Rozlytrek Drug Information
Generic name: ENTRECTINIB
Uses of 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. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
Dosage & Administration of Rozlytrek
Patient Selection
Select patients for the treatment of metastatic NSCLC with ROZLYTREK based on the presence of ROS1 rearrangement(s) in tumor or plasma specimens. 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. 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) serum uric acid levels QT interval and electrolytes
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). 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.
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 /m 2 orally once daily To enable dosing increments of 10 mg, capsules prepared as an oral suspension must be used. 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. Table 3. Recommended Dose Reductions for ROZLYTREK for the Management of Reduce the once daily dose to two thirds of the starting dose To enable dosing increments of 10 mg, capsules prepared as an oral suspension must be used.
Table 4 provides the ROZLYTREK recommended dosage modifications for the management of adverse reactions. Table 4. ROZLYTREK s 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 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.
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 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.
| Age | Recommended Daily Dosage |
|---|---|
| >6 months | ≤0.50 m 2: 300 mg/m 2 0.51 to 0.80 m 2: 200 mg 0.81 to 1.10 m 2: 300 mg 1.11 to 1.50 m 2: 400 mg BSA ≥1.51 m 2: 600 mg once daily |
| >1 month to ≤6 months | 250 mg/m 2 once daily |
| Patient Population | Recommended Dosage of ROZLYTREK | Duration of Treatment |
|---|---|---|
| Adults Pediatric patients with BSA ≥ 1.51 m 2: | 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/m 2 orally once daily To enable dosing increments of 10 mg, capsules prepared as an oral suspension must be used [see Dosage and Administration (2.9) ]. |
| Body Surface Area (BSA) BSA categories and recommended dosage above are based on closely matching exposures to a target dose of 300 mg/m 2 | Recommended Dosage Orally Once Daily |
|---|---|
| ≤0.50 m 2 | 300 mg/m 2 To enable dosing increments of 10 mg, capsules prepared as an oral suspension must be used [see Dosage and Administration (2.9) ]. |
| 0.51 to 0.80 m 2 | 200 mg |
| 0.81 to 1.10 m 2 | 300 mg |
| 1.11 to 1.50 m 2 | 400 mg |
| ≥ 1.51 m 2 | 600 mg |
| Starting Dose once daily | First dose reduction | Second dose reduction | |
|---|---|---|---|
| 250 mg/m 2 or 300 mg/m 2 | Reduce the once daily dose to two thirds of the starting dose To enable dosing increments of 10 mg, capsules prepared as an oral suspension must be used [see Dosage and Administration (2.9) ]. | Reduce the once daily dose to one third of the starting dose | Permanently discontinue ROZLYTREK in patients who are unable to tolerate ROZLYTREK after two dose reductions. |
| 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 |
| Adverse Reaction | Severity Severity as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0. | Dosage Modification |
|---|---|---|
| Congestive Heart Failure [see Warnings and Precautions (5.1) ] | 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 (5.2) ] | 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 (5.4) ] | 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 (5.5) ] | 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 (5.6) ] | 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 (5.7) ] | 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 (6.1) ] | 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 (6.1) ] | 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. |
| Starting dose For pediatric patients with a starting dose less than 200 mg, avoid coadministration with moderate or strong CYP3A inhibitors | 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 |
| 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 |
Side Effects of Rozlytrek
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. ROZLYTREK was studied in one dose-finding trial in adults, one dose-finding and activity-estimating trial in adults, one dose-finding and activity-estimating trial in pediatric and adult patients, and one single arm, activity-estimating trial in adults. 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 once daily in adults and once daily in pediatric patients. Serious adverse reactions occurred in 39% of patients.
Fatal events included dyspnea ( %). 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. Dose reductions due to adverse reactions occurred in 29% of patients who received ROZLYTREK.
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.
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 7 Safety in Pediatric Patients The safety of ROZLYTREK was evaluated was evaluated in pediatric patients with unresectable or metastatic solid tumors with a NTRK gene fusion enrolled in one of three multicenter, open-label clinical trials: STARTRK-NG (n=68), TAPISTRY (n=6) and STARTRK-2 (n=2).
Patients received ROZLYTREK 20 mg to 600 mg based on body surface area (BSA) orally or via enteral feeding tube once daily in 4-week cycles until unacceptable toxicity or disease progression. Among patients who received ROZLYTREK, 58% were exposed for 6 months or longer and 38% were exposed for greater than one year. Serious adverse reactions occurred in 45% of patients who received ROZLYTREK.
Adverse reactions which resulted in permanent discontinuation of ROZLYTREK in > 2% of patients included skeletal fracture. Dosage interruptions of ROZLYTREK due to an adverse reaction occurred in 39% of patients. Adverse reactions which required dosage interruption in > 5% of patients included decreased neutrophil count, pyrexia, vomiting, and diarrhea.
