Rozlytrek

Description for Rozlytrek

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-(4methylpiperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino) benzamide. The chemical structure of entrectinib is as follows:

Entrectinib is white to pale pink powder.

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.

Uses for Rozlytrek

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.

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]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Dosage for Rozlytrek

Patient Selection

Information on FDA-approved tests for the detection of ROS1 rearrangement(s) in NSCLC is available at http://www.fda.gov/CompanionDiagnostics.

• Select patients for the treatment of metastatic NSCLC with ROZLYTREK based on the presence of ROS1 rearrangement(s) in tumor or plasma specimens [see Clinical Studies]. Testing using plasma specimens is only appropriate for patients for whom tumor tissue is not available for testing.
• Select patients for treatment of locally advanced or metastatic solid tumors with ROZLYTREK based on the presence of a NTRK gene fusion in tumor or plasma specimens [see Clinical Studies]. Testing using plasma specimens is only appropriate for patients for whom tumor tissue is not available for testing.

  Information on FDA-approved tests for the detection of NTRK gene fusion(s) in solid tumors is available at http://www.fda.gov/CompanionDiagnostics.

Recommended Evaluation And Testing Before Initiating ROZLYTREK

Before initiating ROZLYTREK, evaluate:

• left ventricular ejection fraction (LVEF) [see WARNINGS AND PRECAUTIONS
• serum uric acid levels [see WARNINGS AND PRECAUTIONS]
• QT interval and electrolytes [see WARNINGS AND PRECAUTIONS]

ROZLYTREK Dosage Form Overview

The physician should prescribe the most appropriate dosage form of ROZLYTREK according to the dose required and patient needs.

ROZLYTREK is available in two dosage forms, and can be administered either as capsules swallowed whole, capsules made into an oral suspension (or for enteral tube administration) and as oral pellets swallowed with soft food.

ROZLYTREK Capsules 100 mg And 200 mg

• Whole capsules: For patients who can swallow whole capsules and whose doses are multiples of 100 mg.
• Capsules prepared as an oral suspension:
  • For patients who have difficulty or are unable to swallow capsules or who require enteral administration (e.g., gastric or nasogastric tube). [see ROZLYTREK Dosage Modifications For Adverse Reactions].
  • For dose increments of 10 mg, only use capsules prepared as a suspension.

ROZLYTREK Oral Pellets 50 mg Per Packet

• Pellets sprinkled on one or more spoonfuls of soft food:
  • For patients who have difficulty or are unable to swallow capsules but can swallow soft food and whose doses are multiples of 50 mg. [see ROZLYTREK Dosage Modifications For Adverse Reactions].
  • Do not use pellets for preparation of suspension.
  • Do not attempt to use partial quantities of pellets from 50 mg pellet packets to prepare a dose.
  • Do not use the pellet formulation for enteral tube administration as the pellets may clog the tube.

ROZLYTREK Administration Overview

• Administer ROZLYTREK capsules, capsules prepared as a suspension, or pellets once daily, with or without food.
• If a dose of ROZYTREK is missed, make up that dose unless the next dose is due within 12 hours.
• If vomiting occurs immediately after taking a dose of ROZLYTREK, repeat that dose.

ROZLYTREK Recommended Dosage For ROS1-Positive Non-Small Cell Lung Cancer

The recommended dosage of ROZLYTREK is 600 mg orally once daily with or without food until disease progression or unacceptable toxicity.

ROZLYTREK Recommended Dosage For NTRK Gene Fusion-Positive Solid Tumors

The recommended dosages of ROZLYTREK for the treatment of adult and pediatric patients with NTRK Gene Fusion-Positive Solid Tumors are provided in Table 1.

Administer the recommended dosage of ROZLYTREK capsules and oral pellets with or without food until disease progression or unacceptable toxicity.

Sprinkle ROZLYTREK oral pellets on one or more spoonfuls of soft food as a vehicle.

Table 1. Recommended dosage for Adults and Pediatric patients for the Treatment of NTRK Gene Fusion-Positive Solid Tumors

Patient Population	Recommended Dosage of ROZLYTREK	Duration of Treatment
Adults Pediatric patients with BSA ≥ 1.51 m2:	600 mg orally once daily	Until disease progression or unacceptable toxicity.
Pediatric patients > 6 months:	see Table 2
Pediatric patients > 1 month to ≤ 6 months:	250 mg/m2 orally once daily*
* To enable dosing increments of 10 mg, capsules prepared as an oral suspension must be used [see ROZLYTREK Preparation And Administration Instructions].

The recommended dosages of ROZLYTREK for the treatment of pediatric patients older than 6 months with NTRK Gene Fusion-Positive Solid Tumors is provided in Table 2.

