Augtyro

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

4 CONTRAINDICATIONS None. None.

11 DESCRIPTION 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

2 DOSAGE AND ADMINISTRATION • 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.

7 DRUG INTERACTIONS • 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) ] .

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Repotrectinib is an inhibitor of proto-oncogene tyrosine-protein kinase ROS1 (ROS1) and of the tropomyosin receptor tyrosine kinases (TRKs) TRKA, TRKB, and TRKC. Fusion proteins that include ROS1 or TRK domains can drive tumorigenic potential through hyperactivation of downstream signaling pathways leading to unconstrained cell proliferation. Repotrectinib exhibited anti-tumor activity in cultured cells expressing ROS1 fusions and mutations including SDC4-ROS1, SDC4-ROS1 G2032R , CD74-ROS1, CD74-ROS1 G2032R , CD74-ROS1 D2033N , and CD74-ROS1 L2026M . Repotrectinib also inhibited cell proliferation in cultured cells expressing NTRK fusions and mutations including LMNA-TRKA, LMNA-TRKA G595R , EVT6-TRKB G639R , and ETV6-TRKC G623R . 12.2 Pharmacodynamics Repotrectinib exposure-response relationships and the time course of pharmacodynamic responses are not fully characterized. Cardiac Electrophysiology AUGTYRO does not cause a mean increase in the QTc interval > 20 milliseconds (ms) at 160 mg QD followed by 160 mg BID, the approved recommended dosage. 12.3 Pharmacokinetics The geometric mean (CV%) of repotrectinib steady state peak concentration (C max,ss ) is 713 (32.5%) ng/mL and the area under the time concentration curve (AUC 0-24h,ss ) is 7210 (40.1%) ng•h/mL following the approved recommended twice daily dosage in patients with cancer. Repotrectinib C max and AUC 0-inf increases approximately dose proportional (but less than linear with estimated slopes of 0.78 and 0.70, respectively) over the single dose range of 40 mg to 240 mg (0.25 to 1.5 times the approved recommended dosage). Steady state PK was time-dependent with an autoinduction of CYP3A4. Steady state is achieved within 14 days of daily administration of 160 mg. Absorption The geometric mean (CV%) absolute bioavailability of repotrectinib is 45.7% (19.6%). Peak repotrectinib concentration occurred at approximately 2 to 3 hours post a single oral dose of 40 mg to 240 mg (0.25 to 1.5 times the approved recommended dosage) under fasted conditions. Effect of Food No clinically significant differences in repotrectinib pharmacokinetics were observed in patients with cancer following administration of a high-fat meal (approximately 800-1000 calories, 50% fat). Distribution The geometric mean (CV%) apparent volume of distribution (Vz/F) was 432 L (55.9 %) in patients with cancer following a single 160 mg oral dose of AUGTYRO. AUGTYRO binding to plasma protein was 95.4% in vitro . The blood-to-plasma ratio was 0.56 in vitro . Elimination Repotrectinib elimination is time-dependent due to autoinduction of CYP3A4. The repotrectinib mean terminal half-life is approximately 60.7 h for patients with cancer following a single dose. The steady state repotrectinib terminal half-life is approximately 40.3 h for patients with cancer. The geometric mean (CV%) apparent oral clearance (CL/F) was 15.9 L/h (45.5%) in patients with cancer following a single 160 mg oral dose of AUGTYRO. Metabolism Repotrectinib is primarily metabolized by CYP3A4 followed by secondary glucuronidation. Excretion Following a single oral 160 mg dose of radiolabeled repotrectinib, 4.84% (0.56% as unchanged) was recovered in urine and 88.8% (50.6% unchanged) in feces. Specific Populations No clinically significant differences in the pharmacokinetics of repotrectinib were observed based on age (12 to 93 years), sex, race (White 50%, Asian 38%, Black 7%), mild to moderate renal impairment (eGFR 30 to < 90 mL/min), or mild hepatic impairment (total bilirubin >1 to 1.5 times ULN or AST > ULN). The effect of moderate (total bilirubin >1.5 to 3 times ULN with any AST) or severe (total bilirubin >3 x ULN with any AST) hepatic impairment, severe renal impairment, kidney failure (eGFR < 30 mL/min), or dialysis on repotrectinib pharmacokinetics is unknown or not fully characterized. Drug Interaction Studies Clinical Studies Strong CYP3A and P-gp inhibitors: Repotrectinib AUC 0-inf increased by 5.9-fold and C max by 1.7-fold following concomitant use with itraconazole (strong CYP3A and P-gp inhibitor). Strong CYP3A and P-gp inducers: Repotrectinib AUC 0-inf decreased by 92% and C max by 79% following concomitant use with rifampin (strong CYP3A and P-gp inducer). CYP3A substrates: Midazolam (CYP3A substrate AUC 0-inf decreased by 69% and C max by 48% following concomitant use in subjects who were previously administered 160 mg repotrectinib once daily for 14 days followed by 160 mg twice daily for 7 days. In vitro Studies CYP Enzymes: Repotrectinib induces CYP3A4, CYP2B6, CYP2C8, CYP2C19, CYP2C9 and inhibits CYP3A4/5 (GI tract). Repotrectinib does not induce CYP1A2. Other Metabolic Pathways: Repotrectinib inhibits UGT1A1. Transporter Systems: Repotrectinib inhibits P-gp, BCRP, OATP1B1, and MATE2-K. Repotrectinib is a substrate for P-gp.

