These Highlights Do Not Include All The Information Needed To Use Rozlytrek®

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 Dosage and Administration (2.7)].
  • For dose increments of 10 mg, only use capsules prepared as a suspension.

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.

INSTRUCTIONS FOR USE

ROZLYTREK^® [roz lye trek]

(entrectinib)

capsules, for oral use

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

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

ROZLYTREK capsules can be swallowed whole or prepared as a suspension and taken or given by mouth or through a nasogastric tube (NG tube) or gastrostomy tube (G tube) feeding tube.

• Your healthcare provider or pharmacist should show you how to correctly prepare and take or give a dose of ROZLYTREK capsules. Always take or give ROZLYTREK capsules exactly as your healthcare provider tells you.
• Do not take or give ROZLYTREK 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.
• Your healthcare provider will tell you what your daily dose of ROZLYTREK is.
• Swallow ROZLYTREK capsules whole, with or without food.
• Swallow whole capsules with drinking water, as directed by your healthcare provider.
• Do not crush or chew the capsules.

If you or your child cannot swallow capsules whole, ROZLYTREK capsules can be prepared as a suspension and taken or given by mouth or through a feeding tube. For doses of 3 mL or higher, a NG or G feeding tube size 8 French or larger should be used.

Your healthcare provider or pharmacist will show you how to prepare and take or give a dose of ROZLYTREK capsules prepared as a suspension.

Table 1 shows the prescribed dose, the number and strength of capsules needed, the amount of water or milk needed to mix the capsules, and the amount of suspension needed to give for the prescribed dose.

Your healthcare provider will tell you the number of capsules to use, the amount of liquid needed to mix the capsules, and the amount of suspension (mL) to take or give to get the correct dose of ROZLYTREK.

You may need to measure a smaller amount of suspension than you prepared to take or give the correct prescribed dose of ROZLYTREK.

Supplies needed to prepare and take or give ROZLYTREK as a suspension:

• the number of capsules needed for your prescribed dose
• a clean empty cup
• a paper towel
• a cup of room temperature drinking water or milk
• an oral syringe (provided by your healthcare provider or pharmacist)

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

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.

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.

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.

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.

Among 355 patients who received ROZLYTREK across clinical trials, 32 patients (9%) experienced hyperuricemia reported as adverse reactions with symptoms, as well as elevated uric acid levels. Grade 4 hyperuricemia occurred in 1.7% of patients, including one patient who died due to tumor lysis syndrome. Among the 32 patients with hyperuricemic adverse reactions, 34% required urate-lowering medication to reduce uric acid levels, 6% required dose reduction and 6% required dose interruption. Hyperuricemia resolved in 73% of patients following initiation of urate-lowering medication without interruption or dose reduction of ROZLYTREK. No patients discontinued ROZLYTREK due to hyperuricemia.

Assess serum uric acid levels prior to initiation of ROZLYTREK and periodically during treatment. Monitor patients for signs and symptoms of hyperuricemia. Initiate treatment with urate-lowering medications as clinically indicated and withhold ROZLYTREK for signs and symptoms of hyperuricemia. Resume ROZLYTREK at same or reduced dose upon improvement of signs or symptoms based on severity [see Dosage and Administration (2.7)].

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.

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.

Among the 355 patients who received ROZLYTREK, increased AST of any grade occurred in 42% of patients and increased ALT of any grade occurred in 36%. Grade 3 – 4 increased AST or ALT occurred in 2.5% and 2.8% of patients, respectively; the incidence may be underestimated as 4.5% of patients had no post-treatment liver function tests [see Adverse Reactions (6.1)]. The median time to onset of increased AST was 2 weeks (range: 1 day to 29.5 months). The median time to onset of increased ALT was 2 weeks (range: 1 day to 9.2 months). Increased AST or ALT leading to dose interruptions or reductions occurred in 0.8% and 0.8% of patients, respectively. ROZLYTREK was discontinued due to increased AST or ALT in 0.8% patients.

Monitor liver tests, including ALT and AST, every 2 weeks during the first month of treatment, then monthly thereafter, and as clinically indicated. Withhold or permanently discontinue ROZLYTREK based on the severity. If withheld, resume ROZLYTREK at the same or reduced dose [see Dosage and Administration (2.7)].

None.