Table 2. Recommended dosage for Pediatric Patients Older than 6 Months for the Treatment of NTRK Gene Fusion-Positive Solid Tumors

Body Surface Area (BSA)*	Recommended Dosage Orally Once Daily
≤0.50 m2	300 mg/m2 **
0.51 to 0.80 m2	200 mg
0.81 to 1.10 m2	300 mg
1.11 to 1.50 m2	400 mg
≥ 1.51 m2	600 mg
*BSA categories and recommended dosage above are based on closely matching exposures to a target dose of 300 mg/m2 **To enable dosing increments of 10 mg, capsules prepared as an oral suspension must be used [see ROZLYTREK Preparation And Administration Instructions].

ROZLYTREK Dosage Modifications For Adverse Reactions

The recommended dosage reductions of ROZLYTREK for the management of adverse reactions for adults and pediatric patients are provided in Table 3.

Table 3. Recommended Dose Reductions for ROZLYTREK for the Management of Adverse Reaction

Starting Dose once daily	First dose reduction	Second dose reduction	Permanently discontinue ROZLYTREK in patients who are unable to tolerate ROZLYTREK after two dose reductions.
250 mg/m2 or 300 mg/m2	Reduce the once daily dose to two thirds of the starting dose*	Reduce the once daily dose to one third of the starting dose*
200 mg	150 mg once daily	100 mg once daily
300 mg	200 mg once daily	100 mg once daily
400 mg	300 mg once daily	200 mg once daily
600 mg	400 mg once daily	200 mg once daily
*To enable dosing increments of 10 mg, capsules prepared as an oral suspension must be used [see ROZLYTREK Preparation And Administration Instructions].

Table 4 provides the ROZLYTREK recommended dosage modifications for the management of adverse reactions.

Table 4. ROZLYTREK Dosage Modifications for the Management of Adverse Reaction

Adverse Reaction	Severity*	Dosage Modification
Congestive Heart Failure [see WARNINGS AND PRECAUTIONS]	Grade 2 or 3	Withhold ROZLYTREK until recovered to less than or equal to Grade 1. Resume at reduced dose.
	Grade 4	Permanently discontinue ROZLYTREK.
Central Nervous System Effects [see WARNINGS AND PRECAUTIONS]	Intolerable Grade 2	Withhold ROZLYTREK until recovery to less than or equal to Grade 1 or to baseline. Resume at same dose or reduced dose, as clinically appropriate.
	Grade 3	Withhold ROZLYTREK until recovery to less than or equal to Grade 1 or to baseline. Resume at reduced dose.
	Grade 4	Permanently discontinue ROZLYTREK.
Hepatotoxicity [see WARNINGS AND PRECAUTIONS]	Grade 3	Withhold ROZLYTREK until recovery to less than or equal to Grade 1 or to baseline. Resume at same dose if resolution occurs within 4 weeks. Permanently discontinue if adverse reaction does not resolve within 4 weeks. Resume at a reduced dose for recurrent Grade 3 events that resolve within 4 weeks.
	Grade 4	Withhold ROZLYTREK until recovery to less than or equal to Grade 1 or to baseline. Resume at reduced dose if resolution occurs within 4 weeks. Permanently discontinue if adverse reaction does not resolve within 4 weeks. Permanently discontinue for recurrent Grade 4 events.
	ALT or AST greater than 3 times ULN with concurrent total bilirubin greater than 1.5 times ULN (in the absence of cholestasis or hemolysis).	Permanently discontinue ROZLYTREK.
Hyperuricemia [see WARNINGS AND PRECAUTIONS]	Symptomatic or Grade 4	Initiate urate-lowering medication. Withhold ROZLYTREK until improvement of signs or symptoms. Resume ROZLYTREK at same or reduced dose.
QT Interval Prolongation [see WARNINGS AND PRECAUTIONS ]	QTc greater than 500 ms	Withhold ROZLYTREK until QTc interval recovers to baseline. Resume at same dose if factors that cause QT prolongation are identified and corrected. Resume at reduced dose if other factors that cause QT prolongation are not identified.
	Torsade de pointes; polymorphic ventricular tachycardia; signs/symptoms of serious arrhythmia	Permanently discontinue ROZLYTREK.
Vision Disorders [see WARNINGS AND PRECAUTIONS]	Grade 2 or above	Withhold ROZLYTREK until improvement or stabilization. Resume at same dose or reduced dose, as clinically appropriate.
Anemia or Neutropenia [see ADVERSE REACTIONS]	Grade 3 or 4	Withhold ROZLYTREK until recovery to less than or equal to Grade 2. Resume at the same dose or reduced dose, as clinically appropriate.
Other Adverse Reactions [see ADVERSE REACTIONS]	Grade 3 or 4	Withhold ROZLYTREK until adverse reaction resolves or improves to recovery or improvement to Grade 1 or baseline. Resume at the same or reduced dose if resolution occurs within 4 weeks. Permanently discontinue if adverse reaction does not resolve within 4 weeks. Permanently discontinue for recurrent Grade 4 events.
*Severity as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0.

