Rozlytrek
Generic: ENTRECTINIB
Basic Information
Manufacturer
Genentech, Inc.
Product Type
HUMAN PRESCRIPTION DRUG
Route of Administration
ORAL
FDA Set ID
c7c71b0c-2549-4495-86b6-c2807fa54908
Indications & Usage
1 INDICATIONS AND USAGE 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 ) 1.1 ROS1 -Positive Non-Small Cell Lung Cancer ROZLYTREK is indicated for the treatment of adult patients with ROS1- positive metastatic non-small cell lung cancer (NSCLC), as detected by an FDA-approved test.
1.2 NTRK Gene Fusion-Positive Solid Tumors ROZLYTREK is indicated for the treatment of adult and pediatric patients older than 1 month of age with solid tumors that: have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion, as detected by an FDA-approved test without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have progressed following treatment or have no satisfactory alternative therapy.
This indication is approved under accelerated approval based on tumor response rate and durability of response [see Clinical Studies (14.2) ] .
Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
( 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 ) 1.1 ROS1 -Positive Non-Small Cell Lung Cancer ROZLYTREK is indicated for the treatment of adult patients with ROS1- positive metastatic non-small cell lung cancer (NSCLC), as detected by an FDA-approved test.
1.2 NTRK Gene Fusion-Positive Solid Tumors ROZLYTREK is indicated for the treatment of adult and pediatric patients older than 1 month of age with solid tumors that: have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion, as detected by an FDA-approved test without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have progressed following treatment or have no satisfactory alternative therapy.
This indication is approved under accelerated approval based on tumor response rate and durability of response [see Clinical Studies (14.2) ] .
Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
Adverse Reactions
6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Congestive Heart Failure [see Warnings and Precautions (5.1) ] Central Nervous System Effects [see Warnings and Precautions (5.2) ] Skeletal Fractures [see Warnings and Precautions (5.3) ] Hepatotoxicity [see Warnings and Precautions (5.4) ] Hyperuricemia [see Warnings and Precautions (5.5) ] QT Interval Prolongation [see Warnings and Precautions (5.6) ] Vision Disorders [see Warnings and Precautions (5.7) ] 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.
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Data in WARNINGS AND PRECAUTIONS and below reflect exposure to ROZLYTREK in 355 patients, including 172 (48%) patients exposed for 6 months or longer and 84 (24%) patients exposed for 1 year or longer.
ROZLYTREK was studied in one dose-finding trial in adults [ALKA (n = 57)], one dose-finding and activity-estimating trial in adults [STARTRK-1 (n = 76)], one dose-finding and activity-estimating trial in pediatric and adult patients [STARTRK-NG (n = 16)], and one single arm, activity-estimating trial in adults [STARTRK-2 (n = 206)].
The population characteristics were: median age 55 years (range: 4 to 86 years); 5% (n = 17) were less than 18 years of age; 55% were female; and 66% were White, 23% were Asian, and 5% were Black; 3% were Hispanic/Latino.
The most common tumors (≥ 5%) were lung (56%), sarcoma (8%), and colon (5%).
ROS1 gene fusions were present in 42% and NTRK gene fusions were present in 20%.
Most adults (75%) received ROZLYTREK 600 mg orally once daily.
The doses ranged from 100 mg/m 2 to 1600 mg/m 2 once daily in adults and 250 mg/m 2 to 750 mg/m 2 once daily in pediatric patients.
Serious adverse reactions occurred in 39% of patients.
The most frequent serious adverse reactions (≥ 2%) were pneumonia (3.9%), dyspnea (3.7%), pleural effusion (3.4%), sepsis (2.5%), pulmonary embolism (2.3%), respiratory failure (2%), and pyrexia (2%).