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)]

• Moderate and Strong CYP3A Inhibitors:
  • For adult and pediatric patients 2 years and older, reduce the dose of ROZLYTREK if coadministration of moderate or strong CYP3A inhibitors cannot be avoided. (2.8, 7.1)
  • For pediatric patients less than 2 years, avoid coadministration with ROZLYTREK. (7.1)
• Moderate and Strong CYP3A Inducers: Avoid coadministration with ROZLYTREK. (7.1)
• Drugs That Prolong QTc Interval: Avoid concomitant use with ROZLYTREK. (7.2)

Among the 355 patients who received ROZLYTREK across clinical trials, vision changes occurred in 21% of patients, including Grade 1 (17%), Grade 2 (2.8%) and Grade 3 (0.8%) [see Adverse Reactions (6.1)]. Vision disorders occurring in ≥ 1% included blurred vision (9%), photophobia (5%), diplopia (3.1%), visual impairment (2%), photopsia (1.1%), cataract (1.1%), and vitreous floaters (1.1%).

For patients with new visual changes or changes that interfere with activities of daily living, withhold ROZLYTREK until improvement or stabilization and conduct an ophthalmological evaluation as clinically appropriate. Upon improvement or stabilization, resume ROZLYTREK at same or reduced dose [see Dosage and Administration (2.7)].

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)].

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

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.

• 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 (14.1)]. 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 ROS1 rearrangement(s) in NSCLC is available at http://www.fda.gov/CompanionDiagnostics.
• 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 (14.2)]. 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.

ROZLYTREK increases the risk of fractures. In an expanded safety population that included 338 adult patients and 76 pediatric patients who received ROZLYTREK across clinical trials, 5% of adult patients and 25% of pediatric patients experienced fractures [see Use in Specific Population (8.4)]. In adult and pediatric patients, some fractures occurred in the setting of a fall or other trauma to the affected area; in pediatric patients some fractures occurred with no trauma. In general, there was inadequate assessment for tumor involvement at the site of fracture; however, radiologic abnormalities possibly indicative of tumor involvement were reported in some adult patients. In both adult and pediatric patients, most fractures were hip or other lower extremity fractures (e.g., femoral or tibial shaft). In two pediatric patients, bilateral femoral neck fractures occurred. A total of 41 fracture events were reported in 19 pediatric patients, with 13 patients who experienced more than one occurrence of fracture. Among the 19 pediatric patients who experienced fractures, 17 patients were less than 12 years of age. Among the 41 fracture events, 27 fracture events resolved, 4 fracture events resolved with sequelae and 3 events were resolving. The median time to fracture was 3.8 months (range 0.3 to 18.5 months) in adults and 4.3 months (range: 2 months to 28.7 months) in pediatric patients. ROZLYTREK was interrupted in 41% of adults and 16% of pediatric patients who experienced fractures. Five pediatric patients discontinued treatment due to fractures.

Promptly evaluate patients with signs or symptoms (e.g., pain, changes in mobility, deformity) of fractures. There are no data on the effects of ROZLYTREK on healing of known fractures and risk of future fractures.

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)].

ROZLYTREK is a kinase inhibitor indicated for the treatment of:

• Adult patients with ROS1-positive metastatic non-small cell lung cancer (NSCLC) as detected by an FDA-approved test. (1.1)
• 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. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. (1.2)

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.

Based on literature reports in humans with congenital mutations leading to changes in TRK signaling, findings from animal studies, and its mechanism of action, ROZLYTREK can cause fetal harm when administered to a pregnant woman. Administration of entrectinib to pregnant rats resulted in malformations at exposures approximately 2.7 times the human exposure at the 600 mg dose based on area under the curve (AUC).

Advise pregnant women of the potential risk to a fetus. Advise female patients of reproductive potential to use effective contraception during treatment with ROZLYTREK and for 5 weeks following the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with ROZLYTREK and for 3 months after the last dose [see Use in Specific Populations (8.1, 8.3)].