ROZLYTREK Dosage Modifications For Drug Interactions

Moderate And Strong CYP3A Inhibitors

Adults and Pediatric Patients 2 Years and Older

Avoid coadministration of ROZLYTREK with moderate or strong CYP3A inhibitors. If coadministration cannot be avoided, reduce the ROZLYTREK dose as shown in Table 5 and limit coadministration to 14 days or less.

Table 5. Recommended Dose Modifications of ROZYLTREK for Concomitant Use with Moderate or Strong CYP3A Inhibitors for Adults and Pediatric Patients 2 Years and Older

Starting dose*	Moderate CYP3A inhibitor	Strong CYP3A inhibitor
200 mg	50 mg once daily	50 mg on alternate days
300 mg	100 mg once daily	50 mg once daily
400 mg	200 mg once daily	50 mg once daily
600 mg	200 mg once daily	100 mg once daily
* For pediatric patients with a starting dose less than 200 mg, avoid coadministration with moderate or strong CYP3A inhibitors

After discontinuation of a strong or moderate CYP3A inhibitor for 3 to 5 elimination half-lives, resume the ROZLYTREK dose that was taken prior to initiating the CYP3A inhibitor [see DRUG INTERACTIONS and CLINICAL PHARMACOLOGY].

ROZLYTREK Preparation And Administration Instructions

ROZLYTREK Capsules

Swallow capsules whole. Do not crush or chew the capsules.

ROZLYTREK Capsules Prepared As A Suspension For Oral Or Enteral Tube Administration

It is recommended that a healthcare provider discuss with the patient or caregiver, the volume of water or milk to be added and oral suspension to withdraw, prior to administration of the first dose (see Table 6).

Table 6 provides the ROZLYTREK dose and volume of room temperature drinking water or milk required to prepare an oral suspension. Instruct patients or caregivers to carefully open capsule(s) and pour the contents into room temperature drinking water or milk to prepare an oral suspension. Let sit for 15 minutes.

Table 6. Preparation of ROZLYTREK Capsules as an Oral Suspension

Dose of ROZLYTREK to be administered	Dose needed for suspension (using 100 mg or 200 mg capsules, as appropriate)	Volume of water or milk to be added	Volume of oral suspension to withdraw and administer
20 mg	100 mg	5 mL	1 mL
30 mg	100 mg	5 mL	1.5 mL
40 mg	100 mg	5 mL	2 mL
50 mg	100 mg	5 mL	2.5 mL
60 mg	100 mg	5 mL	3 mL
70 mg	100 mg	5 mL	3.5 mL
80 mg	100 mg	5 mL	4 mL
90 mg	100 mg	5 mL	4.5 mL
100 mg	100 mg	5 mL	5 mL
110 mg	200 mg	10 mL	5.5 mL
120 mg	200 mg	10 mL	6 mL
130 mg	200 mg	10 mL	6.5 mL
140 mg	200 mg	10 mL	7 mL
150 mg	200 mg	10 mL	7.5 mL
200 mg	200 mg	10 mL	10 mL
300 mg	300 mg	15 mL	15 mL
400 mg	400 mg	20 mL	20 mL
600 mg	600 mg	30 mL	30 mL

Administer ROZLYTREK oral suspension immediately after preparation.

Discard any unused suspension if not used within 2 hours.

Instruct patients to drink water after taking the oral suspension to ensure ROZLYTREK has been completely swallowed.

Enteral Tube Administration

If enteral administration (e.g., gastric or nasogastric tube) is required, administer the oral suspension via the tube. Use an enteral tube that is 8 FR or higher to administer dosing volumes of 3 mL or higher. Instruct patients to divide dosing volumes of 3 mL or higher into at least two aliquots and flush the tube after each administration. Flush the tube with a volume of water or milk that is equal to the aliquot administered. For a dose volume of 30 mL, divide into at least three (10 mL) aliquots. The tube should be flushed with water or milk after delivering each aliquot of ROZLYTREK.

Refer to the Instructions for Use for detailed instructions on preparation and administration of ROZLYTREK capsules as an oral suspension via an enteral tube.

ROZLYTREK Oral Pellets

Sprinkle pellets on one or more spoonfuls of a soft food (e.g., applesauce, yogurt, or pudding) and take within 20 minutes of preparation. Do not crush or chew to avoid a bitter taste.

The patient should drink water after taking the pellets to ensure the drug has been completely swallowed.

Do not attempt to use partial quantities of pellets from 50 mg pellet packets to prepare a dose.

Do not use the pellet formulation for enteral tube administration as the pellets may clog the tube.

Refer to the Instructions for Use for detailed instructions on preparation and administration of ROZLYTREK oral pellets.

HOW SUPPLIED

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.

Storage And Handling

Capsules

• 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

• 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.

Distributed by: Genentech, Inc., A Member of the Roche Group, 1 DNA Way, South San Francisco, CA 94080-4990. Revised: Jan 2024.