Dose reductions of ROZLYTREK due to an adverse reaction occurred in 21% of patients. Adverse reactions which required dose reductions in > 2% of patients included increased blood creatinine and increased weight. Table 9 summarizes the adverse reactions in STARTRK-NG (n=68), TAPISTRY (n=6) and STARTRK-2 (n=2).
Table 9. Adverse Reactions (≥20%) in Pediatric Patients Who Received ROZLYTREK in STARTRK-NG, TAPISTRY and STARTRK-2 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 8 Other clinically relevant laboratory abnormalities in patients who received ROZLYTREK included decreased phosphorous.
| Adverse Reactions | ROZLYTREK n = 355 | |
|---|---|---|
| All Grades (%) | Grade ≥ 3 Grades 3 – 5, inclusive of fatal adverse reactions, including 2 events of pneumonia and 2 events of dyspnea. (%) | |
| General | ||
| Fatigue Includes fatigue, asthenia | 48 | 5 |
| Edema Includes face edema, fluid retention, generalized edema, localized edema, edema, edema peripheral, peripheral swelling | 40 | 1.1 |
| Pyrexia | 21 | 0.8 |
| Gastrointestinal | ||
| Constipation | 46 | 0.6 |
| Diarrhea | 35 | 2.0 |
| Nausea | 34 | 0.3 |
| Vomiting | 24 | 0.8 |
| Abdominal pain Includes abdominal pain upper, abdominal pain, lower abdominal discomfort, abdominal tenderness | 16 | 0.6 |
| Nervous System | ||
| Dysgeusia | 44 | 0.3 |
| Dizziness Includes dizziness, vertigo, dizziness postural | 38 | 0.8 |
| Dysesthesia Includes paresthesia, hyperesthesia, hypoesthesia, dysesthesia, oral hypoesthesia, palmar-plantar erythrodysesthesia, oral paresthesia, genital hypoesthesia | 34 | 0.3 |
| Cognitive impairment Includes amnesia, aphasia, cognitive disorder, confusional state, delirium, disturbance in attention, hallucinations, visual hallucination, memory impairment, mental disorder, mental status changes | 27 | 4.5 |
| Peripheral sensory neuropathy Includes neuralgia, neuropathy peripheral, peripheral motor neuropathy, peripheral sensory neuropathy | 18 | 1.1 |
| Headache | 18 | 0.3 |
| Ataxia Includes ataxia, balance disorder, gait disturbances | 17 | 0.8 |
| Sleep Includes hypersomnia, insomnia, sleep disorder, somnolence | 14 | 0.6 |
| Mood disorders Includes anxiety, affect lability, affective disorder, agitation, depressed mood, euphoric mood, mood altered, mood swings, irritability, depression, persistent depressive disorder, psychomotor retardation | 10 | 0.6 |
| Respiratory, Thoracic and Mediastinal | ||
| Dyspnea | 30 | 6 |
| Cough | 24 | 0.3 |
| Musculoskeletal and Connective Tissue | ||
| Myalgia Includes musculoskeletal pain, musculoskeletal chest pain, myalgia, neck pain | 28 | 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 disorders Includes blindness, cataract, cortical cataract, corneal erosion, diplopia, eye disorder, photophobia, photopsia, retinal hemorrhage, vision blurred, visual impairment, vitreous adhesions, vitreous detachment, vitreous floaters | 21 | 0.8 |
| Infections | ||
| Urinary tract infection | 13 | 2.3 |
| Lung infection Includes lower respiratory tract infection, lung infection, pneumonia, respiratory tract infection | 10 | 6 |
| Vascular | ||
| Hypotension Includes hypotension, orthostatic hypotension | 18 | 2.8 |
| Skin and Subcutaneous Tissue | ||
| Rash Includes rash, rash maculopapular, rash pruritic, rash erythematous, rash papular | 11 | 0.8 |
| Laboratory Abnormality | ROZLYTREK NCI CTCAE Grade | |
|---|---|---|
| All Grades (%) Denominator for each laboratory parameter is based on the number of patients with a baseline and post-treatment laboratory value available which ranged from 111 to 346 patients. | Grade 3 or 4 (%) | |
| AST: Aspartate Aminotransferase; ALT: Alanine Aminotransferase | ||
| Chemistry | ||
| Increased creatinine Based on NCI CTCAE v5.0 | 73 | 2.1 |
| Hyperuricemia | 52 | 10 |
| Increased AST | 44 | 2.7 |
| Increased ALT | 38 | 2.9 |
| Hypernatremia | 35 | 0.9 |
| Hypocalcemia | 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 |
| Hyperglycemia NE = Not evaluable. Grade 1 and 2 could not be determined per NCI CTCAE v5.0, as fasting glucose values were not collected | NE | 3.8 |
| Hematology | ||
| Anemia | 67 | 9 |
| Lymphopenia | 40 | 12 |
| Neutropenia | 28 | 7 |
| Adverse Reaction | ROZLYTREK (n=76) | |
|---|---|---|
| All Grades (%) | Grade 3 or 4 (%) | |
| General Disorders | ||
| Pyrexia | 43 | 1.3 |
| Fatigue Includes fatigue, asthenia | 30 | 2.6 |
| Gastrointestinal Disorders | ||
| Constipation | 41 | 1.3 |
| Vomiting | 38 | 0 |
| Diarrhea | 37 | 0 |
| Nausea | 34 | 0 |
| Abdominal Pain | 20 | 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 Fracture Includes clavicle fracture, tibia fracture, femur fracture, fibula fracture, foot fracture, fracture, pathological fracture, limb fracture, lower limb fracture, pelvic fracture, spinal compression fracture, stress fracture, ulna fracture | 25 | 11 |
| Metabolism And Nutrition Disorders | ||
| Decreased Appetite | 24 | 1.3 |
| Nervous System Disorders | ||
