Repotrectinib

1 INDICATIONS AND USAGE AUGTYRO is a kinase inhibitor indicated for the treatment of • adult patients with locally advanced or metastatic ROS1- positive non-small cell lung cancer (NSCLC). ( 1.1 ) • adult and pediatric patients 12 years of age and older with solid tumors that: • have a neurotrophic tyrosine receptor kinase ( NTRK ) gene fusion and • are locally advanced or metastatic or where surgical resection is likely to result in severe morbidity. • have progressed following treatment or have no satisfactory alternative therapy. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. ( 1.2 ) 1.1 ROS1 -Positive Non-Small Cell Lung Cancer AUGTYRO is indicated for the treatment of adult patients with locally advanced or metastatic ROS1 -positive non-small cell lung cancer (NSCLC) [see Dosage and Administration (2.1) ] . 1.2 NTRK Gene Fusion-Positive Solid Tumors AUGTYRO is indicated for the treatment of adult and pediatric patients 12 years of age and older with solid tumors that: • have a neurotrophic tyrosine receptor kinase ( NTRK ) gene fusion [see Dosage and Administration ( 2.1 )] , • are locally advanced or metastatic or where surgical resection is likely to result in severe morbidity, and • have progressed following treatment or have no satisfactory alternative therapy. This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies ( 14.2 )] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

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 .

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 greate

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, dizz

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 driv

4 CONTRAINDICATIONS None. None.