Side Effects for Rozlytrek

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

• Congestive Heart Failure [see WARNINGS AND PRECAUTIONS
• Central Nervous System Effects [see WARNINGS AND PRECAUTIONS]
• Skeletal Fractures [see WARNINGS AND PRECAUTIONS]
• Hepatotoxicity [see WARNINGS AND PRECAUTIONS]
• Hyperuricemia [see WARNINGS AND PRECAUTIONS]
• QT Interval Prolongation [see WARNINGS AND PRECAUTIONS]
• Vision Disorders [see WARNINGS AND PRECAUTIONS]

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.

Table 7. Adverse Reaction (≥ 10%) in Patients Receiving ROZLYTREK in ALKA, STARTRK-1, STARTRK-2, and STARTRK-NG

Adverse Reaction	ROZLYTREK n = 355
	All Grades (%)	Grade ≥ 3* (%)
General
Fatigue1	48	5
Edema2	40	1.1
Pyrexia	21	0.8
Gastrointestinal
Constipation	46	0.6
Diarrhea	35	2.0
Nausea	34	0.3
Vomiting	24	0.8
Abdominal pain3	16	0.6
Nervous System
Dysgeusia	44	0.3
Dizziness4	38	0.8
Dysesthesia5	34	0.3
Cognitive impairment6	27	4.5
Peripheral sensory neuropathy7	18	1.1
Headache	18	0.3
Ataxia8	17	0.8
Sleep9	14	0.6
Mood disorders10	10	0.6
Respiratory, Thoracic and Mediastinal
Dyspnea	30	6*
Cough	24	0.3
Musculoskeletal and Connective Tissue
Myalgia11	28	1.1
Arthralgia	21	0.6
Muscular weakness	12	0.8
Back pain	12	1
Pain in extremity	11	0.3
Metabolism and Nutritional
Increased weight	25	7
Decreased appetite	13	0.3
Dehydration	10	1.1
Eye
Vision disorders12	21	0.8
Infections
Urinary tract infection	13	2.3
Lung infection13	10	6*
Vascular
Hypotension14	18	2.8
Skin and Subcutaneous Tissue
Rash15	11	0.8
* Grades 3 – 5, inclusive of fatal adverse reactions, including 2 events of pneumonia and 2 events of dyspnea. 1Includes fatigue, asthenia 2 Includes face edema, fluid retention, generalized edema, localized edema, edema, edema peripheral, peripheral swelling 3 Includes abdominal pain upper, abdominal pain, lower abdominal discomfort, abdominal tenderness 4 Includes dizziness, vertigo, dizziness postural 5 Includes paresthesia, hyperesthesia, hypoesthesia, dysesthesia, oral hypoesthesia, palmar-plantar erythrodysesthesia, oral paresthesia, genital hypoesthesia 6 Includes amnesia, aphasia, cognitive disorder, confusional state, delirium, disturbance in attention, hallucinations, visual hallucination, memory impairment, mental disorder, mental status changes 7 Includes neuralgia, neuropathy peripheral, peripheral motor neuropathy, peripheral sensory neuropathy 8 Includes ataxia, balance disorder, gait disturbances 9 Includes hypersomnia, insomnia, sleep disorder, somnolence 10 Includes anxiety, affect lability, affective disorder, agitation, depressed mood, euphoric mood, mood altered, mood swings, irritability, depression, persistent depressive disorder, psychomotor retardation 11 Includes musculoskeletal pain, musculoskeletal chest pain, myalgia, neck pain 12 Includes blindness, cataract, cortical cataract, corneal erosion, diplopia, eye disorder, photophobia, photopsia, retinal hemorrhage, vision blurred, visual impairment, vitreous adhesions, vitreous detachment, vitreous floaters 13 Includes lower respiratory tract infection, lung infection, pneumonia, respiratory tract infection 14 Includes hypotension, orthostatic hypotension 15 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.

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 (%)1	Grade 3 or 4 (%)1
Chemistry
Increased creatinine2	73	2.1
Hyperuricemia	52	10
Increased AST	44	2.7
Increased ALT	38	2.9
Hypernatremia	35	0.9
Hypernatremia	34	1.8
Hypophosphatemia	30	7
Increased lipase	28	10
Hypoalbuminemia	28	2.9
Increased amylase	26	5.4
Hyperkalemia	25	1.5
Increased alkaline phosphatase	25	0.9
Hyperglycemia3	NE3	3.8
Hematology
Anemia	67	9
Lymphopenia	40	12
Neutropenia	28	7
AST: Aspartate Aminotransferase; ALT: Alanine Aminotransferase 1 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. 2 Based on NCI CTCAE v5.0 3 NE = Not evaluable. Grade 1 and 2 could not be determined per NCI CTCAE v5.0, as fasting glucose values were not collected

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 Reaction (≥20%) in Pediatric Patients Who Received ROZLYTREK in STARTRKNG, TAPISTRY and STARTRK-2