• Congestive Heart Failure (CHF): Assess left ventricular ejection fraction (LVEF) prior to initiation of ROZLYTREK. Monitor patients for clinical signs and symptoms of CHF. For patients with myocarditis, with or without a decreased ejection fraction, MRI or cardiac biopsy may be required to make the diagnosis. For new onset or worsening CHF, withhold ROZLYTREK, reassess LVEF and institute appropriate medical management. Reduce dose or permanently discontinue ROZLYTREK based on severity of CHF or worsening LVEF. (2.7, 5.1)
• Central Nervous System (CNS) Effects: CNS adverse reactions including cognitive impairment, mood disorders, dizziness, and sleep disturbances can occur with ROZLYTREK. Withhold and then resume at same or reduced dose upon improvement or permanently discontinue ROZLYTREK based on severity. (2.7, 5.2)
• Skeletal Fractures: ROZLYTREK increases the risk of fractures. Promptly evaluate patients with signs or symptoms of fractures. (5.3)
• Hepatotoxicity: Monitor liver tests, including ALT and AST, every 2 weeks during the first month of treatment, then monthly thereafter, and as clinically indicated. Withhold or permanently discontinue ROZLYTREK based on severity. If withheld, resume ROZLYTREK at same or reduced dose based on severity. (2.7, 5.4)
• Hyperuricemia: Assess serum uric acid levels prior to initiation and periodically during treatment with ROZLYTREK. Monitor patients for signs and symptoms of hyperuricemia. Initiate treatment with urate-lowering medications as clinically indicated and withhold ROZLYTREK for signs and symptoms of hyperuricemia. Resume at same or reduced dose upon improvement based on severity. (2.7, 5.5)
• QT Interval Prolongation: Monitor patients who have or who are at risk for QTc interval prolongation. Assess QT interval and electrolytes at baseline and periodically during treatment. Withhold and then resume at same or reduced dose, or permanently discontinue ROZLYTREK based on severity. (2.7, 5.6)
• Vision Disorders: Withhold for new visual changes or changes that interfere with activities of daily living until improvement or stabilization. Conduct an ophthalmological evaluation as appropriate. Resume at same or reduced dose upon improvement or stabilization. (2.7, 5.7)
• Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and use of effective contraception. (5.8, 8.1, 8.3)

• Select patients for treatment based on the presence of ROS1 rearrangement(s) or NTRK gene fusion. (2.1)
• Evaluate left ventricular ejection fraction, serum uric acid levels and QT interval and electrolytes prior to ROZLYTREK initiation. (2.2)
• Select appropriate dosage form: oral capsules, capsules prepared as an oral suspension or oral pellets. (2.3)
• Use capsules prepared as suspension for enteral tube administration. Do not use pellets for enteral tube administration. (2.3)
• Administer ROZLYTREK capsules, capsules prepared as a suspension, or pellets once daily, with or without food. (2.4)
• Adult Dosage for ROS1-Positive Non-Small Cell Lung Cancer: 600 mg orally once daily. (2.5)
• Adult and Pediatric Dosage for NTRK Gene Fusion-Positive Solid Tumors:
  • Adults: 600 mg orally once daily. (2.6)
  • Pediatric Patients: Recommended dosage is based on age and body surface area (BSA) as shown below. (2.6)

  Age	Recommended Daily Dosage
  >6 months	≤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 BSA ≥1.51 m2: 600 mg once daily
  >1 month to ≤6 months	250 mg/m2 once daily

• Modify dosage of ROZLYTREK if coadministration with moderate or strong CYP3A inhibitors cannot be avoided. (2.8)
• See preparation and administration instructions. (2.9)

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.

Among the 355 patients who received ROZLYTREK across clinical trials, congestive heart failure (CHF) occurred in 3.4% of patients, including Grade 3 (2.3%) [see Adverse Reactions (6.1)]. In clinical trials, baseline cardiac function and routine cardiac monitoring other than electrocardiograms (ECGs) were not conducted and eligibility criteria excluded patients with symptomatic CHF, myocardial infarction, unstable angina, and coronary artery bypass graft within 3 months of study entry. Among the 12 patients with CHF, the median time to onset was 2 months (range: 11 days to 12 months). ROZLYTREK was interrupted in 6 of these patients (50%) and discontinued in 2 of these patients (17%). CHF resolved in 6 patients (50%) following interruption or discontinuation of ROZLYTREK and institution of appropriate medical management. In addition, myocarditis in the absence of CHF was documented in 0.3% of patients.

Assess left ventricular ejection fraction (LVEF) prior to initiation of ROZLYTREK. Monitor patients for clinical signs and symptoms of CHF, including shortness of breath and edema. For patients with myocarditis, with or without a decreased ejection fraction, MRI or cardiac biopsy may be required to make the diagnosis. For patients with new onset or worsening CHF, withhold ROZLYTREK, institute appropriate medical management, and reassess LVEF. Based on the severity of CHF or worsening LVEF, resume ROZLYTREK at a reduced dose upon recovery to baseline or permanently discontinue [see Dosage and Administration (2.7)].

Among the 355 patients who received ROZLYTREK across the clinical trials, 3.1% of patients with at least one post-baseline ECG assessment experienced QTcF interval prolongation of > 60 ms after starting ROZLYTREK and 0.6% had a QTcF interval > 500 ms [see Adverse Reactions (6.1), Clinical Pharmacology (12.2)].

