Augtyro

5 WARNINGS AND PRECAUTIONS • Central Nervous System (CNS) Effects: Can cause CNS adverse reactions including dizziness, ataxia, and cognitive impairment. Withhold and then resume at same or reduced dose upon improvement, or permanently discontinue AUGTYRO based on severity. ( 5.1 ) • Interstitial Lung Disease (ILD)/Pneumonitis: Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis. Immediately withhold in patients with suspected ILD/pneumonitis and permanently discontinue if ILD/pneumonitis is confirmed. ( 5.2 ) • Hepatotoxicity: Monitor liver function tests every 2 weeks during the first month of treatment, and as clinically indicated thereafter. Based on severity, withhold and then resume at same or reduced dose, or permanently discontinue. ( 5.3 ) • Myalgia with Creatine Phosphokinase (CPK) Elevation: Monitor serum CPK levels during treatment in patients reporting unexplained muscle pain, tenderness, or weakness. Based on severity, withhold and resume at same or reduced dose upon improvement. ( 5.4 ) • Hyperuricemia: Monitor serum uric acid levels prior to initiating and periodically during treatment. Initiate treatment with urate-lowering medications as clinically indicated. Withhold and resume at same or reduced dose, or permanently discontinue based on severity. ( 5.5 ) • Skeletal Fractures: Promptly evaluate patients with signs or symptoms (e.g., pain, changes in mobility, deformity) of fractures. ( 5.6 ) • Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use an effective non-hormonal method of contraception. ( 5.7 ) 5.1 Central Nervous System Adverse Reactions AUGTYRO can cause central nervous system adverse reactions. Among the 426 patients who received AUGTYRO in Study TRIDENT-1, a broad spectrum of central nervous system (CNS) adverse reactions including dizziness, ataxia, and cognitive disorders occurred in 77% of patients, with Grade 3 or 4 events occurring in 4.5% of patients. Dizziness, including vertigo, occurred in 65% of patients; Grade 3 dizziness occurred in 2.8% of patients. The median time to onset was 7 days (1 day to 1.4 years). Dose interruption was required in 9% of patients, and 11% required dose reduction of AUGTYRO due to dizziness. Ataxia, including gait disturbance and balance disorder, occurred in 28% of patients; Grade 3 ataxia occurred in 0.5% of patients. The median time to onset was 15 days (1 day to 1.4 years). Dose interruption was required in 5% of patients, 8% required dose reduction, and one patient (0.2%) permanently discontinued AUGTYRO due to ataxia. Cognitive impairment, including memory impairment and disturbance in attention, occurred in 25% of patients. Cognitive impairment included memory impairment (15%), disturbance in attention (12%), and confusional state (2%); Grade 3 cognitive impairment occurred in 0.9% of patients. The median time to onset of cognitive disorders was 37 days (1 day to 1.4 years). Dose interruption was required in 2% of patients, 2.1% required dose reduction, and 0.5% patients permanently discontinued AUGTYRO due to cognitive adverse reactions. Mood disorders occurred in 6% of patients. Mood disorders occurring in > 1% of patients included anxiety (2.6%); Grade 4 mood disorders (mania) occurred in 0.2% of patients. Dose interruption was required in 0.2% of patients and 0.2% of patients required a dose reduction due to mood disorders. Sleep disorders including insomnia and hypersomnia occurred in 18% of patients. Sleep disorders observed in > 1% of patients were somnolence (9%), insomnia (6%) and hypersomnia (1.6%). Dose interruption was required in 0.7% of patients, and 0.2% of patients required a dose reduction due to sleep disorders. The incidences of CNS adverse reactions observed were similar in patients with and without CNS metastases. Advise patients and caregivers of the risk of CNS adverse reactions with AUGTYRO. Advise patients not to drive or use machines if they are experiencing CNS adverse reactions. Withhold and then resume at same or reduced dose upon improvement, or permanently discontinue AUGTYRO based on severity [see Dosage and Administration (2.5) ] . 5.2 Interstitial Lung Disease/Pneumonitis AUGTYRO can cause interstitial lung disease (ILD)/pneumonitis. Among the 426 patients treated with AUGTYRO, ILD/pneumonitis (pneumonitis [2.8%] and ILD [0.2%]) occurred in 3.1% of patients; Grade 3 ILD/pneumonitis occurred in 1.2% of patients. The median time to onset was 45 days (19 days to 0.9 years). Dose interruption was required in 1.4% of patients, 0.5% of patients required dose reduction, and 1.1% of patients permanently discontinued AUGTYRO due to ILD/pneumonitis. Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis. Immediately withhold AUGTYRO in patients with suspected ILD/pneumonitis and permanently discontinue AUGTYRO if ILD/pneumonitis is confirmed [see Dosage and Administration (2.5) ] . 5.3 Hepatotoxicity AUGTYRO can cause hepatotoxicity. Among the 426 patients treated with AUGTYRO, increased alanine transaminase (ALT) occurred in 38%, increased aspartate aminotransferase (AST) occurred in 41%, including Grade 3 or 4 increased ALT in 3.3% and increased AST in 2.9%. The median time to onset of increased ALT or AST was 15 days (range: 1 day to 1.9 years). Increased ALT or AST leading to dose interruptions or reductions occurred in 2.8% and 1.2% of patients, respectively. Hyperbilirubinemia leading to dose interruptions occurred in 0.5%. Monitor liver function tests, including ALT, AST and bilirubin, every 2 weeks during the first month of treatment, then monthly thereafter and as clinically indicated. Withhold and then resume at the same or reduced dose upon improvement, or permanently discontinue AUGTYRO based on the severity [see Dosage and Administration (2.5) ]. 5.4 Myalgia with Creatine Phosphokinase Elevation AUGTYRO can cause myalgia with or without creatine phosphokinase (CPK) elevation. Among the 426 patients treated with AUGTYRO, myalgia occurred in 13% of patients, with Grade 3 in 0.7%. Median time to onset of myalgia was 19 days (range: 1 day to 2 years). Concurrent increased CPK within a 7-day window was observed in 3.7% of patients. AUGTYRO was interrupted in one patient with myalgia and concurrent CPK elevation. Advise patients to report any unexplained muscle pain, tenderness, or weakness. Monitor serum CPK levels during AUGTYRO treatment and monitor CPK levels every 2 weeks during the first month of treatment and as needed in patients reporting unexplained muscle pain, tenderness, or weakness. Initiate supportive care as clinically indicated. Based on severity, withhold and then resume AUGTYRO at the same or reduced dose upon improvement [see Dosage and Administration (2.5) ]. 5.5 Hyperuricemia AUGTYRO can cause hyperuricemia. Among the 426 patients treated with AUGTYRO, 21 patients (5%) experienced hyperuricemia reported as an adverse reaction and 0.7% of patients experienced Grade 3 or 4 hyperuricemia. One patient without pre-existing gout required urate-lowering medication. Monitor serum uric acid levels prior to initiating AUGTYRO and periodically during treatment. Initiate treatment with urate-lowering medications as clinically indicated. Withhold and then resume at the same or reduced dose upon improvement, or permanently discontinue AUGTYRO based on severity [see Dosage and Administration (2.5) ]. 5.6 Skeletal Fractures AUGTYRO can cause skeletal fractures. Among 426 adult patients who received AUGTYRO, fractures occurred in 2.3%. Fractures involved the ribs (0.5%), feet (0.5%), spine (0.2%), acetabulum (0.2%), sternum (0.2%), and ankles (0.2%). Some fractures occurred at sites of disease and prior radiation therapy. The median time to fracture was 71 days (range: 31 days to 1.4 years). AUGTYRO was interrupted in 0.3% of patients. Of 26 evaluable patients in an ongoing open-label study in pediatric patients, fractures occurred in one 12-year-old patient (ankle/foot) and one 10-year-old patient (stress fracture). AUGTYRO was interrupted in both patients. AUGTYRO is not approved for use in pediatric patients less than 12 years of age [see Pediatric Use (8.4) ] . Promptly evaluate patients with signs or symptoms (e.g., pain, changes in mobility, deformity) of fractures. There are no data on the effects of AUGTYRO on healing of known fractures and risk of future fractures. 5.7 Embryo-Fetal Toxicity Based on literature reports in humans with congenital mutations leading to changes in tropomyosin receptor tyrosine kinase (TRK) signaling, findings from animal studies, and its mechanism of action, AUGTYRO can cause fetal harm when administered to a pregnant woman. Oral administration of repotrectinib to pregnant rats during the period of organogenesis resulted in fetal malformations at doses approximately 0.3 times the recommended 160 mg twice daily dose based on body surface area (BSA). Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with AUGTYRO and for 2 months following the last dose, since AUGTYRO can render some hormonal contraceptives ineffective [see Drug Interactions (7.2) ] . Advise male patients with female partners of reproductive potential to use effective contraception during treatment with AUGTYRO and for 4 months after the last dose [see Use in Specific Populations (8.1 , 8.3) ] .