Adverse Reaction	ROZLYTREK (n=76)
	All Grades (%)	Grade 3 or 4 (%)
General Disorders
Pyrexia	43	1.3
Fatigue1	30	2.6
Gastrointestinal Disorders
Constipation	41	1.3
Vomiting	38	0
Diarrhea	37	0
Nausea	34	0
Abdominal Pain	20	2.6
Investigations
Increased Weight	39	18
Respiratory, Thoracic And Mediastinal Disorders
Cough	33	1.3
Nasal Congestion	20	0
Musculoskeletal And Connective Tissue Disorders
Pain in Extremity	26	2.6
Skeletal Fracture2	25	11
Metabolism And Nutrition Disorders
Decreased Appetite	24	1.3
Nervous System Disorders
Headache	22	2.6
Infections
Upper Respiratory Tract Infection	20	1.3
Urinary Tract Infection	20	2.6
1Includes fatigue, asthenia 2Includes 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

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	ROZLYTREK1
	All Grades (%)	Grade 3 or 4 (%)
Hematology
Decreased Hemoglobin	53	7
Decreased Neutrophils	53	22
Decreased Leukocytes	46	1.3
Increased Lymphocytes	33	3
Chemistry
Increased Creatinine	84	5
Increased AST	61	2.7
Increased ALT	53	2.6
Increased Sodium	38	1.4
Increased Magnesium	32	5
Increased Alkaline Phosphatase	25	0
Decreased Glucose	26	0
Increased Potassium	25	2.7
Decreased Albumin	24	9
Increased Calcium	21	8
Increased Bilirubin	20	8
AST: Aspartate Aminotransferase; ALT: Alanine Aminotransferase 1 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

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

Drug Interactions for Rozlytrek

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], 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 and CLINICAL PHARMACOLOGY].

Pediatric Patients less than 2 Years

Avoid coadministration of ROZLYTREK with moderate or strong CYP3A inhibitors [see CLINICAL PHARMACOLOGY].

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], 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 [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].

Overdose Information for Rozlytrek

No Information Provided

Contraindications for Rozlytrek

None.

Clinical Pharmacology for Rozlytrek

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.

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].

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.

Table 11. Pharmacokinetic Parameters for Entrectinib and Metabolite M5

Parameter	Entrectinib Mean* (% CV)	M5 Mean* (% CV)
AUCD1 (nM*h)	31800 (48%)	10200 (82%)
AUCss (nM*h)	48000 (77%)	24000 (97%)
CmaxD1 (nM)	2250 (58%)	622 (79%)
Cmaxss (nM)	3130 (80%)	1250 (90%)
Racc(AUC)	1.55 (49%)	2.84 (93%)
* Geometric mean

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].

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].

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]. 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]. 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].

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.

Clinical Studies

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.

Table 12. Efficacy Results in ROS1-Positive NSCLC Patients per BICR Assessment

Efficacy Parameters	ROZLYTREK n = 92
Overall Response Rate (95% CI)	74% (64, 83)
Complete Response	15%
Partial Response	59%
Duration of Response (DOR)*	n = 68
Range (months)	2.4, 55.2+
% DOR ≥ 9 months	75%
% DOR ≥ 12 months	57%
% DOR ≥ 18 months	38%
Confidence Interval (CI) calculated using the Clopper-Pearson method. * Observed DOR +denotes ongoing response

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.

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.

Table 13. Efficacy Results for Adult Patients with Solid Tumors Harboring NTRK Gene Fusions

Efficacy Parameter	ROZLYTREK n = 54
Overall Response Rate (95% CI)	59% (45, 72)
Complete Response	13%
Partial Response	46%
Duration of Response*	n = 32
Range (months)	2.8, 47.8+
% with duration ≥ 6 months	72%
% with duration ≥ 9 months	66%
% with duration ≥ 12 months	56%
* Observed DOR + denotes ongoing response

Table 14. Efficacy by Tumor Type

Tumor Type	Patients n = 54	ORR		DOR
		%	95% CI	Range (months)
Sarcoma	13	46%	19%, 75%	2.8, 33.6+
Non-small cell lung cancer	10	60%	26%, 88%	3.7, 47.8+
Salivary (MASC)	7	86%	42%, 100%	2.8, 38.5+
Breast cancer	6	83%	36%, 100%	4.2, 42.3+
Thyroid cancer	5	60%	NA	7.9, 31.5+
Colorectal cancer	4	25%	NA	15.1
Neuroendocrine cancers	3	CR	NA	32.9+
Pancreatic cancer	3	PR, PR	NA	7.1, 12.9
Gynecological cancers	2	PR	NA	38.2
Cholangiocarcinoma	1	PR	NA	9.3
+denotes ongoing response MASC: mammary analogue secretory carcinoma; NA = not applicable due to small numbers or lack of response; PR = partial response.

