AUGTYRO

Repotrectinib is a kinase inhibitor. The molecular formula for repotrectinib is C 18 H 18 FN 5 O 2 and the molecular weight is 355.37 Daltons. The chemical name is (3R,11S)-6-Fluoro-3,11-dimethyl-10-oxa-2,13,17,18,21-pentaazatetracyclo[13.5.2.0 4,9 .0 18,22 ]docosa-1(21),4,6,8,15(22),16,19-heptaen-14-one. The chemical structure of repotrectinib is as follows: Repotrectinib is a white to off-white powder. AUGTYRO (repotrectinib) capsules for oral use are supplied as printed hard shell capsules containing 40 mg of repotrectinib. Inactive ingredients are microcrystalline cellulose, sodium lauryl sulfate, croscarmellose sodium, and colloidal silicon dioxide. The white opaque capsule shell contains gelatin and titanium dioxide. The printing ink contains shellac and FD & C blue #2 aluminum lake. AUGTYRO (repotrectinib) capsules for oral use are supplied as printed hard shell capsules containing 160 mg of repotrectinib. Inactive ingredients are microcrystalline cellulose, sodium lauryl sulfate, croscarmellose sodium, magnesium stearate, and colloidal silicon dioxide. The blue opaque capsule shell contains gelatin, titanium dioxide and FD & C blue #1. The printing ink contains shellac and titanium dioxide. repo-chem-structure

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).

• Select patients for the treatment of locally advanced or metastatic NSCLC based on the presence of ROS1 rearrangement(s) in tumor specimens. ( 2.1 ) • Select patients for treatment of locally advanced or metastatic solid tumors based on the presence of an NTRK gene fusion. ( 2.1 ) • Recommended Dosage : 160 mg orally once daily for 14 days, then increase to 160 mg twice daily, with or without food. ( 2.4 ) 2.1 Patient Selection NSCLC Select patients for the treatment of locally advanced or metastatic NSCLC with AUGTYRO based on the presence of ROS1 rearrangement(s) in tumor specimens [see Clinical Studies (14.1) ] . An FDA-approved test to detect ROS1 rearrangements for selecting patients for treatment with AUGTYRO is not currently available. Solid Tumors Select patients for the treatment of solid tumors with AUGTYRO based on the presence of NTRK1/2/3 rearrangements in tumor specimens [see Clinical Studies ( 14.2 )] . An FDA-approved test to detect NTRK1/2/3 rearrangements for selecting patients for treatment with AUGTYRO is not currently available. • In patients with secretory breast cancer or mammary analogue secretory cancer, consider treatment without confirmation of NTRK rearrangements in tumor specimens. 2.2 Important Information Prior to Initiating AUGTYRO Prior to initiating AUGTYRO, discontinue strong and moderate CYP3A inhibitors for 3 to 5 elimination half-lives of the CYP3A inhibitor [see Drug Interactions (7.1) , Clinical Pharmacology (12.3) ]. 2.3 Recommended Evaluation and Testing Before Initiating AUGTYRO Prior to initiation of AUGTYRO, evaluate: • liver function tests including bilirubin [see Warnings and Precautions (5.3) ] • uric acid level [see Warnings and Precautions (5.5) ] 2.4 Recommended Dosage The recommended dosage of AUGTYRO for adult and pediatric patients 12 years of age and older is 160 mg taken orally once daily with or without food [see Clinical Pharmacology (12.3) ] for 14 days, then increase to 160 mg twice daily and continue until disease progression or unacceptable toxicity. 2.5 Dosage Modifications for Adverse Reactions The recommended dosage reductions of AUGTYRO for the management of adverse reactions are provided in Table 1. Table 1: Recommended Dose Reductions for AUGTYRO Adverse Reactions Dose Dose Reduction First Second 160 mg Once Daily 120 mg Once Daily 80 mg Once Daily 160 mg Twice Daily 120 mg Twice Daily 80 mg Twice Daily Recommended dosage modifications of AUGTYRO for the management of adverse reactions are provided in Table 2. Table 2: Recommended Dosage Modifications for AUGTYRO Adverse Reactions *Graded per Common Terminology Criteria for Adverse Events v4.03 Adverse Reaction Severity* Dosage Modification Central Nervous System Effects [see Warnings and Precautions (5.1) ] Intolerable Grade 2 • Withhold AUGTYRO until ≤Grade 1 or baseline. • Resume at same or reduced dose, as clinically appropriate. Grade 3 • Withhold AUGTYRO until ≤Grade 1 or baseline. • Resume at reduced dose. Grade 4 • Permanently discontinue AUGTYRO. Interstitial Lung Disease (ILD)/Pneumonitis [see Warnings and Precautions (5.2) ] Any Grade • Withhold AUGTYRO if ILD/pneumonitis is suspected. • Permanently discontinue if ILD/pneumonitis is confirmed. Hepatotoxicity [see Warnings and Precautions (5.3) ] Grade 3 • Withhold AUGTYRO until ≤Grade 1 or baseline. • Resume at same dose if resolution occurs within 4 weeks. • Resume at a reduced dose for recurrent Grade 3 events that resolve within 4 weeks. Grade 4 • Withhold AUGTYRO until ≤Grade 1 or baseline. • Resume at reduced dose. • 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 AUGTYRO. Creatine Phosphokinase (CPK) Elevation [see Warnings and Precautions (5.4) ] CPK elevation greater than 5 times ULN • Withhold until recovery to baseline or to less than or equal to 2.5 times ULN, then resume at same dose. CPK elevation greater than 10 times ULN or second occurrence of CPK elevation of greater than 5 times ULN • Withhold until recovery to baseline or to less than or equal to 2.5 times ULN, then resume at reduced dose. Hyperuricemia [see Warnings and Precautions (5.5) ] Grade 3 or Grade 4 • Withhold AUGTYRO until improvement of signs or symptoms. • Resume AUGTYRO at same or reduced dose. Other Clinically Relevant Adverse Reactions [see Adverse Reactions (6.1) ] Intolerable Grade 2 or Grade 3 or Grade 4 • Withhold AUGTYRO until ≤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. 2.6 Administration Take AUGTYRO at approximately the same time each day with or without food [see Pharmacokinetics (12.3) ]. Swallow AUGTYRO capsules whole. Do not open, chew, crush, or dissolve the capsule prior to swallowing. Do not take any AUGTYRO capsules that are broken, cracked, or damaged. If a dose of AUGTYRO is missed or if vomiting occurs at any time after taking a dose, skip the dose and resume AUGTYRO at its regularly scheduled time.

None. None.

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

• Strong and Moderate CYP3A Inhibitors : Avoid concomitant use. ( 7.1 ) • P-gp inhibitors : Avoid concomitant use. ( 7.1 ) • Strong and Moderate CYP3A Inducers : Avoid concomitant use. ( 7.1 ) • Certain CYP3A Substrates : Avoid concomitant use with CYP3A substrates, where minimal concentration changes can cause reduced efficacy. ( 7.2 ) • Hormonal contraceptives : Avoid concomitant use. ( 7.2 ) 7.1 Effects of Other Drugs on AUGTYRO Strong and Moderate CYP3A Inhibitors Avoid concomitant use with strong or moderate CYP3A inhibitors. Concomitant use of AUGTYRO with a strong or a moderate CYP3A inhibitor may increase repotrectinib exposure, which may increase the incidence and severity of adverse reactions of AUGTYRO. Discontinue CYP3A inhibitors for 3 to 5 elimination half-lives of the CYP3A inhibitor prior to initiating AUGTYRO [see Clinical Pharmacology (12.3) ] . P-gp Inhibitors Avoid concomitant use with P-gp inhibitors. Concomitant use of AUGTYRO with a P-gp inhibitor may increase repotrectinib exposure, which may increase the incidence and severity of adverse reactions of AUGTYRO [see Clinical Pharmacology (12.3) ] . Strong and Moderate CYP3A Inducers Avoid concomitant use with strong or moderate CYP3A inducers. Concomitant use of AUGTYRO with a strong or moderate CYP3A inducer may decrease repotrectinib plasma concentrations, which may decrease efficacy of AUGTYRO [see Clinical Pharmacology (12.3) ] . 7.2 Effects of AUGTYRO on Other Drugs Certain CYP3A4 Substrates Avoid concomitant use unless otherwise recommended in the Prescribing Information for CYP3A substrates, where minimal concentration changes can cause reduced efficacy. If concomitant use is unavoidable, increase the CYP3A4 substrate dosage in accordance with approved product labeling. Repotrectinib is a CYP3A4 inducer. Concomitant use of repotrectinib decreases the concentration of CYP3A4 substrates [see Clinical Pharmacology (12.3) ] , which can reduce the efficacy of these substrates. Contraceptives Repotrectinib is a CYP3A4 inducer, which can decrease progestin or estrogen exposure to an extent that could reduce the effectiveness of hormonal contraceptives. Avoid concomitant use of AUGTYRO with hormonal contraceptives [see Use in Specific Populations (8.1 , 8.3) ] . Advise females of reproductive potential to use an effective nonhormonal contraceptive [see Use in Specific Populations (8.1 , 8.3) ] .