Monitor patients who already have or who are at significant risk of developing QTc interval prolongation, including patients with known long QT syndromes, clinically significant bradyarrhythmias, severe or uncontrolled heart failure and those taking other medicinal products associated with QT prolongation. Assess QT interval and electrolytes prior to initiation of ROZLYTREK and periodically during treatment, adjusting frequency based upon risk factors such as congestive heart failure, electrolyte abnormalities, or concomitant medications known to prolong the QTc interval. Based on the severity of QTc interval prolongation, withhold ROZLYTREK and then resume at same or reduced dose, or permanently discontinue [see Dosage and Administration (2.7)].

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.

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.

• Lactation: Advise not to breastfeed. (8.2)

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

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.

A broad spectrum of central nervous system (CNS) adverse reactions occurred in patients receiving ROZLYTREK, including cognitive impairment, mood disorders, dizziness, and sleep disturbances.

Among the 355 patients who received ROZLYTREK across clinical trials, 96 (27%) experienced cognitive impairment; symptoms occurred within 3 months of starting ROZLYTREK in 74 (77%). Cognitive impairment included cognitive disorders (8%), confusional state (7%), disturbance in attention (4.8%), memory impairment (3.7%), amnesia (2.5%), aphasia (2.3%), mental status changes (2%), hallucinations (1.1%), and delirium (0.8%). Grade 3 cognitive adverse reactions occurred in 4.5% of patients. Among the 96 patients with cognitive impairment, 13% required a dose reduction, 18% required dose interruption and 1% discontinued ROZLYTREK due to cognitive adverse reactions.

Among the 355 patients who received ROZLYTREK across clinical trials, 36 (10%) experienced mood disorders. The median time to onset of mood disorders was 1 month (range: 1 day to 9 months). Mood disorders occurring in ≥ 1% of patients included anxiety (4.8%), depression (2.8%) and agitation (2%). Grade 3 mood disorders occurred in 0.6% of patients. One completed suicide was reported 11 days after treatment had ended. Among the 36 patients who experienced mood disorders, 6% required a dose reduction, 6% required dose interruption and no patients discontinued ROZLYTREK due to mood disorders.

Dizziness occurred in 136 (38%) of the 355 patients. Among the 136 patients who experienced dizziness, Grade 3 dizziness occurred in 2.2% of patients. Ten percent of patients required a dose reduction, 7% required dose interruption and 0.7% discontinued ROZLYTREK due to dizziness.

Among the 355 patients who received ROZLYTREK across clinical trials, 51 (14%) experienced sleep disturbances. Sleep disturbances included insomnia (7%), somnolence (7%), hypersomnia (1.1%), and sleep disorder (0.3%). Grade 3 sleep disturbances occurred in 0.6% of patients. Among the 51 patients who experienced sleep disturbances, 6% required a dose reduction and no patients discontinued ROZLYTREK due to sleep disturbances.

The incidence of CNS adverse reactions was similar in patients with and without CNS metastases; however, the incidence of dizziness (38% vs 31%), headache (21% vs 13%), paresthesia (20% vs 6%), balance disorder (13% vs 4%), and confusional state (11% vs 2%) appeared to be increased in patients with CNS metastases who had received prior CNS irradiation (n = 90) compared to those who did not (n = 48).

Advise patients and caregivers of these risks with ROZLYTREK. Advise patients not to drive or operate hazardous machinery if they are experiencing CNS adverse reactions. Withhold and then resume at same or reduced dose upon improvement, or permanently discontinue ROZLYTREK based on severity [see Dosage and Administration (2.7)].

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)].

• 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.

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

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.

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.

NDC 50242-623-42

Rozlytrek^®

(entrectinib)

oral pellets

50 mg

42 packets

Rx only

Genentech

11006603

NDC 50242-091-30

Rozlytrek^®

(entrectinib)

capsules

100 mg

PHARMACIST: Dispense with

the included Instructions for Use

30 capsules

Rx only

Genentech

11013439

NDC 50242-094-90

Rozlytrek^®

(entrectinib)

capsules

200 mg

PHARMACIST: Dispense with

the included Instructions for Use

90 capsules

Rx only

Genentech

11013451

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

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

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.

Before initiating ROZLYTREK, evaluate:

• left ventricular ejection fraction (LVEF) [see Warnings and Precautions (5.1)]
• serum uric acid levels [see Warnings and Precautions (5.5)]
• QT interval and electrolytes [see Warnings and Precautions (5.6)]

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 Dosage and Administration (2.7)].
  • For dose increments of 10 mg, only use capsules prepared as a suspension.