Table 15. Efficacy Results by NTRK Gene Fusion Partner

NTRK Partner	Patients n = 54	ORR		DOR
		%	95% CI	Range (months)
ETV6 – NTRK3	25	72%	51%, 88%	2.8, 47.8+
TPM3 – NTRK1	4	50%	7%, 93%	2.8, 15.1
TPR – NTRK1	4	100%	40%, 100%	5.6, 33.6+
LMNA – NTRK1	2	PR, PD	NA	4.2
SQSTM1 – NTRK1	2	PR, PD	NA	18.8+
PEAR1 – NTRK1	2	SD, NE	NA	NA
EML4 – NTRK3	2	PR, NE	NA	13.2
CD74 – NTRK1	1	PR	NA	10.4
PLEKHA6 – NTRK1	1	PR	NA	9.3
CDC42BPA – NTRK1	1	PR	NA	29.4
EPS15L1 – NTRK1	1	PR	NA	3.7
RBPMS – NTRK3	1	PR	NA	4.6
ERC1 – NTRK1	1	SD	NA	NA
PDIA3 – NTRK1	1	SD	NA	NA
TRIM33 – NTRK1	1	SD	NA	NA
AKAP13 – NTRK3	1	SD	NA	NA
KIF7 – NTRK3	1	SD	NA	NA
FAM19A2 – NTRK3	1	PD	NA	NA
CGN – NTRK1	1	NE	NA	NA
SQSTM1 – NTRK2	1	NE	NA	NA
+denotes ongoing response PR = partial response; PD = progressive disease; SD = stable disease; NA = not applicable due to small numbers or lack of response; NE = not evaluable.

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.

Table 16. Efficacy Results for Pediatric Patients with Solid Tumors Harboring NTRK Gene Fusions

Efficacy Parameter*	ROZLYTREK n = 33
Overall Response Rate (95% CI)	70% (51, 84)
Complete Response	42%
Partial Response	27%
Duration of Response**	n = 23
Median in months (95% CI)	25.4 (14.3, NE)
% with duration ≥ 12 months	43%
* Includes patients with measurable and evaluable disease. BICR analysis by RECIST v1.1 for solid tumors (16 patients) and by RANO criteria for primary CNS tumors (17 patients) ** Observed DOR NE = not estimable

Table 17. Efficacy Results for Pediatric Patients with Solid Tumors Harboring NTRK Gene Fusions by Tumor Type

Tumor Type	Patients n = 33	ORR		DOR
		%	95% CI	Range (months)
Primary CNS*	17	53%	28%, 77%	5.5, 30.4+
Infantile fibrosarcoma	8	88%	47%, 100%	3.7+, 24+
Spindle Cell	6	100%	54%, 100%	3.7+, 12.9+
Sarcoma (other)	1	0%**	NA	NA
Melanoma	1	100%	NA	42. 4+
*Median time to first objective response for patients with primary CNS tumors was 1.9 months +denotes ongoing response ** Patient with evaluable but non-measurable disease at baseline NA = not applicable due to small numbers or lack of response

Table 18. Efficacy Results for Pediatric Patients with Solid Tumors Harboring NTRK by Gene Fusion Partner

NTRK Partner	Patients n = 33	ORR		DOR
		%	95% CI	Range (months)
ETV6 – NTRK3	7	86%	42%, 100%	11.9+ -42.4+
LMNA – NTRK1	5	80%	28%, 99%	7.4+ -12.9+
TPM3 – NTRK1	3	100%	29%, 100%	3.7+ -24.0+
TPR – NTRK1	3	67%	9%, 99%	8.1+ -14.3
EML4-NTRK3	2	50%	1.3%, 99%	13.8+
BCAN-NTRK1	1	CR	NA	11.8+
EML1-NTRK2	1	CR	NA	11.8
QKI-NTRK2	1	CR	NA	11.1+
TFG-NTRK3	1	CR	NA	3.7+
KANK1-NTRK2	1	PR	NA	5.5
KIF5B-NTRK2	1	PR	NA	12.9+
TNS3-NRTK2	1	PR	NA	9.5
ARHGEF2-NTRK1	1	SD	NA	NA
KIF21B-NTRK1	1	SD	NA	NA
BCR-NTRK2	1	SD	NA	NA
GKAP1-NTRK2	1	SD	NA	NA
DNM3-NTRK2	1	PD	NA	NA
PARP6-NTRK3	1	PD	NA	NA
+denotes ongoing response PR = partial response; PD = progressive disease; SD = stable disease; NA = not applicable due to small numbers or lack of response

Patient Information for Rozlytrek

ROZLYTREK^®
(roz lye' trek)
(entrectinib) capsules

ROZLYTREK^®
(roz lye' trek)
(entrectinib) oral pellets

What is the most important information I should know about ROZLYTREK?