12.1 Mechanism of Action Repotrectinib is an inhibitor of proto-oncogene tyrosine-protein kinase ROS1 (ROS1) and of the tropomyosin receptor tyrosine kinases (TRKs) TRKA, TRKB, and TRKC. Fusion proteins that include ROS1 or TRK domains can drive tumorigenic potential through hyperactivation of downstream signaling pathways leading to unconstrained cell proliferation. Repotrectinib exhibited anti-tumor activity in cultured cells expressing ROS1 fusions and mutations including SDC4-ROS1, SDC4-ROS1 G2032R , CD74-ROS1, CD74-ROS1 G2032R , CD74-ROS1 D2033N , and CD74-ROS1 L2026M . Repotrectinib also inhibited cell proliferation in cultured cells expressing NTRK fusions and mutations including LMNA-TRKA, LMNA-TRKA G595R , EVT6-TRKB G639R , and ETV6-TRKC G623R .

12.2 Pharmacodynamics Repotrectinib exposure-response relationships and the time course of pharmacodynamic responses are not fully characterized. Cardiac Electrophysiology AUGTYRO does not cause a mean increase in the QTc interval > 20 milliseconds (ms) at 160 mg QD followed by 160 mg BID, the approved recommended dosage.

12.3 Pharmacokinetics The geometric mean (CV%) of repotrectinib steady state peak concentration (C max,ss ) is 713 (32.5%) ng/mL and the area under the time concentration curve (AUC 0-24h,ss ) is 7210 (40.1%) ng•h/mL following the approved recommended twice daily dosage in patients with cancer. Repotrectinib C max and AUC 0-inf increases approximately dose proportional (but less than linear with estimated slopes of 0.78 and 0.70, respectively) over the single dose range of 40 mg to 240 mg (0.25 to 1.5 times the approved recommended dosage). Steady state PK was time-dependent with an autoinduction of CYP3A4. Steady state is achieved within 14 days of daily administration of 160 mg. Absorption The geometric mean (CV%) absolute bioavailability of repotrectinib is 45.7% (19.6%). Peak repotrectinib concentration occurred at approximately 2 to 3 hours post a single oral dose of 40 mg to 240 mg (0.25 to 1.5 times the approved recommended dosage) under fasted conditions. Effect of Food No clinically significant differences in repotrectinib pharmacokinetics were observed in patients with cancer following administration of a high-fat meal (approximately 800-1000 calories, 50% fat). Distribution The geometric mean (CV%) apparent volume of distribution (Vz/F) was 432 L (55.9 %) in patients with cancer following a single 160 mg oral dose of AUGTYRO. AUGTYRO binding to plasma protein was 95.4% in vitro . The blood-to-plasma ratio was 0.56 in vitro . Elimination Repotrectinib elimination is time-dependent due to autoinduction of CYP3A4. The repotrectinib mean terminal half-life is approximately 60.7 h for patients with cancer following a single dose. The steady state repotrectinib terminal half-life is approximately 40.3 h for patients with cancer. The geometric mean (CV%) apparent oral clearance (CL/F) was 15.9 L/h (45.5%) in patients with cancer following a single 160 mg oral dose of AUGTYRO. Metabolism Repotrectinib is primarily metabolized by CYP3A4 followed by secondary glucuronidation. Excretion Following a single oral 160 mg dose of radiolabeled repotrectinib, 4.84% (0.56% as unchanged) was recovered in urine and 88.8% (50.6% unchanged) in feces. Specific Populations No clinically significant differences in the pharmacokinetics of repotrectinib were observed based on age (12 to 93 years), sex, race (White 50%, Asian 38%, Black 7%), mild to moderate renal impairment (eGFR 30 to < 90 mL/min), or mild hepatic impairment (total bilirubin >1 to 1.5 times ULN or AST > ULN). The effect of moderate (total bilirubin >1.5 to 3 times ULN with any AST) or severe (total bilirubin >3 x ULN with any AST) hepatic impairment, severe renal impairment, kidney failure (eGFR < 30 mL/min), or dialysis on repotrectinib pharmacokinetics is unknown or not fully characterized. Drug Interaction Studies Clinical Studies Strong CYP3A and P-gp inhibitors: Repotrectinib AUC 0-inf increased by 5.9-fold and C max by 1.7-fold following concomitant use with itraconazole (strong CYP3A and P-gp inhibitor). Strong CYP3A and P-gp inducers: Repotrectinib AUC 0-inf decreased by 92% and C max by 79% following concomitant use with rifampin (strong CYP3A and P-gp inducer). CYP3A substrates: Midazolam (CYP3A substrate AUC 0-inf decreased by 69% and C max by 48% following concomitant use in subjects who were previously administered 160 mg repotrectinib once daily for 14 days followed by 160 mg twice daily for 7 days. In vitro Studies CYP Enzymes: Repotrectinib induces CYP3A4, CYP2B6, CYP2C8, CYP2C19, CYP2C9 and inhibits CYP3A4/5 (GI tract). Repotrectinib does not induce CYP1A2. Other Metabolic Pathways: Repotrectinib inhibits UGT1A1. Transporter Systems: Repotrectinib inhibits P-gp, BCRP, OATP1B1, and MATE2-K. Repotrectinib is a substrate for P-gp.