Grade 3 or 4 adverse reactions occurred in 60% of patients; the most common (≥ 2%) were lung infection (5%), increased weight (7%), dyspnea (6%), fatigue/asthenia (5%), cognitive disorders (4.5%), syncope (2.5%), pulmonary embolism (3.4%), hypoxia (3.4%), pleural effusion (3.1%), hypotension (2.8%), diarrhea (2%), and urinary tract infection (2.5%).
Fatal events included dyspnea (0.6%), pneumonia (0.6%), sepsis (0.6%), completed suicide (0.3%), large intestine perforation (0.3%) and tumor lysis syndrome (0.3%).
One patient developed Grade 4 myocarditis after one dose of ROZLYTREK which resolved after discontinuation of ROZLYTREK and administration of high-dose corticosteroids.
Permanent discontinuation due to an adverse reaction occurred in 9% of patients who received ROZLYTREK.
The most frequent adverse reactions (< 1% each) that resulted in permanent discontinuation were pneumonia, cardio-respiratory arrest, dyspnea, and fatigue.
Dose interruptions due to adverse reactions occurred in 46% of patients.
The most frequent adverse reactions (≥ 2%) that resulted in interruption were increased blood creatinine (4%), fatigue (3.7%), anemia (3.1%), diarrhea (2.8%), pyrexia (2.8%), dizziness (2.5%), dyspnea (2.3%), nausea (2.3%), pneumonia (2.3%), cognitive disorder (2%) and neutropenia (2%).
Dose reductions due to adverse reactions occurred in 29% of patients who received ROZLYTREK.
The most frequent adverse reactions resulting in dose reductions (≥ 1%) were dizziness (3.9%), increased blood creatinine (3.1%), fatigue (2.3%), anemia (1.7%), and increased weight (1.4%).
The most common adverse reactions (≥ 20%) were fatigue, constipation, dysgeusia, edema, dizziness, diarrhea, nausea, dysesthesia, dyspnea, myalgia, cognitive impairment, increased weight, cough, vomiting, pyrexia, arthralgia and vision disorders.
Table 7 summarizes the adverse reactions observed in these 355 patients.
Table 7.
Adverse Reactions (≥ 10%) in Patients Receiving ROZLYTREK in ALKA, STARTRK-1, STARTRK-2, and STARTRK-NG Adverse Reactions ROZLYTREK n = 355 All Grades (%) Grade ≥ 3 Grades 3 – 5, inclusive of fatal adverse reactions, including 2 events of pneumonia and 2 events of dyspnea.
(%) General Fatigue Includes fatigue, asthenia 48 5 Edema Includes face edema, fluid retention, generalized edema, localized edema, edema, edema peripheral, peripheral swelling 40 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 Clinically relevant adverse reactions occurring in ≤ 10% of patients include dysphagia (10%), fall (8%), pleural effusion (8%), fractures (6%), hypoxia (4.2%), pulmonary embolism (3.9%), syncope (3.9%), congestive heart failure (3.4%), and QT prolongation (3.1%) .
Table 8 summarizes the laboratory abnormalities.
Table 8.
Laboratory Abnormalities (≥ 20%) Worsening from Baseline in Patients Receiving ROZLYTREK in ALKA, STARTRK-1, STARTRK-2, and STARTRK-NG Laboratory Abnormality ROZLYTREK NCI CTCAE Grade All Grades (%) Denominator for each laboratory parameter is based on the number of patients with a baseline and post-treatment laboratory value available which ranged from 111 to 346 patients.
Grade 3 or 4 (%) AST: Aspartate Aminotransferase; ALT: Alanine Aminotransferase Chemistry Increased creatinine Based on NCI CTCAE v5.0 73 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 Safety in Pediatric Patients The safety of ROZLYTREK was evaluated was evaluated in pediatric patients with unresectable or metastatic solid tumors with a NTRK gene fusion enrolled in one of three multicenter, open-label clinical trials: STARTRK-NG (n=68), TAPISTRY (n=6) and STARTRK-2 (n=2).