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.

INSTRUCTIONS FOR USE

ROZLYTREK^® [roz lye trek]

(entrectinib)

capsules, for oral use

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

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

ROZLYTREK capsules can be swallowed whole or prepared as a suspension and taken or given by mouth or through a nasogastric tube (NG tube) or gastrostomy tube (G tube) feeding tube.

• Your healthcare provider or pharmacist should show you how to correctly prepare and take or give a dose of ROZLYTREK capsules. Always take or give ROZLYTREK capsules exactly as your healthcare provider tells you.
• Do not take or give ROZLYTREK 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.
• Your healthcare provider will tell you what your daily dose of ROZLYTREK is.
• Swallow ROZLYTREK capsules whole, with or without food.
• Swallow whole capsules with drinking water, as directed by your healthcare provider.
• Do not crush or chew the capsules.

If you or your child cannot swallow capsules whole, ROZLYTREK capsules can be prepared as a suspension and taken or given by mouth or through a feeding tube. For doses of 3 mL or higher, a NG or G feeding tube size 8 French or larger should be used.

Your healthcare provider or pharmacist will show you how to prepare and take or give a dose of ROZLYTREK capsules prepared as a suspension.

Table 1 shows the prescribed dose, the number and strength of capsules needed, the amount of water or milk needed to mix the capsules, and the amount of suspension needed to give for the prescribed dose.

Your healthcare provider will tell you the number of capsules to use, the amount of liquid needed to mix the capsules, and the amount of suspension (mL) to take or give to get the correct dose of ROZLYTREK.

You may need to measure a smaller amount of suspension than you prepared to take or give the correct prescribed dose of ROZLYTREK.

Supplies needed to prepare and take or give ROZLYTREK as a suspension:

• the number of capsules needed for your prescribed dose
• a clean empty cup
• a paper towel
• a cup of room temperature drinking water or milk
• an oral syringe (provided by your healthcare provider or pharmacist)

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

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.

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.

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.

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.

Among 355 patients who received ROZLYTREK across clinical trials, 32 patients (9%) experienced hyperuricemia reported as adverse reactions with symptoms, as well as elevated uric acid levels. Grade 4 hyperuricemia occurred in 1.7% of patients, including one patient who died due to tumor lysis syndrome. Among the 32 patients with hyperuricemic adverse reactions, 34% required urate-lowering medication to reduce uric acid levels, 6% required dose reduction and 6% required dose interruption. Hyperuricemia resolved in 73% of patients following initiation of urate-lowering medication without interruption or dose reduction of ROZLYTREK. No patients discontinued ROZLYTREK due to hyperuricemia.

Assess serum uric acid levels prior to initiation of ROZLYTREK and periodically during treatment. Monitor patients for signs and symptoms of hyperuricemia. Initiate treatment with urate-lowering medications as clinically indicated and withhold ROZLYTREK for signs and symptoms of hyperuricemia. Resume ROZLYTREK at same or reduced dose upon improvement of signs or symptoms based on severity [see Dosage and Administration (2.7)].

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.

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.

Among the 355 patients who received ROZLYTREK, increased AST of any grade occurred in 42% of patients and increased ALT of any grade occurred in 36%. Grade 3 – 4 increased AST or ALT occurred in 2.5% and 2.8% of patients, respectively; the incidence may be underestimated as 4.5% of patients had no post-treatment liver function tests [see Adverse Reactions (6.1)]. The median time to onset of increased AST was 2 weeks (range: 1 day to 29.5 months). The median time to onset of increased ALT was 2 weeks (range: 1 day to 9.2 months). Increased AST or ALT leading to dose interruptions or reductions occurred in 0.8% and 0.8% of patients, respectively. ROZLYTREK was discontinued due to increased AST or ALT in 0.8% patients.

Monitor liver tests, including ALT and AST, every 2 weeks during the first month of treatment, then monthly thereafter, and as clinically indicated. Withhold or permanently discontinue ROZLYTREK based on the severity. If withheld, resume ROZLYTREK at the same or reduced dose [see Dosage and Administration (2.7)].

None.