| Headache | 22 | 2.6 |
| Infections | ||
| Upper Respiratory Tract Infection | 20 | 1.3 |
| Urinary Tract Infection | 20 | 2.6 |
| Laboratory Abnormality | ROZLYTREK The denominator used to calculate the rate varied from 67 to 76 based on the number of patients with a baseline value and at least one post-treatment value. All values based on NCI CTCAE v5.0 | |
|---|---|---|
| All Grades (%) | Grade 3 or 4 (%) | |
| AST: Aspartate Aminotransferase; ALT: Alanine Aminotransferase | ||
| Hematology | ||
| Decreased Hemoglobin | 53 | 7 |
| Decreased Neutrophils | 53 | 22 |
| Decreased Leukocytes | 46 | 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 |
Warnings & Cautions for Rozlytrek
Congestive Heart Failure 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%). 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. 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.
Central Nervous System Effects
A broad spectrum of central nervous system (CNS) adverse reactions occurred in patients receiving ROZLYTREK, including cognitive impairment, mood disorders, dizziness, and sleep disturbances. Grade 3 cognitive adverse reactions occurred in 4.5% of patients. 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). 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. 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. 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.
Skeletal Fractures
ROZLYTREK increases the risk of fractures. 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. 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.
Hepatotoxicity 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%. 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.
Hyperuricemia 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. 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.
QT Interval Prolongation 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. 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.
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.
Embryo-Fetal Toxicity 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.
Drug Interactions with 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, which could increase the frequency or severity of adverse reactions. If coadministration is unavoidable, reduce the ROZLYTREK dose. Pediatric Patients less than 2 Years Avoid coadministration of ROZLYTREK with moderate or strong CYP3A inhibitors.
Avoid grapefruit products during treatment with ROZLYTREK, as they contain inhibitors of CYP3A. Moderate and Strong CYP3A Inducers Coadministration of ROZLYTREK with a strong or moderate CYP3A inducer decreases entrectinib plasma concentrations, which may reduce ROZLYTREK efficacy.
Drugs That Prolong QTc Interval
QTc interval prolongation can occur with ROZLYTREK. Avoid coadministration of ROZLYTREK with other products with a known potential to prolong QT/QTc interval.
Pregnancy Safety for Rozlytrek
Pregnancy Risk Summary Based on literature reports in humans with congenital mutations leading to changes in TRK signaling, findings from animal studies, and its mechanism of action, ROZLYTREK can cause fetal harm when administered to a pregnant woman. There are no available data on ROZLYTREK use in pregnant women. Administration of entrectinib to pregnant rats during the period of organogenesis resulted in malformations at maternal exposures approximately 2.7 times the human exposure at the 600 mg dose (see Data ).
Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively. Data Human Data Published reports of individuals with congenital mutations in TRK pathway proteins suggest that decreases in TRK-mediated signaling are correlated with obesity, developmental delays, cognitive impairment, insensitivity to pain, and anhidrosis.
Animal Data Entrectinib administration to pregnant rats during the period of organogenesis at a dose of 200 mg/kg resulted in maternal toxicity and fetal malformations including body closure defects (omphalocele and gastroschisis) and malformations of the vertebrae, ribs, and limbs (micromelia and adactyly), but not embryolethality. Lower fetal weights and reduced skeletal ossification occurred at doses ≥ 12.5 and 50 mg/kg, respectively.
Pediatric Use of Rozlytrek
Pediatric Use The safety and effectiveness of ROZLYTREK have been established in pediatric patients older than 1 month of age. Use of ROZLYTREK in these age groups is supported by evidence from adequate and well-controlled studies of ROZLYTREK in adults and pediatric patients with additional population pharmacokinetic data demonstrating that the exposure of drug substance in pediatric patients greater than 1 month of age is expected to be in the adult range, and that the course of disease is sufficiently similar in adult and pediatric patients to allow extrapolation of data in adults to pediatric patients. The safety and effectiveness of ROZLYTREK have not been established in pediatric patients with ROS1 -positive NSCLC.