Patients received ROZLYTREK 20 mg to 600 mg based on body surface area (BSA) orally or via enteral feeding tube once daily in 4-week cycles until unacceptable toxicity or disease progression.
Among patients who received ROZLYTREK, 58% were exposed for 6 months or longer and 38% were exposed for greater than one year.
The median age of patients who received ROZLYTREK was 6 years (range: 0 to 17); 51% were females; 68% were White, 18% Asian, 7% Black or African American, and 7% were other races.
Serious adverse reactions occurred in 45% of patients who received ROZLYTREK.
Serious adverse reactions in > 2% of patients included skeletal fractures (12%), pneumonia (5%), pyrexia (5%), hydrocephalus (5%), device related infection (4%), hypoxia (4%), dyspnea (3%), headache (3%), gait disturbance (3%), pain (3%), upper respiratory infection (3%), and sepsis (3%).
Permanent discontinuation of ROZLYTREK due to an adverse reaction occurred in 13% of patients.
Adverse reactions which resulted in permanent discontinuation of ROZLYTREK in > 2% of patients included skeletal fracture.
Dosage interruptions of ROZLYTREK due to an adverse reaction occurred in 39% of patients.
Adverse reactions which required dosage interruption in > 5% of patients included decreased neutrophil count, pyrexia, vomiting, and diarrhea.
Dose reductions of ROZLYTREK due to an adverse reaction occurred in 21% of patients.
Adverse reactions which required dose reductions in > 2% of patients included increased blood creatinine and increased weight.
Table 9 summarizes the adverse reactions in STARTRK-NG (n=68), TAPISTRY (n=6) and STARTRK-2 (n=2).
Table 9.
Adverse Reactions (≥20%) in Pediatric Patients Who Received ROZLYTREK in STARTRK-NG, TAPISTRY and STARTRK-2 Adverse Reaction ROZLYTREK (n=76) All Grades (%) Grade 3 or 4 (%) General Disorders Pyrexia 43 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 Clinically relevant adverse reactions in <20% of patients who received ROZLYTREK included pruritus, rash, urinary incontinence, eye pain and photophobia.
Tables 10 summarizes the laboratory abnormalities in STARTRK-NG (n=68), TAPISTRY (n=6) and STARTRK-2 (n=2).
Table 10.
Select Laboratory Abnormalities (≥20%) That Worsened from Baseline in Pediatric Patients Who Received ROZLYTREK in STARTRK-NG, TAPISTRY and STARTRK-2 Laboratory Abnormality ROZLYTREK The denominator used to calculate the rate varied from 67 to 76 based on the number of patients with a baseline value and at least one post-treatment value.
All values based on NCI CTCAE v5.0 All Grades (%) Grade 3 or 4 (%) AST: Aspartate Aminotransferase; ALT: Alanine Aminotransferase Hematology Decreased Hemoglobin 53 7 Decreased Neutrophils 53 22 Decreased Leukocytes 46 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 Other clinically relevant laboratory abnormalities in patients who received ROZLYTREK included decreased phosphorous.
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Data in WARNINGS AND PRECAUTIONS and below reflect exposure to ROZLYTREK in 355 patients, including 172 (48%) patients exposed for 6 months or longer and 84 (24%) patients exposed for 1 year or longer.
ROZLYTREK was studied in one dose-finding trial in adults [ALKA (n = 57)], one dose-finding and activity-estimating trial in adults [STARTRK-1 (n = 76)], one dose-finding and activity-estimating trial in pediatric and adult patients [STARTRK-NG (n = 16)], and one single arm, activity-estimating trial in adults [STARTRK-2 (n = 206)].
The population characteristics were: median age 55 years (range: 4 to 86 years); 5% (n = 17) were less than 18 years of age; 55% were female; and 66% were White, 23% were Asian, and 5% were Black; 3% were Hispanic/Latino.
The most common tumors (≥ 5%) were lung (56%), sarcoma (8%), and colon (5%).
ROS1 gene fusions were present in 42% and NTRK gene fusions were present in 20%.
Most adults (75%) received ROZLYTREK 600 mg orally once daily.
The doses ranged from 100 mg/m 2 to 1600 mg/m 2 once daily in adults and 250 mg/m 2 to 750 mg/m 2 once daily in pediatric patients.
Serious adverse reactions occurred in 39% of patients.
The most frequent serious adverse reactions (≥ 2%) were pneumonia (3.9%), dyspnea (3.7%), pleural effusion (3.4%), sepsis (2.5%), pulmonary embolism (2.3%), respiratory failure (2%), and pyrexia (2%).
Grade 3 or 4 adverse reactions occurred in 60% of patients; the most common (≥ 2%) were lung infection (5%), increased weight (7%), dyspnea (6%), fatigue/asthenia (5%), cognitive disorders (4.5%), syncope (2.5%), pulmonary embolism (3.4%), hypoxia (3.4%), pleural effusion (3.1%), hypotension (2.8%), diarrhea (2%), and urinary tract infection (2.5%).
Fatal events included dyspnea (0.6%), pneumonia (0.6%), sepsis (0.6%), completed suicide (0.3%), large intestine perforation (0.3%) and tumor lysis syndrome (0.3%).
One patient developed Grade 4 myocarditis after one dose of ROZLYTREK which resolved after discontinuation of ROZLYTREK and administration of high-dose corticosteroids.
Permanent discontinuation due to an adverse reaction occurred in 9% of patients who received ROZLYTREK.
The most frequent adverse reactions (< 1% each) that resulted in permanent discontinuation were pneumonia, cardio-respiratory arrest, dyspnea, and fatigue.
Dose interruptions due to adverse reactions occurred in 46% of patients.
The most frequent adverse reactions (≥ 2%) that resulted in interruption were increased blood creatinine (4%), fatigue (3.7%), anemia (3.1%), diarrhea (2.8%), pyrexia (2.8%), dizziness (2.5%), dyspnea (2.3%), nausea (2.3%), pneumonia (2.3%), cognitive disorder (2%) and neutropenia (2%).
Dose reductions due to adverse reactions occurred in 29% of patients who received ROZLYTREK.
The most frequent adverse reactions resulting in dose reductions (≥ 1%) were dizziness (3.9%), increased blood creatinine (3.1%), fatigue (2.3%), anemia (1.7%), and increased weight (1.4%).
The most common adverse reactions (≥ 20%) were fatigue, constipation, dysgeusia, edema, dizziness, diarrhea, nausea, dysesthesia, dyspnea, myalgia, cognitive impairment, increased weight, cough, vomiting, pyrexia, arthralgia and vision disorders.
Table 7 summarizes the adverse reactions observed in these 355 patients.
Table 7.
Adverse Reactions (≥ 10%) in Patients Receiving ROZLYTREK in ALKA, STARTRK-1, STARTRK-2, and STARTRK-NG Adverse Reactions ROZLYTREK n = 355 All Grades (%) Grade ≥ 3 Grades 3 – 5, inclusive of fatal adverse reactions, including 2 events of pneumonia and 2 events of dyspnea.
(%) General Fatigue Includes fatigue, asthenia 48 5 Edema Includes face edema, fluid retention, generalized edema, localized edema, edema, edema peripheral, peripheral swelling 40 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 Clinically relevant adverse reactions occurring in ≤ 10% of patients include dysphagia (10%), fall (8%), pleural effusion (8%), fractures (6%), hypoxia (4.2%), pulmonary embolism (3.9%), syncope (3.9%), congestive heart failure (3.4%), and QT prolongation (3.1%) .
Table 8 summarizes the laboratory abnormalities.
Table 8.
Laboratory Abnormalities (≥ 20%) Worsening from Baseline in Patients Receiving ROZLYTREK in ALKA, STARTRK-1, STARTRK-2, and STARTRK-NG Laboratory Abnormality ROZLYTREK NCI CTCAE Grade All Grades (%) Denominator for each laboratory parameter is based on the number of patients with a baseline and post-treatment laboratory value available which ranged from 111 to 346 patients.
Grade 3 or 4 (%) AST: Aspartate Aminotransferase; ALT: Alanine Aminotransferase Chemistry Increased creatinine Based on NCI CTCAE v5.0 73 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 Safety in Pediatric Patients The safety of ROZLYTREK was evaluated was evaluated in pediatric patients with unresectable or metastatic solid tumors with a NTRK gene fusion enrolled in one of three multicenter, open-label clinical trials: STARTRK-NG (n=68), TAPISTRY (n=6) and STARTRK-2 (n=2).
Patients received ROZLYTREK 20 mg to 600 mg based on body surface area (BSA) orally or via enteral feeding tube once daily in 4-week cycles until unacceptable toxicity or disease progression.
Among patients who received ROZLYTREK, 58% were exposed for 6 months or longer and 38% were exposed for greater than one year.
The median age of patients who received ROZLYTREK was 6 years (range: 0 to 17); 51% were females; 68% were White, 18% Asian, 7% Black or African American, and 7% were other races.
Serious adverse reactions occurred in 45% of patients who received ROZLYTREK.
Serious adverse reactions in > 2% of patients included skeletal fractures (12%), pneumonia (5%), pyrexia (5%), hydrocephalus (5%), device related infection (4%), hypoxia (4%), dyspnea (3%), headache (3%), gait disturbance (3%), pain (3%), upper respiratory infection (3%), and sepsis (3%).
Permanent discontinuation of ROZLYTREK due to an adverse reaction occurred in 13% of patients.
Adverse reactions which resulted in permanent discontinuation of ROZLYTREK in > 2% of patients included skeletal fracture.
Dosage interruptions of ROZLYTREK due to an adverse reaction occurred in 39% of patients.
Adverse reactions which required dosage interruption in > 5% of patients included decreased neutrophil count, pyrexia, vomiting, and diarrhea.
Dose reductions of ROZLYTREK due to an adverse reaction occurred in 21% of patients.
Adverse reactions which required dose reductions in > 2% of patients included increased blood creatinine and increased weight.
Table 9 summarizes the adverse reactions in STARTRK-NG (n=68), TAPISTRY (n=6) and STARTRK-2 (n=2).
Table 9.
Adverse Reactions (≥20%) in Pediatric Patients Who Received ROZLYTREK in STARTRK-NG, TAPISTRY and STARTRK-2 Adverse Reaction ROZLYTREK (n=76) All Grades (%) Grade 3 or 4 (%) General Disorders Pyrexia 43 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 Clinically relevant adverse reactions in <20% of patients who received ROZLYTREK included pruritus, rash, urinary incontinence, eye pain and photophobia.
Tables 10 summarizes the laboratory abnormalities in STARTRK-NG (n=68), TAPISTRY (n=6) and STARTRK-2 (n=2).
Table 10.
Select Laboratory Abnormalities (≥20%) That Worsened from Baseline in Pediatric Patients Who Received ROZLYTREK in STARTRK-NG, TAPISTRY and STARTRK-2 Laboratory Abnormality ROZLYTREK The denominator used to calculate the rate varied from 67 to 76 based on the number of patients with a baseline value and at least one post-treatment value.
All values based on NCI CTCAE v5.0 All Grades (%) Grade 3 or 4 (%) AST: Aspartate Aminotransferase; ALT: Alanine Aminotransferase Hematology Decreased Hemoglobin 53 7 Decreased Neutrophils 53 22 Decreased Leukocytes 46 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 Other clinically relevant laboratory abnormalities in patients who received ROZLYTREK included decreased phosphorous.