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)]

• Moderate and Strong CYP3A Inhibitors:
  • For adult and pediatric patients 2 years and older, reduce the dose of ROZLYTREK if coadministration of moderate or strong CYP3A inhibitors cannot be avoided. (2.8, 7.1)
  • For pediatric patients less than 2 years, avoid coadministration with ROZLYTREK. (7.1)
• Moderate and Strong CYP3A Inducers: Avoid coadministration with ROZLYTREK. (7.1)
• Drugs That Prolong QTc Interval: Avoid concomitant use with ROZLYTREK. (7.2)

Among the 355 patients who received ROZLYTREK across clinical trials, vision changes occurred in 21% of patients, including Grade 1 (17%), Grade 2 (2.8%) and Grade 3 (0.8%) [see Adverse Reactions (6.1)]. Vision disorders occurring in ≥ 1% included blurred vision (9%), photophobia (5%), diplopia (3.1%), visual impairment (2%), photopsia (1.1%), cataract (1.1%), and vitreous floaters (1.1%).

For patients with new visual changes or changes that interfere with activities of daily living, withhold ROZLYTREK until improvement or stabilization and conduct an ophthalmological evaluation as clinically appropriate. Upon improvement or stabilization, resume ROZLYTREK at same or reduced dose [see Dosage and Administration (2.7)].

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)].

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

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.

• 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 (14.1)]. 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 ROS1 rearrangement(s) in NSCLC is available at http://www.fda.gov/CompanionDiagnostics.
• 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 (14.2)]. 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.

ROZLYTREK increases the risk of fractures. In an expanded safety population that included 338 adult patients and 76 pediatric patients who received ROZLYTREK across clinical trials, 5% of adult patients and 25% of pediatric patients experienced fractures [see Use in Specific Population (8.4)]. In adult and pediatric patients, some fractures occurred in the setting of a fall or other trauma to the affected area; in pediatric patients some fractures occurred with no trauma. In general, there was inadequate assessment for tumor involvement at the site of fracture; however, radiologic abnormalities possibly indicative of tumor involvement were reported in some adult patients. In both adult and pediatric patients, most fractures were hip or other lower extremity fractures (e.g., femoral or tibial shaft). In two pediatric patients, bilateral femoral neck fractures occurred. A total of 41 fracture events were reported in 19 pediatric patients, with 13 patients who experienced more than one occurrence of fracture. Among the 19 pediatric patients who experienced fractures, 17 patients were less than 12 years of age. Among the 41 fracture events, 27 fracture events resolved, 4 fracture events resolved with sequelae and 3 events were resolving. The median time to fracture was 3.8 months (range 0.3 to 18.5 months) in adults and 4.3 months (range: 2 months to 28.7 months) in pediatric patients. ROZLYTREK was interrupted in 41% of adults and 16% of pediatric patients who experienced fractures. Five pediatric patients discontinued treatment due to fractures.

Promptly evaluate patients with signs or symptoms (e.g., pain, changes in mobility, deformity) of fractures. There are no data on the effects of ROZLYTREK on healing of known fractures and risk of future fractures.

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)].

ROZLYTREK is a kinase inhibitor indicated for the treatment of:

• Adult patients with ROS1-positive metastatic non-small cell lung cancer (NSCLC) as detected by an FDA-approved test. (1.1)
• 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. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. (1.2)

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.

Based on literature reports in humans with congenital mutations leading to changes in TRK signaling, findings from animal studies, and its mechanism of action, ROZLYTREK can cause fetal harm when administered to a pregnant woman. Administration of entrectinib to pregnant rats resulted in malformations at exposures approximately 2.7 times the human exposure at the 600 mg dose based on area under the curve (AUC).

Advise pregnant women of the potential risk to a fetus. Advise female patients of reproductive potential to use effective contraception during treatment with ROZLYTREK and for 5 weeks following the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with ROZLYTREK and for 3 months after the last dose [see Use in Specific Populations (8.1, 8.3)].