ROZLYTREK may cause serious side effects, including:

• Congestive heart failure. ROZLYTREK may cause congestive heart failure or make the congestive heart failure that you already have worse. Your healthcare provider will do tests before your treatment and may do tests during your treatment with ROZLYTREK to check your heart function. Tell your healthcare provider right away if you have any of the following signs and symptoms of congestive heart failure:
  • persistent coughing or wheezing
  • increasing shortness of breath
  • trouble breathing when lying down
  • tiredness, weakness, or fatigue
  • sudden weight gain
  • swelling in ankles, feet, or legs
• Central nervous system (CNS) effects. ROZLYTREK may cause dizziness, changes in your mood, or may affect how you think and cause confusion, hallucinations, and problems with concentration, attention, memory, speaking, understanding what your hear or read, and sleep. Tell your healthcare provider right away if you have any of these symptoms.
• Bone fractures. ROZLYTREK may increase your risk for bone fractures. Bone fractures may happen with or without a fall or other injury. Tell your healthcare provider if you develop pain, changes in movement, or bone abnormalities.
• Liver problems (hepatotoxicity). Your healthcare provider will do blood tests to check your liver function during treatment with ROZLYTREK. Tell your healthcare provider right away if you develop any of the following symptoms of liver problems:
  • loss of appetite
  • yellowing of your skin or the white part of your eyes
  • nausea or vomiting
  • dark urine
  • pain in your upper right stomach area
• Increased uric acid level in your blood (hyperuricemia). ROZLYTREK may cause too much uric acid in your blood. Your healthcare provider will do tests before and during your treatment with ROZLYTREK to check the uric acid level in your blood. Your healthcare provider may prescribe medications if you have high blood uric acid levels. Tell your healthcare provider if you develop any of the following symptoms of hyperuricemia:
  • red, hot, tender, or swollen joints, especially in your big toe
  • nausea or vomiting
  • pain in your stomach-area or sides
  • pink or brown urine
• Changes in the electrical activity of your heart called QT prolongation. QT prolongation can cause irregular heartbeats that can be life-threatening. Your healthcare provider will do tests before and during your treatment with ROZLYTREK to check the electrical activity of your heart and your body salts (electrolytes). Tell your healthcare provider right away if you feel faint, lightheaded, dizzy, or feel your heart beating irregularly or fast during your treatment with ROZLYTREK. These may be symptoms related to QT prolongation.
• Vision problems. ROZLYTREK may cause vision problems. Your healthcare provider may stop ROZLYTREK and refer you to an eye specialist if you develop severe vision problems during treatment with ROZLYTREK. Tell your healthcare provider right away if you have any loss of vision or any change in vision, including:
  • double vision
  • seeing flashes of light
  • blurry vision
  • light hurting your eyes
  • new or increased floaters

Your healthcare provider may temporarily stop treatment, decrease your dose, or permanently stop ROZLYTREK if you develop certain side effects during treatment with ROZLYTREK.

What is ROZLYTREK?

ROZLYTREK is a prescription medicine used to treat:

• Adults with non-small cell lung cancer (NSCLC) that has spread to other parts of the body and is caused by an abnormal ROS1 gene.
• Adults and children 1 month of age and older with solid tumors (cancer) that:
  • are caused by certain abnormal NTRK genes, and
  • have spread or if surgery to remove their cancer is likely to cause severe complications, and
  • there is no satisfactory alternative treatment option or the cancer grew or spread on other treatment.

It is not known if ROZLYTREK is safe and effective in children with ROS1 NSCLC or in children under 1 month of age with NTRK solid tumors.

Before taking ROZLYTREK, tell your healthcare provider about all your medical conditions, including if you:

• have liver or kidney problems
• have any heart problems, including a condition called long QT syndrome
• have nervous system (neurological) problems
• have or have had eye or vision problems
• are pregnant or plan to become pregnant. ROZLYTREK can cause harm to your unborn baby. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with ROZLYTREK.

  Females who can become pregnant:

  • Your healthcare provider will do a pregnancy test before you start treatment with ROZLYTREK.
  • Use effective birth control (contraception) during treatment with ROZLYTREK and for at least 5 weeks after the last dose.

  Males with female partners that can become pregnant:

  • Use effective birth control (contraception) during treatment with ROZLYTREK and for 3 months after the last dose.
• are breastfeeding or plan to breastfeed. It is not known if ROZLYTREK passes into your breast milk. Do not breastfeed during treatment with ROZLYTREK and for 7 days (1 week) after the last dose of ROZLYTREK. Talk to your healthcare provider about the best way to feed your baby during this time.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, or herbal supplements.

Taking ROZLYTREK with certain other medicines may affect the amount of ROZLYTREK or other medicine in your blood and may cause side effects or affect the way that ROZLYTREK or the other medicine work. Know the medicines you take. Keep a list of them to show to your healthcare provider and pharmacist when you get a new medicine.

How should I take ROZLYTREK?

