Augtyro
Generic: REPOTRECTINIB
Basic Information
Manufacturer
E.R. Squibb & Sons, L.L.C.
Product Type
HUMAN PRESCRIPTION DRUG
Route of Administration
ORAL
FDA Set ID
fb526827-40ba-4462-94cf-179ae3b0cb8a
Indications & Usage
1 INDICATIONS AND USAGE AUGTYRO is a kinase inhibitor indicated for the treatment of • adult patients with locally advanced or metastatic ROS1- positive non-small cell lung cancer (NSCLC).
( 1.1 ) • adult and pediatric patients 12 years of age and older with solid tumors that: • have a neurotrophic tyrosine receptor kinase ( NTRK ) gene fusion and • are locally advanced or metastatic or where surgical resection is likely to result in severe morbidity.
• have progressed following treatment or have no satisfactory alternative therapy.
This indication is approved under accelerated approval based on overall response rate and duration 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 AUGTYRO is indicated for the treatment of adult patients with locally advanced or metastatic ROS1 -positive non-small cell lung cancer (NSCLC) [see Dosage and Administration (2.1) ] .
1.2 NTRK Gene Fusion-Positive Solid Tumors AUGTYRO is indicated for the treatment of adult and pediatric patients 12 years of age and older with solid tumors that: • have a neurotrophic tyrosine receptor kinase ( NTRK ) gene fusion [see Dosage and Administration ( 2.1 )] , • are locally advanced or 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 overall response rate and duration of response [see Clinical Studies ( 14.2 )] .
Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).
( 1.1 ) • adult and pediatric patients 12 years of age and older with solid tumors that: • have a neurotrophic tyrosine receptor kinase ( NTRK ) gene fusion and • are locally advanced or metastatic or where surgical resection is likely to result in severe morbidity.
• have progressed following treatment or have no satisfactory alternative therapy.
This indication is approved under accelerated approval based on overall response rate and duration 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 AUGTYRO is indicated for the treatment of adult patients with locally advanced or metastatic ROS1 -positive non-small cell lung cancer (NSCLC) [see Dosage and Administration (2.1) ] .
1.2 NTRK Gene Fusion-Positive Solid Tumors AUGTYRO is indicated for the treatment of adult and pediatric patients 12 years of age and older with solid tumors that: • have a neurotrophic tyrosine receptor kinase ( NTRK ) gene fusion [see Dosage and Administration ( 2.1 )] , • are locally advanced or 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 overall response rate and duration of response [see Clinical Studies ( 14.2 )] .
Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).
Adverse Reactions
6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Central Nervous System Adverse Reactions [see Warnings and Precautions (5.1) ] • Interstitial Lung Disease (ILD)/Pneumonitis [see Warnings and Precautions (5.2) ] • Hepatotoxicity [see Warnings and Precautions (5.3) ] • Myalgia with Creatine Phosphokinase Elevation [see Warnings and Precautions (5.4) ] • Hyperuricemia [see Warnings and Precautions (5.5) ] • Skeletal Fractures [see Warnings and Precautions (5.6) ] • Embryo-Fetal Toxicity [see Warnings and Precautions (5.7) ] The most common adverse reactions (≥20%) were dizziness, dysgeusia, peripheral neuropathy, constipation, dyspnea, fatigue, ataxia, cognitive impairment, muscular weakness, and nausea.
( 6.1) To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates reported 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.
The pooled safety population described in WARNINGS AND PRECAUTIONS and below reflects exposure to AUGTYRO in 426 patients with ROS1 -positive NSCLC (n=320), NTRK1/2/3 -positive solid tumors (n=104), or other solid tumors (n=2) in TRIDENT-1.
Patients received AUGTYRO at a dose of 160 mg orally once daily for the first 14 days, then increased to 160 mg orally twice daily until disease progression or unacceptable toxicity [see Clinical Studies ( 14.1 ), ( 14.2 )] .
Eligible patients had an ECOG status of ≤1.
Patients with a history of ILD, drug-related pneumonitis, significant, uncontrolled, active cardiovascular disease, or prolonged QTc interval were excluded from enrollment in this trial.
Forty-eight percent of patients were exposed to AUGTYRO for at least 6 months, and 28% were exposed for greater than 1 year.