Juvenile Animal Toxicity Data In a 13-week juvenile rat toxicology study, animals were dosed daily from post-natal day 7 to day 97 (approximately equivalent to neonate to adulthood). Entrectinib resulted in: decreased body weight gain and delayed sexual maturation at doses ≥ 4 mg/kg/day (approximately 0.06 times the human exposure (AUC) at the 600 mg dose), deficits in neurobehavioral assessments including functional observational battery and learning and memory (at doses ≥ 8 mg/kg/day, approximately 0.14 times the human exposure at the 600 mg dose), and decreased femur length at doses ≥ 16 mg/kg/day (approximately 0.18 times the human exposure at the 600 mg dose).
Clinical Studies of Rozlytrek
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. 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 BI 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.
Efficacy was assessed in the first 54 adult patients with solid tumors with an NTRK gene fusion enrolled into these trials. 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).
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 Table 15. Efficacy Results by NTRK Gene Fusion Partner 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. 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 by Table 18. Efficacy Results for Pediatric Patients with Solid Tumors Harboring NTRK by Gene Fusion Partner
| Efficacy Parameters | ROZLYTREK n = 92 |
|---|---|
| Confidence Interval (CI) calculated using the Clopper-Pearson method. | |
| Overall Response Rate (95% CI) | 74% (64, 83) |
| Complete Response | 15% |
| Partial Response | 59% |
| Duration of Response (DOR) Observed DOR | n = 68 |
| Range (months) | 2.4, 55.2 denotes ongoing response |
| % DOR ≥ 9 months | 75% |
| % DOR ≥ 12 months | 57% |
| % DOR ≥ 18 months | 38% |
| Efficacy Parameter | ROZLYTREK n = 54 |
|---|---|
| Overall Response Rate (95% CI) | 59% (45, 72) |
| Complete Response | 13% |
| Partial Response | 46% |
| Duration of Response Observed DOR | n = 32 |
| Range (months) | 2.8, 47.8 denotes ongoing response |
| % with duration ≥ 6 months | 72% |
| % with duration ≥ 9 months | 66% |
| % with duration ≥ 12 months | 56% |
| Tumor Type | Patients n = 54 | ORR | DOR | |
|---|---|---|---|---|
| % | 95% CI | Range (months) | ||
| MASC: mammary analogue secretory carcinoma; NA = not applicable due to small numbers or lack of response; PR = partial response. | ||||
| Sarcoma | 13 | 46% | 19%, 75% | 2.8, 33.6 denotes ongoing response |
| 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 |
| NTRK Partner | Patients n = 54 | ORR | DOR | |
|---|---|---|---|---|
| % | 95% CI | Range (months) | ||
| PR = partial response; PD = progressive disease; SD = stable disease; NA = not applicable due to small numbers or lack of response; NE = not evaluable. | ||||
| ETV6 – NTRK3 | 25 | 72% | 51%, 88% | 2.8, 47.8 denotes ongoing response |
| 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 |
| Efficacy Parameter 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) | ROZLYTREK n = 33 |
|---|---|
| NE = not estimable | |
| Overall Response Rate (95% CI) | 70% (51, 84) |
| Complete Response | 42% |
| Partial Response | 27% |
| Duration of Response Observed DOR | n = 23 |
| Median in months (95% CI) | 25.4 (14.3, NE) |
| % with duration ≥ 12 months | 43% |
| Tumor Type | Patients n = 33 | ORR | DOR | |
|---|---|---|---|---|
| % | 95% CI | Range (months) | ||
| NA = not applicable due to small numbers or lack of response | ||||
| Primary CNS Median time to first objective response for patients with primary CNS tumors was 1.9 months | 17 | 53% | 28%, 77% | 5.5, 30.4 denotes ongoing response |
| Infantile fibrosarcoma | 8 | 88% | 47%, 100% | 3.7, 24 |
| Spindle Cell | 6 | 100% | 54%, 100% | 3.7, 12.9 |
| Sarcoma (other) | 1 | 0% Patient with evaluable but non-measurable disease at baseline | NA | NA |
| Melanoma | 1 | 100% | NA | 42.4 |
| NTRK Partner | Patients n = 33 | ORR | DOR | |
|---|---|---|---|---|
| % | 95% CI | Range (months) | ||
| PR = partial response; PD = progressive disease; SD = stable disease; NA = not applicable due to small numbers or lack of response | ||||
| ETV6 – NTRK3 | 7 | 86% | 42%, 100% | 11.9 - 42.4 denotes ongoing response |
| 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 |
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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