20240613

5

3 DOSAGE FORMS AND STRENGTHS Capsules: 40 mg, white, opaque, immediate release, Size 0, hard shell capsule, filled with white to off-white powder which may appear as a plug, imprinted with “REP 40” in blue text on the cap. Capsules: 160 mg, blue, opaque, immediate release, Size 0, hard shell capsule, filled with white to off-white powder which may appear as a plug, imprinted with “REP 160” in white text on the cap. Capsules: 40 mg, 160 mg ( 3 )

Augtyro repotrectinib REPOTRECTINIB REPOTRECTINIB MICROCRYSTALLINE CELLULOSE SODIUM LAURYL SULFATE CROSCARMELLOSE SODIUM SILICON DIOXIDE OPAQUE REP;40 Augtyro repotrectinib REPOTRECTINIB REPOTRECTINIB MICROCRYSTALLINE CELLULOSE SODIUM LAURYL SULFATE CROSCARMELLOSE SODIUM SILICON DIOXIDE MAGNESIUM STEARATE OPAQUE REP;160

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies with repotrectinib were not conducted. Repotrectinib was genotoxic in an in vitro assay in human lymphoblastoid TK6 cells and in an in vivo rat bone marrow micronucleus assay via an aneugenic mechanism of action. Repotrectinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay. Dedicated fertility studies were not conducted with repotrectinib. There were no effects on male and female reproductive organs observed in general repeat-dose toxicology studies of up to 3 months in duration in rats and monkeys at any dose level tested, which equated to exposures of up to approximately 3 times the human exposure at the 160 mg twice daily dose based on AUC.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies with repotrectinib were not conducted. Repotrectinib was genotoxic in an in vitro assay in human lymphoblastoid TK6 cells and in an in vivo rat bone marrow micronucleus assay via an aneugenic mechanism of action. Repotrectinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay. Dedicated fertility studies were not conducted with repotrectinib. There were no effects on male and female reproductive organs observed in general repeat-dose toxicology studies of up to 3 months in duration in rats and monkeys at any dose level tested, which equated to exposures of up to approximately 3 times the human exposure at the 160 mg twice daily dose based on AUC.

NDA218213

Augtyro

repotrectinib

0003-4040

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL NDC 0003-4160-14 14 Capsules AUGTYRO TM (repotrectinib) capsules 160mg Swallow capsules whole Rx only Bristol Myers Squibb NDC 0003-4160-14 14 Capsules AUGTYRO TM (repotrectinib) capsules 160mg Swallow capsules whole Rx only Bristol Myers Squibb NDC 0003-4040-60 60 Capsules AUGTYRO TM (repotrectinib) capsules 40mg Swallow capsules whole Rx only Bristol Myers Squibb NDC 0003-4040-60 60 Capsules AUGTYRO TM (repotrectinib) capsules 40mg Swallow capsules whole Rx only Bristol Myers Squibb NDC 0003-4040-12 120 Capsules AUGTYRO TM (repotrectinib) capsules 40mg Swallow capsules whole Rx only Bristol Myers Squibb Augtyro 160 mg capsules_2.PNG Augtyro 160 mg\augtyro 160 mg_1.PNG repo-40mg-60ct-btl-lbl repo-40mg-60ct-car repo-40mg-120ct-btl-lbl

Indications and Usage ( 1.2 ) 06/2024 Dosage and Administration ( 2.1 ) 06/2024 Warnings and Precautions ( 5.6 ) 06/2024