The median age of patients who received AUGTYRO was 57 years (range: 18 to 93); 59% female; 43% White, 47% Asian, 2.8% Black, 0.5% Native Hawaiian or Other Pacific Islander, 0.5% American Indian or Alaska Native, 6.1% race not reported or other, and 0.7% unknown.
Serious adverse reactions occurred in 35% of patients who received AUGTYRO.
Serious adverse reactions in ≥2% of patients included pneumonia (6.3%), dyspnea (3.1%), pleural effusion (2.8%), and hypoxia (2.6%).
Fatal adverse reactions occurred in 3.5% of patients who received AUGTYRO, including pneumonia, pneumonia aspiration, cardiac arrest, sudden cardiac death, cardiac failure, hypoxia, dyspnea, respiratory failure, tremor, and disseminated intravascular coagulation.
Permanent discontinuation of AUGTYRO due to an adverse reaction occurred in 7% of patients.
There were no specific adverse reactions that accounted for ≥1% of permanent discontinuations.
Dosage interruptions of AUGTYRO due to an adverse reaction occurred in 50% of patients.
Adverse reactions that required dosage interruption in ≥2% of patients were dizziness, dyspnea, muscular weakness, ataxia, pneumonia, peripheral neuropathy, anemia, and vomiting.
Dose reductions of AUGTYRO due to an adverse reaction occurred in 38% of patients.
Adverse reactions that required dosage reductions in ≥2% of patients included dizziness, ataxia, muscular weakness, peripheral neuropathy, and cognitive impairment.
The most common (≥20%) adverse reactions that occurred in patients receiving AUGTYRO were dizziness, dysgeusia, peripheral neuropathy, constipation, dyspnea, fatigue, ataxia, cognitive impairment, muscular weakness and nausea.
Table 3 summarizes the adverse reactions that occurred in TRIDENT-1.
Table 3: Adverse Reactions (≥10%) in Patients with ROS1-Positive NSCLC or NTRK-Positive Solid Tumors Who Received AUGTYRO in TRIDENT-1 1 Based on NCI CTCAE v4.03 a Includes terms dizziness, vertigo, dizziness postural, dizziness exertional, vertigo positional b Includes terms dysgeusia, ageusia, anosmia, hypogeusia c Includes terms neuralgia, neuropathy peripheral, peripheral sensory neuropathy, dysesthesia, peripheral motor neuropathy, polyneuropathy, paresthesia, hypoesthesia, hyperesthesia d Includes terms ataxia, gait disturbance, balance disorder, cerebellar ataxia and coordination abnormal e Includes terms memory impairment, disturbance in attention, cognitive disorder, confusional state, amnesia, attention deficit hyperactivity disorder, delirium, altered state of consciousness, aphasia, delusion, depressed level of consciousness, hallucination, mental status changes, neurological decompensation f Includes terms headache, migraine, tension headache g Includes terms dyspnea and dyspnea exertional h Includes terms productive cough, cough, and upper-airway cough syndrome i Includes terms pneumonia, pneumonia aspiration, lower respiratory tract infection, pneumonia viral, pneumonia bacterial, lower respiratory tract infection bacterial, pneumonia klebsiella j Includes terms fatigue and asthenia k Includes terms generalized edema, periorbital edema, localized edema, face edema, edema peripheral, edema, eye edema, scrotal edema l Includes terms myalgia, myositis, musculoskeletal discomfort, musculoskeletal pain m Includes terms vision blurred, dry eye, visual impairment, visual field defect, cataract, conjunctivitis, eye pain, photophobia, photosensitivity reaction, visual acuity reduced, vitreous floaters, blepharospasm, color blindness, diplopia, eye hematoma, eye swelling, eyelid disorder, eyelid injury, eyelids pruritus, glaucoma, night blindness, ophthalmic herpes zoster Adverse Reaction 1 AUGTYRO N=426 All Grades (%) Grade 3 or 4 (%) Nervous System Disorders Dizziness a 65 2.8 Dysgeusia b 54 0 Peripheral neuropathy c 49 1.4 Ataxia d 28 0.5 Cognitive impairment e 25 0.9 Headache f 19 0 Gastrointestinal Disorders Constipation 38 0.2 Nausea 20 0.7 Diarrhea 14 0.7 Vomiting 12 1.2 Respiratory, Thoracic, and Mediastinal Disorders Dyspnea g 30 6 Cough h 18 0.2 Pneumonia i 11 6 General Disorders Fatigue j 30 1.2 Edema k 15 0.5 Decreased appetite 11 0.2 Musculoskeletal and Connective Tissue Disorders Muscular weakness 20 2 Myalgia l 13 0.7 Metabolism and Nutritional Increased weight 16 3 Eye Disorders Vision disorders m 12 0.5 Clinically relevant adverse reactions occurring in <10% of patients receiving AUGTYRO were pyrexia (9.2%) and fall (3.8%).