• Congestive Heart Failure (CHF): Assess left ventricular ejection fraction (LVEF) prior to initiation of ROZLYTREK. Monitor patients for clinical signs and symptoms of CHF. For patients with myocarditis, with or without a decreased ejection fraction, MRI or cardiac biopsy may be required to make the diagnosis. For new onset or worsening CHF, withhold ROZLYTREK, reassess LVEF and institute appropriate medical management. Reduce dose or permanently discontinue ROZLYTREK based on severity of CHF or worsening LVEF. (2.7, 5.1)
• Central Nervous System (CNS) Effects: CNS adverse reactions including cognitive impairment, mood disorders, dizziness, and sleep disturbances can occur with ROZLYTREK. Withhold and then resume at same or reduced dose upon improvement or permanently discontinue ROZLYTREK based on severity. (2.7, 5.2)
• Skeletal Fractures: ROZLYTREK increases the risk of fractures. Promptly evaluate patients with signs or symptoms of fractures. (5.3)
• Hepatotoxicity: Monitor liver tests, including ALT and AST, every 2 weeks during the first month of treatment, then monthly thereafter, and as clinically indicated. Withhold or permanently discontinue ROZLYTREK based on severity. If withheld, resume ROZLYTREK at same or reduced dose based on severity. (2.7, 5.4)
• Hyperuricemia: Assess serum uric acid levels prior to initiation and periodically during treatment with ROZLYTREK. Monitor patients for signs and symptoms of hyperuricemia. Initiate treatment with urate-lowering medications as clinically indicated and withhold ROZLYTREK for signs and symptoms of hyperuricemia. Resume at same or reduced dose upon improvement based on severity. (2.7, 5.5)
• QT Interval Prolongation: Monitor patients who have or who are at risk for QTc interval prolongation. Assess QT interval and electrolytes at baseline and periodically during treatment. Withhold and then resume at same or reduced dose, or permanently discontinue ROZLYTREK based on severity. (2.7, 5.6)
• Vision Disorders: Withhold for new visual changes or changes that interfere with activities of daily living until improvement or stabilization. Conduct an ophthalmological evaluation as appropriate. Resume at same or reduced dose upon improvement or stabilization. (2.7, 5.7)
• Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and use of effective contraception. (5.8, 8.1, 8.3)

• Select patients for treatment based on the presence of ROS1 rearrangement(s) or NTRK gene fusion. (2.1)
• Evaluate left ventricular ejection fraction, serum uric acid levels and QT interval and electrolytes prior to ROZLYTREK initiation. (2.2)
• Select appropriate dosage form: oral capsules, capsules prepared as an oral suspension or oral pellets. (2.3)
• Use capsules prepared as suspension for enteral tube administration. Do not use pellets for enteral tube administration. (2.3)
• Administer ROZLYTREK capsules, capsules prepared as a suspension, or pellets once daily, with or without food. (2.4)
• Adult Dosage for ROS1-Positive Non-Small Cell Lung Cancer: 600 mg orally once daily. (2.5)
• Adult and Pediatric Dosage for NTRK Gene Fusion-Positive Solid Tumors:
  • Adults: 600 mg orally once daily. (2.6)
  • Pediatric Patients: Recommended dosage is based on age and body surface area (BSA) as shown below. (2.6)

  Age	Recommended Daily Dosage
  >6 months	≤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 BSA ≥1.51 m2: 600 mg once daily
  >1 month to ≤6 months	250 mg/m2 once daily

• Modify dosage of ROZLYTREK if coadministration with moderate or strong CYP3A inhibitors cannot be avoided. (2.8)
• See preparation and administration instructions. (2.9)

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.

Among the 355 patients who received ROZLYTREK across clinical trials, congestive heart failure (CHF) occurred in 3.4% of patients, including Grade 3 (2.3%) [see Adverse Reactions (6.1)]. In clinical trials, baseline cardiac function and routine cardiac monitoring other than electrocardiograms (ECGs) were not conducted and eligibility criteria excluded patients with symptomatic CHF, myocardial infarction, unstable angina, and coronary artery bypass graft within 3 months of study entry. Among the 12 patients with CHF, the median time to onset was 2 months (range: 11 days to 12 months). ROZLYTREK was interrupted in 6 of these patients (50%) and discontinued in 2 of these patients (17%). CHF resolved in 6 patients (50%) following interruption or discontinuation of ROZLYTREK and institution of appropriate medical management. In addition, myocarditis in the absence of CHF was documented in 0.3% of patients.

Assess left ventricular ejection fraction (LVEF) prior to initiation of ROZLYTREK. Monitor patients for clinical signs and symptoms of CHF, including shortness of breath and edema. For patients with myocarditis, with or without a decreased ejection fraction, MRI or cardiac biopsy may be required to make the diagnosis. For patients with new onset or worsening CHF, withhold ROZLYTREK, institute appropriate medical management, and reassess LVEF. Based on the severity of CHF or worsening LVEF, resume ROZLYTREK at a reduced dose upon recovery to baseline or permanently discontinue [see Dosage and Administration (2.7)].

Among the 355 patients who received ROZLYTREK across the clinical trials, 3.1% of patients with at least one post-baseline ECG assessment experienced QTcF interval prolongation of > 60 ms after starting ROZLYTREK and 0.6% had a QTcF interval > 500 ms [see Adverse Reactions (6.1), Clinical Pharmacology (12.2)].