17 PATIENT COUNSELING INFORMATION Advise patients to read the FDA-approved patient labeling (Patient Information). Central Nervous System (CNS) Effects • Advise patients to inform their healthcare provider if they experience new or worsening CNS symptoms. Instruct patients not to drive or operate hazardous machinery if they are experiencing CNS adverse reactions [see Warnings and Precautions (5.1) ] . Interstitial Lung Disease (ILD)/Pneumonitis • Advise patients to inform their healthcare provider if they experience new or worsening pulmonary symptoms indicative of ILD/pneumonitis [see Warnings and Precautions (5.2) ] . Hepatotoxicity • Advise patients of the need for laboratory tests to monitor liver function and to immediately report symptoms of hepatotoxicity [see Warnings and Precautions (5.3) ] . Myalgia with Creatine Phosphokinase Elevation • Advise patients to inform their healthcare provider if they experience muscle pain [see Warnings and Precautions (5.4) ] . Hyperuricemia • Advise patients to inform their healthcare provider if they experience signs or symptoms associated with hyperuricemia [see Warnings and Precautions (5.5) ] . Skeletal Fractures • Inform patients that bone fractures have occurred in patients taking AUGTYRO and advise patients to report symptoms to their healthcare provider [see Warnings and Precautions (5.6) ] . Embryo-Fetal Toxicity • Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.7) , Use in Specific Populations (8.1 , 8.3) ] . • Advise females of reproductive potential to use effective non-hormonal contraception during treatment with AUGTYRO and for 2 months after 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) ] . Lactation • Advise females not to breastfeed during treatment with AUGTYRO and for 10 days after the last dose [see Use in Specific Populations (8.2) ] . Drug Interactions • Advise patients to inform their healthcare providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions (7) ] . • Advise patients to avoid grapefruit or grapefruit juice while taking AUGTYRO [see Drug Interactions (7) ] . • Advise patients that hormonal contraceptives can be ineffective while taking AUGTYRO [see Drug Interactions (7) ] . Administration • Advise patients to swallow AUGTYRO capsules whole with or without food [see Dosage and Administration (2.6) , Pharmacokinetics (12.3) ] . • Instruct patients if they miss a dose, or vomit at any time after taking a dose of AUGTYRO, not to “make it up,” but take the next dose of AUGTYRO at the next scheduled time [see Dosage and Administration (2.6) ] . For more information, go to www.AUGTYRO.com or call 1-877-284-8976. Distributed by: Bristol-Myers Squibb Company Princeton, NJ 08543 USA U.S. License No. 1713 AUGTYRO TM is a trademark of Turning Point Therapeutics, Inc., a Bristol Myers Squibb company.

