing significant morbidity for locally advanced disease; measurable disease per RECIST v1.1; at least 2 years of follow-up from first post-treatment tumor assessment; and no prior therapy with a TRK inhibitor. Patients received ROZLYTREK at various doses and schedules (94% received ROZLYTREK 600 mg orally once daily) until unacceptable toxicity or disease progression. Identification of positive NTRK gene fusion status was prospectively determined in local laboratories or a central laboratory using various nucleic acid-based tests. The major efficacy outcome measures were ORR and DOR, as determined by a BICR according to RECIST v1.1. Intracranial response according to RECIST v1.1 as evaluated by BICR. Tumor assessments with imaging were performed every 8 weeks.

Efficacy was assessed in the first 54 adult patients with solid tumors with an NTRK gene fusion enrolled into these trials. The median age was 58 years (range: 21 to 83); female (59%); White (80%), Asian (13%) and Hispanic or Latino (7%); and ECOG performance status 0 (43%) or 1 (46%). Ninety-six percent of patients had metastatic disease, including 22% with CNS metastases, and 4% had locally advanced, unresectable disease. All patients had received prior treatment for their cancer including surgery (n = 43), radiotherapy (n = 36), or systemic therapy (n = 48). Forty patients (74%) received prior systemic therapy for metastatic disease with a median of 1 prior systemic regimen and 17% (n = 9) received 3 or more prior systemic regimens. The most common cancers were sarcoma (24%), lung cancer (19%), salivary gland tumors (13%), breast cancer (11%), thyroid cancer (9%), and colorectal cancer (7%). A total of 52 (96%) patients had an NTRK gene fusion detected by NGS and 2 (4%) had an NTRK gene fusion detected by other nucleic acid-based tests. Eighty- three percent of patients had central laboratory confirmation of NTRK gene fusion using an analytically validated NGS test.

Efficacy results are summarized in Tables 13, 14, and 15.

Among the subset of patients who received prior systemic therapy for metastatic disease, the ORR was 53%, similar to that seen in the overall population. Among the 54 adult patients, 4 had measurable CNS metastases at baseline as assessed by BICR and had not received radiation therapy to the brain within 2 months of study entry. Responses in intracranial lesions were observed in 3 of these 4 patients.

Efficacy in Pediatric Patients

The efficacy of ROZLYTREK was evaluated in pediatric patients with unresectable or metastatic solid tumors with a NTRK gene fusion enrolled in one of two multicenter, open-label clinical trials: STARTRK-NG (NCT02650401) and TAPISTRY (NCT04589845). To be included in the analysis, patients were required to have received at least 1 dose of ROZLYTREK; measurable or evaluable disease at baseline; at least 6 months of follow-up; and no prior therapy with a TRK inhibitor. 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. The major efficacy outcome measure was overall response rate (ORR) as assessed by BICR according to RECIST v1.1 for extracranial tumors and according to Response Assessment in Neuro-Oncology (RANO) for primary central nervous system (CNS) tumors. An additional efficacy outcome measure was DOR as evaluated by BICR.

Efficacy was assessed in 33 pediatric patients with NTRK fusion-positive solid tumors treated with ROZLYTREK. The median age was 4 years (range: 2 months to 15 years); male (52%); White (58%), Asian (30%), other races (9%), Black or African American (3.0%), and Hispanic or Latino (9%). Seventy-one percent of patients had locally advanced disease and 29% had metastatic disease. Eighty- five percent of patients had received prior treatment for their cancer including surgery (n=20), radiotherapy (n=7) and/or systemic therapy (n=22). The sites for metastatic disease included other (4 patients), brain (3 patients) and lung (2 patients).

Efficacy results are summarized in Tables 16 and 17.

16 HOW SUPPLIED/STORAGE AND HANDLING

Capsules

How Supplied

• 100 mg hard capsules: Size 2 yellow opaque, with "ENT 100" printed in blue ink; available in HDPE bottles of 30 capsules: NDC 50242-091-30
• 200 mg hard capsules: Size 0 orange opaque, with "ENT 200" printed in blue ink; available in HDPE bottles of 90 capsules: NDC 50242-094-90

Storage:

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature].

Store ROZLYTREK capsules in the original container and keep the bottle tightly closed in order to protect from moisture.

Storage time should not exceed 2 hours (below 30°C (86°F)) if capsules are prepared as an oral suspension using drinking water or milk. Discard any unused suspension if not used within 2 hours of preparation.

Pellets

How Supplied

• ROZLYTREK oral pellets are supplied as brownish orange to grayish orange, round pellets, available in: 42-count carton (each packet contains 50 mg entrectinib): NDC 50242-623-42

Storage:

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature].

Store ROZLYTREK oral pellets in the original container in order to protect from moisture.