Monitor patients who already have or who are at significant risk of developing QTc interval prolongation, including patients with known long QT syndromes, clinically significant bradyarrhythmias, severe or uncontrolled heart failure and those taking other medicinal products associated with QT prolongation. Assess QT interval and electrolytes prior to initiation of ROZLYTREK and periodically during treatment, adjusting frequency based upon risk factors such as congestive heart failure, electrolyte abnormalities, or concomitant medications known to prolong the QTc interval. Based on the severity of QTc interval prolongation, withhold ROZLYTREK and then resume at same or reduced dose, or permanently discontinue [see Dosage and Administration (2.7)].

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.

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.

• Lactation: Advise not to breastfeed. (8.2)

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

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.

A broad spectrum of central nervous system (CNS) adverse reactions occurred in patients receiving ROZLYTREK, including cognitive impairment, mood disorders, dizziness, and sleep disturbances.

Among the 355 patients who received ROZLYTREK across clinical trials, 96 (27%) experienced cognitive impairment; symptoms occurred within 3 months of starting ROZLYTREK in 74 (77%). Cognitive impairment included cognitive disorders (8%), confusional state (7%), disturbance in attention (4.8%), memory impairment (3.7%), amnesia (2.5%), aphasia (2.3%), mental status changes (2%), hallucinations (1.1%), and delirium (0.8%). Grade 3 cognitive adverse reactions occurred in 4.5% of patients. Among the 96 patients with cognitive impairment, 13% required a dose reduction, 18% required dose interruption and 1% discontinued ROZLYTREK due to cognitive adverse reactions.

Among the 355 patients who received ROZLYTREK across clinical trials, 36 (10%) experienced mood disorders. The median time to onset of mood disorders was 1 month (range: 1 day to 9 months). Mood disorders occurring in ≥ 1% of patients included anxiety (4.8%), depression (2.8%) and agitation (2%). Grade 3 mood disorders occurred in 0.6% of patients. One completed suicide was reported 11 days after treatment had ended. Among the 36 patients who experienced mood disorders, 6% required a dose reduction, 6% required dose interruption and no patients discontinued ROZLYTREK due to mood disorders.

Dizziness occurred in 136 (38%) of the 355 patients. Among the 136 patients who experienced dizziness, Grade 3 dizziness occurred in 2.2% of patients. Ten percent of patients required a dose reduction, 7% required dose interruption and 0.7% discontinued ROZLYTREK due to dizziness.

Among the 355 patients who received ROZLYTREK across clinical trials, 51 (14%) experienced sleep disturbances. Sleep disturbances included insomnia (7%), somnolence (7%), hypersomnia (1.1%), and sleep disorder (0.3%). Grade 3 sleep disturbances occurred in 0.6% of patients. Among the 51 patients who experienced sleep disturbances, 6% required a dose reduction and no patients discontinued ROZLYTREK due to sleep disturbances.

The incidence of CNS adverse reactions was similar in patients with and without CNS metastases; however, the incidence of dizziness (38% vs 31%), headache (21% vs 13%), paresthesia (20% vs 6%), balance disorder (13% vs 4%), and confusional state (11% vs 2%) appeared to be increased in patients with CNS metastases who had received prior CNS irradiation (n = 90) compared to those who did not (n = 48).

Advise patients and caregivers of these risks with ROZLYTREK. Advise patients not to drive or operate hazardous machinery if they are experiencing CNS adverse reactions. Withhold and then resume at same or reduced dose upon improvement, or permanently discontinue ROZLYTREK based on severity [see Dosage and Administration (2.7)].

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)].

• 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.

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

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.

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.

NDC 50242-623-42

Rozlytrek^®

(entrectinib)

oral pellets

50 mg

42 packets

Rx only

Genentech

11006603

NDC 50242-091-30

Rozlytrek^®

(entrectinib)

capsules

100 mg

PHARMACIST: Dispense with

the included Instructions for Use

30 capsules

Rx only

Genentech

11013439

NDC 50242-094-90

Rozlytrek^®

(entrectinib)

capsules

200 mg

PHARMACIST: Dispense with

the included Instructions for Use

90 capsules

Rx only

Genentech

11013451

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

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

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.

Before initiating ROZLYTREK, evaluate:

• left ventricular ejection fraction (LVEF) [see Warnings and Precautions (5.1)]
• serum uric acid levels [see Warnings and Precautions (5.5)]
• QT interval and electrolytes [see Warnings and Precautions (5.6)]