14 CLINICAL STUDIES 14.1 Locally Advanced or Metastatic ROS1 -Positive NSCLC The efficacy of AUGTYRO was evaluated in TRIDENT-1, a multicenter, single-arm, open-label, multi-cohort clinical trial (NCT03093116). Patients were required to have ROS1- positive locally advanced or metastatic NSCLC, ECOG performance status ≤1, measurable disease per RECIST v 1.1, and ≥8 months from first dose. All patients were assessed for CNS lesions at baseline, and patients with symptomatic brain metastases were excluded from the trial. Patients received AUGTYRO 160 mg orally once daily for 14 days, then increased to 160 mg twice daily until disease progression or unacceptable toxicity. Tumor assessments were performed at least every 8 weeks. Identification of ROS1 gene fusions in tumor specimens was prospectively determined in local laboratories using next-generation sequencing (NGS), polymerase chain reaction (PCR) or fluorescence in situ hybridization (FISH) tests. All ROS1 -positive patients by local FISH testing required central laboratory confirmation of ROS1 fusion using an analytically validated NGS test. ROS1 fusions were identified by NGS in 51%, FISH in 26%, and PCR in 23%. The major efficacy outcome measures were overall response rate (ORR) and duration of response (DOR) according to RECIST v1.1 as assessed by blinded independent central review (BICR). Intracranial response according to modified RECIST v1.1 was assessed by BICR. Tumor assessments with imaging were performed every 8 weeks. The efficacy populations included 71 ROS1 TKI-naïve patients who received up to 1 prior line of platinum-based chemotherapy and/or immunotherapy and 56 patients who received 1 prior ROS1 TKI with no prior platinum-based chemotherapy or immunotherapy. Among the 71 ROS1 TKI-naïve patients, the median age was 57 years (range: 28 to 80); female (60.6%); Asian (67.6%), White (25.4%), Hispanic or Latino (4.2%), Black or African American (1.4%); never smoked (63.4%); and ECOG performance status of 1 at baseline (66.2%). At baseline, 94.4% of patients had metastatic disease, 25.4% of patients had CNS metastases by BICR; 97.2% had adenocarcinoma; and 28.2% patients had prior chemotherapy consisting of platinum-based chemotherapy and/or immunotherapy for locally advanced or metastatic disease. Among the 56 patients who had received 1 prior ROS1 TKI (including crizotinib [82%] and entrectinib [16%]) with no prior platinum-based chemotherapy or immunotherapy, the median age was 57 years (range: 33 – 78); female (67.9%); Asian (48.2%), White (44.6%), Black or African American and Hispanic or Latino (1.8% each); never smoked (64.3%); and ECOG performance status of 1 at baseline (67.9%). At baseline, 98.2% patients had metastatic disease, 42.9% with CNS metastases by BICR, and 94.6% had adenocarcinoma. Efficacy results are summarized in Table 5. Table 5: Efficacy Results for Patients with ROS1-Positive NSCLC in TRIDENT-1 Abbreviations: CI = confidence interval; NE = not evaluable; “+” indicates ongoing response a DOR results are based on the updated data as of 19 December 2022. b Median DOR (95% CI) are based on Kaplan-Meier estimates. c DOR landmark analysis is based on the observed DOR. Efficacy Parameters ROS1 Inhibitor Naïve Patients (N=71) ROS1 Inhibitor Pretreated Patients (N=56) Confirmed Overall Response Rate, % (95% CI) 79% (68, 88) 38% (25, 52) Complete Response 6% 5% Partial Response 73% 32% Duration of Response (DOR) a Median in Months (95% CI) b 34.1 (25.6, NE) 14.8 (7.6, NE) Range (months) 1.4+, 42.4+ 3.6, 22.9+ % DOR ≥12 months c 70 48 Among TKI-naïve patients, 8 had measurable CNS metastases at baseline as assessed by BICR; responses in intracranial lesions were observed in 7 of these 8 patients. Among the TKI pretreated patients with no prior platinum-based chemotherapy, 12 had measurable CNS metastases at baseline as assessed by BICR; responses in intracranial lesions were observed in 5 of these 12 patients. Among the 56 ROS1 inhibitor-pretreated patients, 8 had resistance mutations following TKI therapy. Responses were observed in 6 of these 8 patients; responders included patients with solvent front ( ROS1 G2032R ), gatekeeper ( ROS1 L2026M ), and other mutations ( ROS1 S1986F/Y ). 14.2 Locally Advanced or Metastatic NTRK Gene Fusion-Positive Solid Tumors The efficacy of AUGTYRO was evaluated in TRIDENT-1 (NCT03093116), a multi-center, single-arm, open-label, multi-cohort clinical trial in 88 adult patients with locally advanced or metastatic NTRK gene fusion-positive ( NTRK1/2/3 ) solid tumors who had either received a prior TKI treatment or were TKI-naïve. All patients were assessed for CNS lesions at baseline, and patients with symptomatic brain metastases were excluded from the trial. Patients received AUGTYRO 160 mg orally once daily for 14 days, then increased to 160 mg twice daily until disease progression or unacceptable toxicity. Tumor assessments were performed every 8 weeks. NTRK gene fusions were identified prospectively using NGS in 94%, FISH in 5%, and PCR in 1%. NTRK gene fusion-positive tumors identified by local FISH testing required central laboratory confirmation using an analytically validated NGS test. The major efficacy outcome measures were ORR and DOR according to RECIST v1.1 as assessed by BICR. Intracranial response according to modified RECIST v1.1 was assessed by BICR. Among the 40 TRK TKI-naïve patients, the median age was 61 years (range: 25 to 84); 60% were female patients; race was Asian 53%, White 25%, Black or African American 5%, and other or not reported 18%; ethnicity was Hispanic or Latino 5%, not Hispanic or Latino 87%, and not reported 8%; and ECOG performance