• Take ROZLYTREK exactly as your healthcare provider tells you. Do not change your dose or stop taking ROZLYTREK unless your healthcare provider tells you to.
• Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with ROZLYTREK if you develop certain side effects.
• Take ROZLYTREK 1 time each day with or without food.
• Your healthcare provider will either prescribe:
  • ROZLYTREK capsules to be swallowed whole or prepared and taken or given as a suspension or
  • ROZLYTREK oral pellets to be sprinkled on 1 or more spoonfuls of soft food before taking.
• If you miss a dose of ROZLYTREK, take it as soon as you remember. If your next dose is due within 12 hours, skip the missed dose and take your next dose at your regular time.
• If you vomit right after taking a dose of ROZLYTREK, you may take the dose again.

See the detailed Instructions for Use for information on how to give or take a dose of ROZLYTREK capsules or oral pellets.

If you are taking whole ROZLYTREK capsules:

• Swallow whole capsules with drinking water, as directed by your healthcare provider.
• Do not crush or chew the capsule.

If you are taking ROZLYTREK capsules prepared as a suspension:

• Carefully open the prescribed number of capsules and pour the contents into room temperature drinking water or milk. Your healthcare provider will tell you how much water or milk to use, how much suspension to take or give, and provide you with a measuring device like an oral syringe or measuring cup.
• Let the suspension sit for 15 minutes before taking.
• You may need to take less suspension than you prepared depending on your prescribed dose.
• Drink water after taking the suspension to make sure you have swallowed all the medicine.
• If you do not take the suspension right away, you can store it for up to 2 hours at room temperature below 86°F (30°C). Throw away (discard) the unused suspension if it is not used within 2 hours of preparation.
• If you cannot swallow and have a gastric or nasogastric tube, the suspension can be given through the feeding tube.

If you are taking ROZLYTREK oral pellets:

• Sprinkle the prescribed number of packets of pellets on 1 or more spoonfuls of a soft food like applesauce, yogurt, or pudding, and take within 20 minutes of sprinkling the pellets on the soft food.
• Do not crush or chew the pellets to avoid a bitter taste.
• Drink water after taking the prescribed dose to make sure you have swallowed all the medicine.
• Use the whole packet of pellets. Do not use part of the packet to try to prepare a dose.
• Do not use the pellets to make a suspension.
• Do not give the pellets through a gastric or nasogastric tube because the pellets may clog the feeding tube.

What should I avoid while taking ROZLYTREK?

• You should not drink grapefruit juice or eat grapefruit during your treatment with ROZLYTREK. It may increase the amount of entrectinib in your blood to a harmful level and increase your chance of getting side effects.
• Do not drive or operate heavy machinery until you know how ROZLYTREK affects you. If you experience dizziness, fainting, tiredness, blurred vision, memory loss, changes in mental status, confusion, or hallucinations, do not drive or operate heavy machines until your symptoms resolve.

What are the possible side effects of ROZLYTREK?

ROZLYTREK may cause serious side effects, including:

• See “What is the most important information I should know about ROZLYTREK?”

The most common side effects of ROZLYTREK include:

• tiredness
• nausea
• weight gain
• constipation
• abnormal touch sensation
• cough
• change in taste
• shortness of breath
• vomiting
• swelling
• muscle pain
• fever
• dizziness
• confusion, mental status changes,
• joint pain
• diarrhea memory problems, and hallucinations
• vision changes

These are not all the possible side effects of ROZLYTREK.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store ROZLYTREK?

ROZLYTREK capsules

• Store ROZLYTREK at room temperature between 68°F to 77°F (20°C to 25°C).
• Store ROZLYTREK capsules in the original container and keep the bottle tightly closed to protect from moisture.

ROZLYTREK oral pellets

• Store ROZLYTREK oral pellets at room temperature between 68°F to 77°F (20°C to 25°C).
• Store ROZLYTREK oral pellets in the original container to protect from moisture.

Keep ROZLYTREK and all medicines out of the reach of children.

General information about the safe and effective use of ROZLYTREK.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use ROZLYTREK for a condition for which it was not prescribed. Do not give ROZLYTREK to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about ROZLYTREK that is written for health professionals.

What are the ingredients in ROZLYTREK?

Active ingredient: entrectinib

Inactive ingredients:

Capsules: tartaric acid, lactose anhydrous, hypromellose, crospovidone, microcrystalline cellulose, colloidal silicon dioxide, and magnesium stearate.

• Yellow opaque capsule shell: hypromellose, titanium dioxide, and yellow iron oxide
• Orange opaque capsule shell: hypromellose, titanium dioxide, and FD&C Yellow No. 6
• Printing ink: shellac, propylene glycol, strong ammonia solution, and FD&C Blue No. 2 aluminum lake

Pellets: tartaric acid, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, sodium stearyl fumarate, mannitol, and magnesium stearate

• Film-coating: polyvinyl alcohol (partially hydrolyzed), titanium dioxide, polyethylene glycol 3350, talc, yellow iron oxide, red iron oxide, and ferrosoferric oxide.

This Patient Information has been approved by the U.S. Food and Drug Administration.