Table 4 summarizes the laboratory abnormalities in TRIDENT-1.
Table 4: Laboratory Abnormalities (≥20%) that Worsened from Baseline in Patients with ROS1-Positive NSCLC or NTRK-Positive Solid Tumors Who Received AUGTYRO in TRIDENT-1 Laboratory Abnormality 1 AUGTYRO 2 N=426 All Grades (%) Grade 3 or 4 (%) 1 Based on NCI CTCAE v4.03 2 The denominator used to calculate the rate varied from 233 to 423 based on the number of patients with a baseline value and at least one post-treatment value.
Hematology Decreased hemoglobin 79 8.4 Decreased lymphocytes 43 10 Decreased neutrophils 34 9 Increased activated partial thromboplastin time 26 0.3 Increased INR 24 0 Chemistry Increased creatine phosphokinase 61 7 Increased gamma glutamyl transferase 50 13 Increased aspartate aminotransferase 41 2.9 Increased alanine aminotransferase 38 3.3 Increased sodium 33 0.2 Increased alkaline phosphatase 29 2.1 Increased glucose 26 2.4 Increased urate 23 12 Decreased phosphate 22 6 Increased potassium 22 0.7 Decreased glucose 20 0.2
( 6.1) To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates reported 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.
The pooled safety population described in WARNINGS AND PRECAUTIONS and below reflects exposure to AUGTYRO in 426 patients with ROS1 -positive NSCLC (n=320), NTRK1/2/3 -positive solid tumors (n=104), or other solid tumors (n=2) in TRIDENT-1.
Patients received AUGTYRO at a dose of 160 mg orally once daily for the first 14 days, then increased to 160 mg orally twice daily until disease progression or unacceptable toxicity [see Clinical Studies ( 14.1 ), ( 14.2 )] .
Eligible patients had an ECOG status of ≤1.
Patients with a history of ILD, drug-related pneumonitis, significant, uncontrolled, active cardiovascular disease, or prolonged QTc interval were excluded from enrollment in this trial.
Forty-eight percent of patients were exposed to AUGTYRO for at least 6 months, and 28% were exposed for greater than 1 year.
The median age of patients who received AUGTYRO was 57 years (range: 18 to 93); 59% female; 43% White, 47% Asian, 2.8% Black, 0.5% Native Hawaiian or Other Pacific Islander, 0.5% American Indian or Alaska Native, 6.1% race not reported or other, and 0.7% unknown.
Serious adverse reactions occurred in 35% of patients who received AUGTYRO.
Serious adverse reactions in ≥2% of patients included pneumonia (6.3%), dyspnea (3.1%), pleural effusion (2.8%), and hypoxia (2.6%).
Fatal adverse reactions occurred in 3.5% of patients who received AUGTYRO, including pneumonia, pneumonia aspiration, cardiac arrest, sudden cardiac death, cardiac failure, hypoxia, dyspnea, respiratory failure, tremor, and disseminated intravascular coagulation.
Permanent discontinuation of AUGTYRO due to an adverse reaction occurred in 7% of patients.
There were no specific adverse reactions that accounted for ≥1% of permanent discontinuations.
Dosage interruptions of AUGTYRO due to an adverse reaction occurred in 50% of patients.
Adverse reactions that required dosage interruption in ≥2% of patients were dizziness, dyspnea, muscular weakness, ataxia, pneumonia, peripheral neuropathy, anemia, and vomiting.
Dose reductions of AUGTYRO due to an adverse reaction occurred in 38% of patients.
Adverse reactions that required dosage reductions in ≥2% of patients included dizziness, ataxia, muscular weakness, peripheral neuropathy, and cognitive impairment.
The most common (≥20%) adverse reactions that occurred in patients receiving AUGTYRO were dizziness, dysgeusia, peripheral neuropathy, constipation, dyspnea, fatigue, ataxia, cognitive impairment, muscular weakness and nausea.
Table 3 summarizes the adverse reactions that occurred in TRIDENT-1.
Table 3: Adverse Reactions (≥10%) in Patients with ROS1-Positive NSCLC or NTRK-Positive Solid Tumors Who Received AUGTYRO in TRIDENT-1 1 Based on NCI CTCAE v4.03 a Includes terms dizziness, vertigo, dizziness postural, dizziness exertional, vertigo positional b Includes terms dysgeusia, ageusia, anosmia, hypogeusia c Includes terms neuralgia, neuropathy peripheral, peripheral sensory neuropathy, dysesthesia, peripheral motor neuropathy, polyneuropathy, paresthesia, hypoesthesia, hyperesthesia d Includes terms ataxia, gait disturbance, balance disorder, cerebellar ataxia and coordination abnormal e Includes terms memory impairment, disturbance in attention, cognitive disorder, confusional state, amnesia, attention deficit hyperactivity disorder, delirium, altered state of consciousness, aphasia, delusion, depressed level of consciousness, hallucination, mental status changes, neurological decompensation f Includes terms headache, migraine, tension headache g Includes terms dyspnea and dyspnea exertional h Includes terms productive cough, cough, and upper-airway cough syndrome i Includes terms pneumonia, pneumonia aspiration, lower respiratory tract infection, pneumonia viral, pneumonia bacterial, lower respiratory tract infection bacterial, pneumonia klebsiella j Includes terms fatigue and asthenia k Includes terms generalized edema, periorbital edema, localized edema, face edema, edema peripheral, edema, eye edema, scrotal edema l Includes terms myalgia, myositis, musculoskeletal discomfort, musculoskeletal pain m Includes terms vision blurred, dry eye, visual impairment, visual field defect, cataract, conjunctivitis, eye pain, photophobia, photosensitivity reaction, visual acuity reduced, vitreous floaters, blepharospasm, color blindness, diplopia, eye hematoma, eye swelling, eyelid disorder, eyelid injury, eyelids pruritus, glaucoma, night blindness, ophthalmic herpes zoster Adverse Reaction 1 AUGTYRO N=426 All Grades (%) Grade 3 or 4 (%) Nervous System Disorders Dizziness a 65 2.8 Dysgeusia b 54 0 Peripheral neuropathy c 49 1.4 Ataxia d 28 0.5 Cognitive impairment e 25 0.9 Headache f 19 0 Gastrointestinal Disorders Constipation 38 0.2 Nausea 20 0.7 Diarrhea 14 0.7 Vomiting 12 1.2 Respiratory, Thoracic, and Mediastinal Disorders Dyspnea g 30 6 Cough h 18 0.2 Pneumonia i 11 6 General Disorders Fatigue j 30 1.2 Edema k 15 0.5 Decreased appetite 11 0.2 Musculoskeletal and Connective Tissue Disorders Muscular weakness 20 2 Myalgia l 13 0.7 Metabolism and Nutritional Increased weight 16 3 Eye Disorders Vision disorders m 12 0.5 Clinically relevant adverse reactions occurring in <10% of patients receiving AUGTYRO were pyrexia (9.2%) and fall (3.8%).
Table 4 summarizes the laboratory abnormalities in TRIDENT-1.
Table 4: Laboratory Abnormalities (≥20%) that Worsened from Baseline in Patients with ROS1-Positive NSCLC or NTRK-Positive Solid Tumors Who Received AUGTYRO in TRIDENT-1 Laboratory Abnormality 1 AUGTYRO 2 N=426 All Grades (%) Grade 3 or 4 (%) 1 Based on NCI CTCAE v4.03 2 The denominator used to calculate the rate varied from 233 to 423 based on the number of patients with a baseline value and at least one post-treatment value.
Hematology Decreased hemoglobin 79 8.4 Decreased lymphocytes 43 10 Decreased neutrophils 34 9 Increased activated partial thromboplastin time 26 0.3 Increased INR 24 0 Chemistry Increased creatine phosphokinase 61 7 Increased gamma glutamyl transferase 50 13 Increased aspartate aminotransferase 41 2.9 Increased alanine aminotransferase 38 3.3 Increased sodium 33 0.2 Increased alkaline phosphatase 29 2.1 Increased glucose 26 2.4 Increased urate 23 12 Decreased phosphate 22 6 Increased potassium 22 0.7 Decreased glucose 20 0.2