status of 1 at baseline was 55%. At baseline, 98% of patients had metastatic disease and 23% of patients had CNS metastases by BICR. Seventy percent (n=28) of patients received prior systemic therapy with a median of one prior systemic regimen, and 7.5% (n=3) received three or more prior systemic regimens. Among the 48 TRK TKI-pretreated patients, the median age was 58 years (range: 20 to 81); 48% were female patients; race was White 65%, Asian 25%, Black or African American 2%, and not reported 8%; ethnicity was not Hispanic or Latino 92%, and missing 8%; and ECOG performance status of 1 at baseline was 60%. At baseline, 96% of patients had metastatic disease and 25% of patients had CNS metastases by BICR. Seventy-seven percent (n=37) of patients received 2 or more prior systemic regimens, and 46% (n=22) received three or more prior systemic regimens, and 7 patients (15%) received 2 prior TKI therapies. Efficacy results are summarized in Table 6. Table 6: Efficacy Results for Patients with NTRK Gene Fusion-Positive Tumors in TRIDENT-1 NE = not evaluable; “+” indicates ongoing response a Median DOR (95% CI) are based on Kaplan-Meier estimates. b DOR landmark analysis is based on the observed DOR. Efficacy Parameters TKI-Naïve Patients (n=40) TKI-Pretreated Patients (n=48) Confirmed Overall Response Rate , % (95% CI) 58 (41, 73) 50 (35, 65) Complete Response, % 15 0 Partial Response, % 43 50 Median Duration of Response (mDOR) a , in Months (95% CI) NE (NE, NE) 9.9 (7.4, 13.0) Range (months) 3.7+, 43.9+ 1.8, 26.5+ % with DOR ≥ 6 months b 87 71 % with DOR ≥ 9 months b 83 63 % with DOR ≥ 12 months b 83 42 Among the 88 patients, 5 had measurable CNS metastases at baseline as assessed by BICR. Responses were seen in 2 (100%) TKI-naïve patients and 3 (100%) TKI-pretreated patients. One out of 2 TKI-naïve and 2 out of 3 TKI-pretreated patients received prior radiotherapy to the brain, all more than 2 months prior to study entry. Twenty-six of the TRK TKI-pretreated patients had a resistance mutation at baseline, including 24 with solvent front mutations ( NTRK1 G595R and NTRK3 G623L/R/E/V mutations), one with both a solvent front mutation and a gatekeeper mutation ( NTRK1 F589L ), and one with another mutation ( NTRK1 G667C ). In the 25 TKI-pretreated patients with solvent front mutations at baseline, ORR was 60% (95% CI: 39, 79). ORR and DOR by tumor type in adult patients with NTRK gene fusion-positive solid tumors are presented in Tables 7 and 8 below. Table 7: Efficacy Results by Tumor Type in TKI-naïve NTRK Gene Fusion Patients * Includes esophageal cancer and head and neck cancer PD: progressive disease; PR: partial response; SD: stable disease; NA: not applicable “+” indicates ongoing response Tumor type Patients (n=40) ORR DOR n (%) 95% CI Range (months) NSCLC 21 13 (62) 38, 82 3.7+, 31.3+ Thyroid Cancer 5 5 (100) 48, 100 4.7, 43.9+ Salivary Gland Cancer 3 3 (100.0) 29, 100 17.7+, 31.4+ Secretory carcinoma 1 PR NA 23.0+ Sarcoma, Soft tissue 3 1 (33) 0.8, 91 14.7+ Breast Cancer (adenocarcinoma) 2 PD, PD NA NA Other* 2 SD, SD NA NA Glioblastoma 1 SD NA NA Cholangiocarcinoma 1 PD NA NA Colorectal cancer 1 SD NA NA Peripheral Nerve Sheath Tumor 1 PR NA 23.0+ Table 8: Efficacy Results by Tumor Type in TKI-pretreated NTRK Gene Fusion-Positive Patients * Includes gallbladder cancer and unknown primary cancer PD: progressive disease; PR: partial response; SD: stable disease; NA: not applicable “+” indicates ongoing response Tumor type Patients (n=48) ORR DOR n (%) 95% CI Range (months) NSCLC 14 6 (43) 18, 71 1.9, 23.0+ Salivary Gland Cancer 8 7 (88) 47, 100 3.7, 26.5+ Secretory carcinoma 3 3 (100) 29, 100 7.9, 26.5+ Sarcoma, Soft tissue 6 1 (17) 0.4, 64 5.6 Thyroid Cancer 4 2 (50) 7, 93 2.0, 9.6 Glioblastoma 3 1 (33.3) 0.8, 91 23.5 Cholangiocarcinoma 2 PR, PD NA 1.8 Colorectal cancer 2 PR, SD NA 17.5 Peripheral Nerve Sheath Tumor 2 PR, PR NA 5.5, 11.1 Neuroendocrine Tumor 2 PR, PR NA 5.5, 9.1 Pancreatic Cancer 2 PD, PD NA NA Other* 2 SD, PD NA NA Breast Cancer (adenocarcinoma) 1 PR NA 15.6+ ORR and DOR in adult patients are presented by NTRK gene fusion partner Tables 9 and 10 below. Table 9: Efficacy Results by NTRK Gene Fusion Partner in TRK TKI-Naïve Patients PD: progressive disease; PR: partial response; SD: stable disease; NA: not applicable “+” indicates ongoing response NTRK Partner Subjects (n=40) ORR DOR n (%) 95% CI Range (Months) ETV6-NTRK3 12 9 (75) (43, 95) 4.7, 31.4+ TPM3-NTRK1 7 5 (71) (29, 96) 3.8, 23.1+ EML4-NTRK3 2 Missing, PR NA 14.8+ IRF2BP2-NTRK1 2 PR, PR NA 3.7+, 20.3+ PEAR1-NTRK1 2 Missing, PD NA NA Unknown 2 PD, SD NA NA ATP2B2-IT2-NTRK1 1 SD NA NA GOLGB1-NTRK1 1 SD NA NA IL1RL2-NTRK2 1 SD NA NA LRPPRC-NTRK3 1 SD NA NA LRRC71-NTRK1 1 Missing NA NA Multiple 1 PR NA 28.6+ RBPMS-NTRK3 1 PR NA 34.3+ SLC28A3-NTRK2 1 PD NA NA SQSTM1-NTRK1 1 PR NA 15.7+ STRN3-NTRK1 1 PR NA 23.9+ TMED3-NTRK3 1 PD NA NA TPR-NTRK1 1 PR NA 43.9+ TRIM33-NTRK1 1 CR NA 17.8+ Table 10: Efficacy Results by NTRK Gene Fusion Partner in TRK TKI-Pretreated Subjects PR = partial response; PD = progressive disease; SD = stable disease; NA = not applicable; NE = not evaluable “+” indicates ongoing response NTRK Partner Subjects (n=48) ORR DOR n (%) 95% CI Range (Months) ETV6-NTRK3 24 16 (67) (45, 84) 1.8, 26.5+ EML4-NTRK3 5 4 (80) (28, 99) 1.9, 12.9 LMNA-NTRK1 4 1 (25) (0.6, 81) 5.6 TPM3-NTRK1 3 0 (0) (0, 71) NA ATP1B1-NTRK1 1 PD NA NA BCR-NTRK2 1 SD NA NA ETV6-NTRK2 1 NE NA NA GP2-NTRK1 1 PD NA NA IRF2BP2-NTRK1 1 Missing NA NA KANK2-NTRK2 1 PR NA 23.5 Multiple 1 PD NA NA PRDX1-NTRK1 1 Missing NA NA RBPMS-NTRK3 1 PD NA NA SEL1L-NTRK1 1 PD NA NA SQSTM1-NTRK3 1 PR NA 5.5 STRN3-NTRK3 1 PR NA 11.1