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

<table width="100%"><caption>Table 3: Adverse Reactions (&#x2265;10%) in Patients with ROS1-Positive NSCLC or NTRK-Positive Solid Tumors Who Received AUGTYRO in TRIDENT-1</caption><col width="50%"/><col width="26%"/><col width="24%"/><tfoot><tr><td align="left" colspan="3" valign="top">¹ Based on NCI CTCAE v4.03</td></tr><tr><td align="left" colspan="3" valign="top">^a Includes terms dizziness, vertigo, dizziness postural, dizziness exertional, vertigo positional</td></tr><tr><td align="left" colspan="3" valign="top">^b Includes terms dysgeusia, ageusia, anosmia, hypogeusia</td></tr><tr><td align="left" colspan="3" valign="top">^c Includes terms neuralgia, neuropathy peripheral, peripheral sensory neuropathy, dysesthesia, peripheral motor neuropathy, polyneuropathy, paresthesia, hypoesthesia, hyperesthesia </td></tr><tr><td align="left" colspan="3" valign="top">^d Includes terms ataxia, gait disturbance, balance disorder, cerebellar ataxia and coordination abnormal </td></tr><tr><td align="left" colspan="3" valign="top">^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</td></tr><tr><td align="left" colspan="3" valign="top">^f Includes terms headache, migraine, tension headache</td></tr><tr><td align="left" colspan="3" valign="top">^g Includes terms dyspnea and dyspnea exertional</td></tr><tr><td align="left" colspan="3" valign="top">^h Includes terms productive cough, cough, and upper-airway cough syndrome</td></tr><tr><td align="left" colspan="3" valign="top">ⁱ Includes terms pneumonia, pneumonia aspiration, lower respiratory tract infection, pneumonia viral, pneumonia bacterial, lower respiratory tract infection bacterial, pneumonia klebsiella </td></tr><tr><td align="left" colspan="3" valign="top">^j Includes terms fatigue and asthenia </td></tr><tr><td align="left" colspan="3" valign="top">^k Includes terms generalized edema, periorbital edema, localized edema, face edema, edema peripheral, edema, eye edema, scrotal edema</td></tr><tr><td align="left" colspan="3" valign="top">^l Includes terms myalgia, myositis, musculoskeletal discomfort, musculoskeletal pain</td></tr><tr><td align="left" colspan="3" valign="top">^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</td></tr></tfoot><tbody><tr><td rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Adverse Reaction¹</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">AUGTYRO</content></paragraph><paragraph><content styleCode="bold">N=426</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">All Grades (%)</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Grade 3 or 4 (%)</content></paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Nervous System Disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Dizziness^a</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>65</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2.8</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Dysgeusia^b</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>54</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Peripheral neuropathy^c</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>49</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.4</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Ataxia^d</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>28</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.5</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Cognitive impairment^e</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>25</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.9</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Headache^f</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>19</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Gastrointestinal Disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Constipation</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>38</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.2</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Nausea</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>20</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.7</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Diarrhea</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>14</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.7</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Vomiting</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>12</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.2</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Respiratory, Thoracic, and Mediastinal Disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Dyspnea^g</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>30</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>6</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Cough^h</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>18</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.2</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Pneumoniaⁱ</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>11</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>6</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">General Disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Fatigue^j</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>30</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.2</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Edema^k</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>15</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.5</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Decreased appetite</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>11</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.2</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Musculoskeletal and Connective Tissue Disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Muscular weakness</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>20</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Myalgia^l</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>13</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.7</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Metabolism and Nutritional</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Increased weight </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>16</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Eye Disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Vision disorders^m</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>12</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>0.5</paragraph></td></tr></tbody></table>

<table width="95%"><caption>Table 4: Laboratory Abnormalities (&#x2265;20%) that Worsened from Baseline in Patients with ROS1-Positive NSCLC or NTRK-Positive Solid Tumors Who Received AUGTYRO in TRIDENT-1</caption><col width="53%"/><col width="26%"/><col width="21%"/><thead><tr><th align="left" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><content styleCode="bold">Laboratory Abnormality¹</content></th><th align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top">AUGTYRO² N=426</th></tr><tr><th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><content styleCode="bold">All Grades</content> <content styleCode="bold">(%)</content></th><th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><content styleCode="bold">Grade 3 or 4</content> <content styleCode="bold">(%)</content></th></tr></thead><tfoot><tr><td align="left" colspan="3" valign="top">¹ Based on NCI CTCAE v4.03</td></tr><tr><td align="left" colspan="3" valign="top">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.</td></tr></tfoot><tbody><tr><td colspan="3" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Hematology</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph> Decreased hemoglobin </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>79</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>8.4</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph> Decreased lymphocytes </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>43</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>10</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph> Decreased neutrophils </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>34</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>9</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph> Increased activated partial thromboplastin time</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>26</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.3</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph> Increased INR</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>24</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Chemistry</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph> Increased creatine phosphokinase</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>61</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>7</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph> Increased gamma glutamyl transferase</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>50</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>13</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph> Increased aspartate aminotransferase</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>41</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2.9</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph> Increased alanine aminotransferase</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>38</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3.3</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph> Increased sodium </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>33</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.2</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph> Increased alkaline phosphatase</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>29</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2.1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph> Increased glucose</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>26</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2.4</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph> Increased urate</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>23</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>12</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph> Decreased phosphate</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>22</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>6</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph> Increased potassium</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>22</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.7</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph> Decreased glucose</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>20</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>0.2</paragraph></td></tr></tbody></table>