8.5 Geriatric Use Of the 426 patients who received AUGTYRO, in the TRIDENT-1 study for ROS1 -positive non-small cell lung cancer or NTRK gene fusion-positive solid tumors, 19% were 65 to 75 years old, and 6% were 75 years of age or older. There were no clinically meaningful differences in safety and efficacy between patients younger than 65 years of age and patients 65 years of age or older.

8.4 Pediatric Use The safety and effectiveness of AUGTYRO in pediatric patients with ROS1 -positive NSCLC have not been established. The safety and effectiveness of AUGTYRO have not been established in pediatric patients younger than 12 years of age with solid tumors who have an NTRK gene fusion. The safety and effectiveness of AUGTYRO for the treatment of locally advanced or metastatic NTRK -positive solid tumors have been established in pediatric patients 12 years of age or older. Use of AUGTYRO in this age group is supported by evidence from an adequate and well-controlled study in adult patients with additional pharmacokinetic and safety data in pediatric patients aged 12 years and older. This includes data demonstrating that the exposure of repotrectinib in pediatric patients 12 years of age and older is expected to result in similar safety and efficacy to that of adults, and that the course of locally advanced or metastatic NTRK -positive solid tumors is sufficiently similar in adults and pediatric patients 12 years of age or older to allow extrapolation of data in adult to pediatric patients 12 years of age or older [see Dosage and Administration (2.4) , Warnings and Precautions (5.7) , Adverse Reactions (6.1) and Clinical Pharmacology (12.3) ] . Juvenile Animal Data Daily oral administration of repotrectinib to juvenile rats for 8 weeks starting on postnatal day 12 (approximately equal to a human pediatric age of a newborn) resulted in toxicities similar to those observed in adult rats, though juvenile animals showed decreased body weight gain at doses ≥1 mg/kg (approximately ≥0.04 times the human exposure based on AUC at the recommended clinical dose of 160 mg BID) and decreased femur lengths at 3 mg/kg (approximately 0.1 times the human exposure based on AUC at the recommended clinical dose of 160 mg BID). Decreased body weight gain and decreased femur lengths persisted following 4 weeks of recovery.

8.1 Pregnancy Risk Summary Based on literature reports in humans with congenital mutations leading to changes in TRK signaling, findings from animal studies, and its mechanism of action [see Clinical Pharmacology (12.1) ], AUGTYRO can cause fetal harm when administered to a pregnant woman. There are no available data on AUGTYRO use in pregnant women. Oral administration of repotrectinib to pregnant rats during the period of organogenesis resulted in fetal malformations at doses approximately 0.3 times the recommended dose of 160 mg twice daily based on BSA (see Data) . Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Human Data Published reports of individuals with congenital mutations in TRK pathway proteins suggest that decreases in TRK-mediated signaling are correlated with obesity, developmental delays, cognitive impairment, insensitivity to pain, and anhidrosis. Animal Data In an embryo-fetal development study, once daily oral administration of repotrectinib to pregnant rats during the period of organogenesis from gestation day 6 to 17 resulted in maternal effects of increased body weight and skin abrasions/ulcerations at doses ≥6 mg/kg, fetal malformations of malrotated hindlimbs and lower fetal body weights at doses ≥12 mg/kg [approximately 0.3 times the recommended dose of 160 mg twice daily based on BSA]. No embryolethality was observed.

8 USE IN SPECIFIC POPULATIONS • Lactation : Advise not to breastfeed. ( 8.2 ) 8.1 Pregnancy Risk Summary Based on literature reports in humans with congenital mutations leading to changes in TRK signaling, findings from animal studies, and its mechanism of action [see Clinical Pharmacology (12.1) ], AUGTYRO can cause fetal harm when administered to a pregnant woman. There are no available data on AUGTYRO use in pregnant women. Oral administration of repotrectinib to pregnant rats during the period of organogenesis resulted in fetal malformations at doses approximately 0.3 times the recommended dose of 160 mg twice daily based on BSA (see Data) . Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Human Data Published reports of individuals with congenital mutations in TRK pathway proteins suggest that decreases in TRK-mediated signaling are correlated with obesity, developmental delays, cognitive impairment, insensitivity to pain, and anhidrosis. Animal Data In an embryo-fetal development study, once daily oral administration of repotrectinib to pregnant rats during the period of organogenesis from gestation day 6 to 17 resulted in maternal effects of increased body weight and skin abrasions/ulcerations at doses ≥6 mg/kg, fetal malformations of malrotated hindlimbs and lower fetal body weights at doses ≥12 mg/kg [approximately 0.3 times the recommended dose of 160 mg twice daily based on BSA]. No embryolethality was observed. 8.2 Lactation Risk Summary There are no data on the presence of AUGTYRO in human milk or its effects on either the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children from AUGTYRO, advise a lactating woman to discontinue breastfeeding during treatment with AUGTYRO and for 10 days after the last dose. 8.3 Females and Males of Reproductive Potential AUGTYRO can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ] . Pregnancy Testing Verify the pregnancy status of females of childbearing potential prior to initiating AUGTYRO [see Use in Specific Populations (8.1) ] . Contraception AUGTYRO can cause embryo-fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ] . Females Advise females of childbearing potential to use effective non-hormonal contraception during treatment with AUGTYRO and for 2 months following the last dose. AUGTYRO can render some hormonal contraceptives ineffective [see Drug Interactions (7.2) ]. Males Based on genotoxicity findings, advise male patients with female partners of childbearing potential to use effective contraception during treatment with AUGTYRO and for 4 months following the last dose [see Nonclinical Toxicology (13.1) ] . 8.4 Pediatric Use The safety and effectiveness of AUGTYRO in pediatric patients with ROS1 -positive NSCLC have not been established. The safety and effectiveness of AUGTYRO have not been established in pediatric patients younger than 12 years of age with solid tumors who have an NTRK gene fusion. The safety and effectiveness of AUGTYRO for the treatment of locally advanced or metastatic NTRK -positive solid tumors have been established in pediatric patients 12 years of age or older. Use of AUGTYRO in this age group is supported by evidence from an adequate and well-controlled study in adult patients with additional pharmacokinetic and safety data in pediatric patients aged 12 years and older. This includes data demonstrating that the exposure of repotrectinib in pediatric patients 12 years of age and older is expected to result in similar safety and efficacy to that of adults, and that the course of locally advanced or metastatic NTRK -positive solid tumors is sufficiently similar in adults and pediatric patients 12 years of age or older to allow extrapolation of data in adult to pediatric patients 12 years of age or older [see Dosage and Administration (2.4) , Warnings and Precautions (5.7) , Adverse Reactions (6.1) and Clinical Pharmacology (12.3) ] . Juvenile Animal Data Daily oral administration of repotrectinib to juvenile rats for 8 weeks starting on postnatal day 12 (approximately equal to a human pediatric age of a newborn) resulted in toxicities similar to those observed in adult rats, though juvenile animals showed decreased body weight gain at doses ≥1 mg/kg (approximately ≥0.04 times the human exposure based on AUC at the recommended clinical dose of 160 mg BID) and decreased femur lengths at 3 mg/kg (approximately 0.1 times the human exposure based on AUC at the recommended clinical dose of 160 mg BID). Decreased body weight gain and decreased femur lengths persisted following 4 weeks of recovery. 8.5 Geriatric Use Of the 426 patients who received AUGTYRO, in the TRIDENT-1 study for ROS1 -positive non-small cell lung cancer or NTRK gene fusion-positive solid tumors, 19% were 65 to 75 years old, and 6% were 75 years of age or older. There were no clinically meaningful differences in safety and efficacy between patients younger than 65 years of age and patients 65 years of age or older. 8.6 Renal Impairment The recommended dosage of AUGTYRO has not been established in patients with severe renal impairment or kidney failure (eGFR <30 mL/min) and patients on dialysis [see Clinical Pharmacology (12.3) ] . No dosage modification is recommended for patients with mild or moderate renal impairment (eGFR 30 to 90 mL/min). 8.7 Hepatic Impairment The recommended dosage of AUGTYRO has not been established in patients with moderate (total bilirubin >1.5 to 3 times upper limit of normal [ULN] with any AST) or severe (total bilirubin >3 times ULN with any AST) hepatic impairment [see Clinical Pharmacology (12.3) ] . No dosage modification is recommended for patients with mild (total bilirubin >1 to 1.5 times ULN or AST > ULN) hepatic impairment.

16 HOW SUPPLIED/STORAGE AND HANDLING AUGTYRO (repotrectinib) 40 mg, Size 0, white opaque cap, white opaque body, hard shell capsules, filled with a white to off-white powder which may appear as a plug, imprinted with “REP 40” in blue text on the cap are supplied as follows: • Bottles of 60 capsules (NDC 0003-4040-60) • Bottles of 120 capsules (NDC 0003-4040-12) AUGTYRO (repotrectinib) 160 mg, Size 0, blue opaque cap, blue opaque body, hard shell capsules, filled with a white to off-white powder which may appear as a plug, imprinted with “REP 160” in white text on the cap are supplied as follows: • Bottles of 14 capsules (NDC 0003-4160-14) • Bottles of 60 capsules (NDC 0003-4160-60) Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature].