IBTROZI

1 INDICATIONS AND USAGE IBTROZI ® (taletrectinib) 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 )] . IBTROZI 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 )

2 DOSAGE AND ADMINISTRATION Select patients for the treatment of locally advanced or metastatic NSCLC based on the presence of ROS1 rearrangement(s). ( 2.1 ) Recommended Dosage: 600 mg orally once daily on an empty stomach (no food intake at least 2 hours before and 2 hours after taking IBTROZI). ( 2.3 ) Continue treatment until disease progression or unacceptable toxicity. ( 2.3 ) 2.1 Patient Selection Select patients for the treatment of locally advanced or metastatic NSCLC with IBTROZI based on the presence of ROS1 rearrangement(s) in tumor specimens [see Clinical Studies ( 14.1 )] . An FDA-approved test to detect ROS1 rearrangement(s) for selecting patients for treatment with IBTROZI is not currently available. 2.2 Recommended Testing and Evaluation Before Initiating IBTROZI Before initiating IBTROZI, evaluate liver function tests (including ALT, AST, and bilirubin), electrolytes, ECG, and uric acid [see Warnings and Precautions ( 5.1 , 5.3 , 5.4 )]. 2.3 Recommended Dosage and Administration The recommended dosage of IBTROZI is 600 mg orally once daily on an empty stomach (no food intake at least 2 hours before and 2 hours after taking IBTROZI) [see Clinical Pharmacology ( 12.2 , 12.3 )] until disease progression or unacceptable toxicity. Take IBTROZI at approximately the same time each day. Swallow IBTROZI capsules whole. Do not open, chew, crush, or dissolve the capsule prior to swallowing. Avoid food or drink containing grapefruit during treatment with IBTROZI. Minimize sun exposure and use sun protection, including broad-spectrum sunscreen, during treatment with IBTROZI and for at least 5 days after discontinuation [see Adverse Reactions ( 6.1 )] . Missed Dose If a dose is missed, take the next dose at its scheduled time on the following day. Vomiting If vomiting occurs at any time after taking a dose, take the next dose at its scheduled time on the following day. 2.4 Dosage Modifications for Adverse Reactions The recommended dosage reductions for the management of adverse reactions are provided in Table 1 . Table 1: Recommended Dose Reductions for IBTROZI Adverse Reactions Dosage Reduction Recommended Dosage First Dose Reduction 400 mg once daily Second Dose Reduction 200 mg once daily Permanently discontinue IBTROZI capsules in patients unable to tolerate 200 mg once daily. The recommended dosage modifications of IBTROZI for the management of adverse reactions are provided in Table 2 . Table 2: Recommended Dosage Modifications for IBTROZI Adverse Reactions Adverse Reaction Severity* Dosage Modification Hepatotoxicity (Elevation of ALT or AST) [see Warnings and Precautions ( 5.1 )] Grade 3 (>5 - 20 × ULN) Withhold IBTROZI until recovery to Grade ≤1 or baseline. If resolved within 6 weeks, resume IBTROZI at a reduced dose level. If unresolved after 6 weeks, permanently discontinue IBTROZI. Recurrence: If resolved within 6 weeks, resume IBTROZI at a reduced dose level. If unresolved after 6 weeks, permanently discontinue IBTROZI. Grade 4 (>20 × ULN) Withhold IBTROZI until recovery to Grade ≤1 or baseline. If resolved within 6 weeks, resume IBTROZI at a reduced dose level. If unresolved after 6 weeks, permanently discontinue IBTROZI. Recurrence: Permanently discontinue IBTROZI. ALT or AST ≥3 × ULN with concurrent total bilirubin ≥2 × ULN (in the absence of cholestasis or hemolysis) Permanently discontinue IBTROZI. ILD/pneumonitis [see Warnings and Precautions ( 5.2 )] Grade 1 Withhold IBTROZI if ILD/pneumonitis occurs or is suspected until recovery to Grade 0 or baseline. If resolved within 6 weeks, resume IBTROZI at the same dose level. If unresolved after 6 weeks, permanently discontinue IBTROZI. Recurrence: Permanently discontinue IBTROZI. Grade 2 Withhold IBTROZI if ILD/pneumonitis occurs or is suspected until recovery to Grade 0 or baseline. If resolved within 6 weeks, resume IBTROZI at a reduced dose level. If unresolved after 6 weeks, permanently discontinue IBTROZI. Recurrence: Permanently discontinue IBTROZI. Grade 3 or 4 Permanently discontinue IBTROZI. QTc Interval Prolongation [see Warnings and Precautions ( 5.3 )] Grade 2 (QTc interval 481-500 msec) Withhold IBTROZI until recovery to Grade ≤1 or baseline. Correct electrolytes and/or change concomitant medications. Resume IBTROZI at same dose. Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = Upper limit of normal *Graded per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0. Adverse Reaction Severity* Dosage Modification Grade 3 (QTc interval ≥501 msec or QTc interval increase of >60 msec from baseline) Withhold IBTROZI until recovery to Grade ≤1 or baseline. Correct electrolytes and/or change concomitant medications. Resume IBTROZI at a reduced dose. Grade 4 (Torsade de pointes; polymorphic ventricular tachycardia; signs/symptoms of serious arrhythmia) Permanently discontinue IBTROZI. Hyperuricemia [see Warnings and Precautions ( 5.4 )] Grade 3 or 4 Withhold IBTROZI until improvement of signs or symptoms. Resume IBTROZI at same or reduced dose level or permanently discontinue. Creatine Phosphokinase Elevation [see Warnings and Precautions ( 5.5 )] CPK elevation >5 times ULN Withhold until recovery to baseline or ≤2.5 times ULN, then resume at same dose. CPK elevation >10 times ULN or second occurrence of CPK elevation of >5 times ULN Withhold until recovery to baseline or ≤2.5 times ULN, then resume at a reduced dose. Other Adverse Reactions [see Adverse Reactions ( 6.1 )] Grade 3 Withhold IBTROZI until recovery to Grade ≤1 or baseline. If resolved within 6 weeks, resume IBTROZI at a reduced dose level. If unresolved after 6 weeks, permanently discontinue IBTROZI. Recurrence: Resume treatment at a reduced dose or permanently discontinue IBTROZI. Grade 4 Withhold IBTROZI until recovery to Grade ≤1 or baseline. Resume IBTROZI at reduced dose or permanently discontinue as clinically indicated. Recurrence: Permanently discontinue IBTROZI.

4 CONTRAINDICATIONS None. None ( 4 )

5 WARNINGS AND PRECAUTIONS Hepatotoxicity: Monitor liver function tests prior to initiating, every 2 weeks during the first 2 months of treatment, then monthly thereafter as clinically indicated, with more frequent testing in patients who develop transaminase elevations. Based on severity and resolution, withhold and then resume at reduced dose, or permanently discontinue. ( 2.4 , 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. Based on severity and resolution, resume at the same or reduced dose, or permanently discontinue. ( 2.4 , 5.2 ) QTc Interval Prolongation: Monitor ECG and electrolytes prior to initiating and periodically during treatment. Based on severity and resolution, withhold and then resume at same or reduced dose, or permanently discontinue. ( 2.4 , 5.3 ) 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. ( 2.4 , 5.4 ) 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. ( 2.4 , 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 patients of the potential risk to a fetus and to use effective contraception. ( 5.7 ) 5.1 Hepatotoxicity IBTROZI can cause hepatotoxicity, including drug-induced liver injury and fatal adverse reactions. In the pooled safety population [see Adverse Reactions ( 6.1 )], based on laboratory values, 88% of patients treated with IBTROZI experienced increased aspartate aminotransferase (AST), including 10% Grade 3 or 4. Increased alanine aminotransferase (ALT) occurred in 85% of patients treated with IBTROZI, including 13% Grade 3 or 4. The median time to first onset of AST or ALT elevation was 15 days (range: 3 days to 20.8 months). Increased AST or ALT each led to dose interruption in 7% of patients. Increased AST and ALT leading to dose reduction occurred in 5% and 9% of patients, respectively. Increased AST and ALT each led to permanent discontinuation of IBTROZI in 0.3% of patients. Other liver-related adverse reactions leading to permanent discontinuation of IBTROZI were hepatotoxicity (0.6% of patients) and increased bilirubin (0.3% of patients). Concurrent elevations in AST or ALT ≥3 times the upper limit of normal (ULN) and total bilirubin ≥2 times the ULN, with normal alkaline phosphatase, occurred in 2 (0.6%) patients treated with IBTROZI. Fatal liver events occurred in 2 (0.6%) patients. Monitor liver function tests (AST, ALT, and bilirubin) prior to administration of IBTROZI, every 2 weeks during the first 2 months of treatment, and then monthly thereafter as clinically indicated with more frequent testing in patients who develop transaminase elevations. Withhold, then resume at reduced dose upon improvement, or permanently discontinue IBTROZI based on severity [see Dosage and Administration ( 2.4 )] . 5.2 Interstitial Lung Disease/Pneumonitis IBTROZI can cause severe, life-threatening, or fatal interstitial lung disease (ILD) or pneumonitis. In the pooled safety population [see Adverse Reactions ( 6.1 )], interstitial lung disease (ILD)/pneumonitis occurred in 2.3% of patients treated with IBTROZI, including Grade 3 or 4 in 1.1% of patients. The median time to first onset of ILD/pneumonitis was 3.8 months (range: 12 days to 11.8 months). ILD/pneumonitis led to dose interruption of IBTROZI in 1.1% of patients. ILD/pneumonitis required dose reduction in 0.6% of patients and permanent discontinuation of IBTROZI in 0.6% of patients. One fatal ILD case occurred in a patient who received 400 mg once daily dose of IBTROZI. Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis. Immediately withhold IBTROZI in patients with suspected ILD/pneumonitis. Withhold, then reduce the dose or permanently discontinue IBTROZI if Grade ≥2 ILD/pneumonitis is confirmed [see Dosage and Administration ( 2.4 )] . 5.3 QTc Interval Prolongation IBTROZI can cause QTc interval prolongation, which can increase the risk for ventricular tachyarrhythmias (e.g., torsades de pointes) or sudden death. IBTROZI prolongs the QTc interval in a concentration-dependent manner [see Clinical Pharmacology ( 12.2 )] . In the pooled safety population [see Adverse Reactions ( 6.1 )], of the 351 patients who underwent at least one post baseline ECG assessment, 13% experienced an increase in QTcF of >60 msec compared to baseline after receiving IBTROZI and 2.6% had an increase in QTcF to >500 msec. Overall, 3.4% of patients had Grade ≥3 QTc interval prolongation. The median time from the first dose of IBTROZI to the onset of ECG QT prolongation was 22 days (range: 1 day to 38.7 months). QTc prolongation led to dose interruption and dose reduction, each in 2.8% of patients treated with IBTROZI. Monitor ECGs and electrolytes prior to administration of IBTROZI, and then periodically thereafter as clinically indicated during treatment. Adjust the frequency of monitoring based on risk factors such as known long QT syndromes, clinically significant bradyarrhythmias, severe or uncontrolled heart failure, and concomitant medications associated with QTc interval prolongation. Significant prolongation of the QTc interval may occur when IBTROZI is taken with food, strong and moderate CYP3A inhibitors, and/or drugs with a known potential to prolong QTc. Administer IBTROZI on an empty stomach. Avoid coadministration of IBTROZI with strong and moderate CYP3A inhibitors and/or drugs with a known potential to prolong QTc [see Dosage and Administration ( 2.3 ), Drug Interactions ( 7.1 , 7.2 )] . Withhold, then resume at the same or reduced dose, or permanently discontinue IBTROZI based on severity [see Dosage and Administration ( 2.4 )] . 5.4 Hyperuricemia IBTROZI can cause hyperuricemia. In the pooled safety population [see Adverse Reactions ( 6.1 )], 14% of patients treated with IBTROZI experienced hyperuricemia reported as an adverse reaction, with 16% of these patients requiring urate-lowering medication without pre-existing gout or hyperuricemia. Hyperuricemia Grade ≥3 occurred in one patient. The median time to first onset of hyperuricemia was 2.1 months (range: 7 days to 35.8 months). Hyperuricemia leading to dose interruption occurred in 0.3% of patients. Monitor serum uric acid levels prior to administration of IBTROZI and periodically during treatment. Initiate treatment with urate-lowering medications as clinically indicated. Withhold, then resume at the same or reduced dose, or permanently discontinue IBTROZI based on severity [see Dosage and Administration ( 2.4 )]. 5.5 Myalgia with Creatine Phosphokinase Elevation IBTROZI can cause myalgia with or without creatine phosphokinase (CPK) elevation. In the pooled safety population [see Adverse Reactions ( 6.1 )], myalgia occurred in 10% of patients treated with IBTROZI. The median time to first onset of myalgia was 11 days (range: 2 days to 10 months). Concurrent myalgia with increased CPK within a 7-day time period was observed in 0.9% of patients. IBTROZI was interrupted in one patient (0.3%) with myalgia, who also presented with concurrent CPK elevation. Advise patients to report any unexplained muscle pain, tenderness, or weakness. Monitor serum CPK levels during IBTROZI treatment every 2 weeks during the first month of treatment and then as clinically indicated in patients reporting unexplained muscle pain, tenderness, or weakness. Withhold, then resume at the same or reduced dose upon improvement [see Dosage and Administration ( 2.4 )]. 5.6 Skeletal Fractures IBTROZI can increase the risk of fractures. ROS1 inhibitors as a class have been associated with skeletal fractures. In the pooled safety population [see Adverse Reactions ( 6.1 )], 3.4% of patients experienced fractures including 1.4% Grade 3. Some fractures occurred in the setting of an accidental fall or other predisposing factors such as osteoporosis, bone metastasis, and age-related degenerative conditions. Fractures involved the ribs (1.4%), spine (0.9%), femur (0.6%), humerus (0.3%), and acetabulum (0.3%). The median time to first onset of fracture was 10.7 months (range: 26 days to 29.1 months). Dose interruption occurred in 0.3% of patients. Promptly evaluate patients with signs or symptoms (e.g., pain, changes in mobility, deformity) of fractures. There are no data on the effects of IBTROZI 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 kinase (TRK) signaling, findings from animal studies and its mechanism of action, IBTROZI can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of taletrectinib to pregnant rats during the period of organogenesis caused structural abnormalities. Oral administration of taletrectinib to pregnant rabbits during the period of organogenesis resulted in embryo-fetal mortalities and structural abnormalities. Findings in both species occurred at doses resulting in exposures below or equal to the human exposure based on AUC at the recommended dose. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with IBTROZI and for 3 weeks after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with IBTROZI and for 3 weeks after the last dose [see Use in Specific Populations ( 8.1 , 8.3 )] .

7 DRUG INTERACTIONS Strong and Moderate CYP3A inhibitors : Avoid concomitant use. ( 7.1 ) Strong and Moderate CYP3A inducers: Avoid concomitant use. ( 7.1 ) Gastric Acid Reducing Agents: Avoid concomitant use with proton pump inhibitors (PPIs) and H2 receptor antagonists. If an acid-reducing agent cannot be avoided, administer IBTROZI 2 hours before or 2 hours after taking a locally acting antacid. ( 7.1 ) Drugs That Prolong the QTc Interval: Avoid concomitant use. ( 7.2 ) 7.1 Effects of Other Drugs on IBTROZI Strong and Moderate CYP3A Inhibitors Avoid concomitant use with strong or moderate CYP3A inhibitors. Taletrectinib is a CYP3A substrate. Concomitant use of IBTROZI with a strong or moderate CYP3A inhibitor increases taletrectinib exposure [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of IBTROZI adverse reactions. Strong and Moderate CYP3A Inducers Avoid concomitant use with strong or moderate CYP3A inducers. Concomitant use of IBTROZI with a strong or moderate CYP3A inducer decreases taletrectinib exposure [see Clinical Pharmacology ( 12.3 )] , which may reduce the effectiveness of IBTROZI. Gastric Acid Reducing Agents Avoid concomitant use with proton pump inhibitors (PPI) and H2 receptor antagonists. Administer locally acting antacids at least 2 hours before or 2 hours after taking IBTROZI [see Clinical Pharmacology ( 12.3 )]. Concomitant use of a proton pump inhibitor decreases taletrectinib exposure [see Clinical Pharmacology ( 12.3 )], which may reduce the effectiveness of IBTROZI. 7.2. Drugs That Prolong the QTc Interval Avoid concomitant use of IBTROZI with other drug(s) with a known potential to prolong the QTc interval, such as antiarrhythmic drugs. If concomitant use cannot be avoided, adjust the frequency of monitoring as recommended [see Warnings and Precautions ( 5.3 ), Clinical Pharmacology ( 12.2 )]. Withhold IBTROZI if the QTc interval is >500 msec or the change from baseline is >60 msec [see Dosage and Administration ( 2.4 )]. IBTROZI causes QTc interval prolongation [see Warnings and Precautions ( 5.3 ), Clinical Pharmacology ( 12.2 )] . Concomitant use of IBTROZI with other drugs known to prolong the QTc interval may increase the risk of QTc interval prolongation.

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in the WARNINGS AND PRECAUTIONS section: Hepatotoxicity [see Warnings and Precautions ( 5.1 )] Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions ( 5.2 )] QTc Interval Prolongation [see Warnings and Precautions ( 5.3 )] Hyperuricemia [see Warnings and Precautions ( 5.4 )] Myalgia with Creatine Phosphokinase Elevation [see Warnings and Precautions ( 5.5 )] Skeletal fractures [see Warnings and Precautions ( 5.6 )] The most frequently reported adverse reactions (≥20%) were: diarrhea, nausea, vomiting, dizziness, rash, constipation, and fatigue. ( 6.1 ) The most frequently reported Grade 3 or 4 laboratory abnormalities (≥5%) were: increased ALT, increased AST, decreased neutrophils, and increased creatine phosphokinase. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Nuvation Bio Inc. at 1-844-688-4550 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 observed 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 the WARNINGS AND PRECAUTIONS section and below reflects exposure to IBTROZI as a single agent at 600 mg orally once daily until disease progression or unacceptable toxicity in 352 patients with ROS1 -positive NSCLC (N=337) and other solid tumors (N=15). Among the 352 patients who received IBTROZI, 68% were exposed for at least 6 months, and 47% were exposed for greater than 1 year. In this pooled safety population, the most common (≥20%) adverse reactions were diarrhea, nausea, vomiting, dizziness, rash, constipation, and fatigue. The most common (≥2%) Grade 3 or 4 laboratory abnormalities were increased ALT, increased AST, decreased neutrophils, increased creatine phosphokinase, decreased lymphocytes, increased magnesium, decreased hemoglobin, and increased triglycerides. Locally Advanced or Metastatic ROS1-Positive NSCLC The safety of IBTROZI was evaluated in the TRUST-I and TRUST-II studies [see Clinical Studies ( 14.1 )]. Key eligibility criteria were histologically confirmed, locally advanced or metastatic, ROS1 -positive NSCLC, ECOG performance status ≤1, and measurable disease per RECIST v1.1. Patients received IBTROZI as a single agent at 600 mg orally once daily until disease progression or unacceptable toxicity. Among patients who received IBTROZI, 68% were exposed for 6 months or longer and 47% were exposed for greater than one year. The median age of patients who received IBTROZI was 56 years (range: 26 to 83); 56% female; 76% Asian, 15% White, 0.6% Black or African American, 8% unknown or other races; and 1.8% were of Hispanic or Latino ethnicity. Serious adverse reactions occurred in 31% of patients who received IBTROZI. Serious adverse reactions in ≥2% of patients included pneumonia (7%), pleural effusion (4.7%), and hepatotoxicity (2.4%). Fatal adverse reactions occurred in 18 (5%) patients who received IBTROZI, including pneumonia (2.4%), multiple organ dysfunction syndrome (0.6%), hepatotoxicity (0.6%), cardiac arrest (0.6%), cardiac failure (0.3%), cardiopulmonary failure (0.3%), respiratory failure (0.3%), and death not otherwise specified (0.3%). Permanent discontinuation of IBTROZI was required in 7% of patients due to adverse reactions. Adverse reactions resulting in permanent discontinuation of IBTROZI in ≥2 patients were pneumonia, ILD, and hepatotoxicity. Dosage interruptions of IBTROZI due to an adverse reaction occurred in 41% of patients. Adverse reactions which required dosage interruption in ≥5% of patients included increased AST and increased ALT. Dose reductions of IBTROZI due to an adverse reaction occurred in 29% of patients. Adverse reactions that required dosage reductions in ≥5% of patients included increased ALT and increased AST. Table 3 summarizes the adverse reactions in this population. Table 3: Adverse Reactions (≥15%) in Patients with ROS1-Positive NSCLC Who Received IBTROZI in TRUST-I and TRUST-II 1 Based on NCI CTCAE version 5.0 a Includes enterocolitis b Includes vertigo, and vertigo positional c Includes dysesthesia, hypoesthesia, neuralgia, paresthesia, and peripheral sensory neuropathy d Includes ageusia e Includes dermatitis, dermatitis acneiform, drug eruption, eczema, eyelid rash, palmar-plantar erythrodysesthesia syndrome, rash maculo-papular, rash papular, skin exfoliation, and drug reaction with eosinophilia and systemic symptoms (DRESS) f Includes asthenia g Includes productive cough Adverse Reaction 1 IBTROZI N=337 All Grades (%) Grade 3 or 4 (%) Gastrointestinal Disorders Diarrhea a 64 2.1 Nausea 47 1.5 Vomiting 43 1.5 Constipation 21 0 Nervous System Disorders Dizziness b 22 0.3 Peripheral neuropathy c 17 0.3 Dysgeusia d 15 0 Skin and Subcutaneous Tissue Rash e 22 1.8 General Disorders Fatigue f 20 0.9 Cardiac Electrocardiogram QT prolonged 19 3.6 Metabolism and Nutritional Decreased appetite 16 0.3 Respiratory, thoracic and mediastinal disorders Cough g 16 0 Clinically relevant adverse reactions in <15% of patients receiving IBTROZI were pneumonia, eye disorders, myalgia, skeletal fracture, ILD/pneumonitis, dermatologic adverse reactions including drug reaction with eosinophilia and systemic symptoms (DRESS), and photosensitivity reactions. Table 4 summarizes the laboratory abnormalities. Table 4: Select Laboratory Abnormalities (≥20%) That Worsened from Baseline in Patients with ROS1-Positive NSCLC Who Received IBTROZI in TRUST-I and TRUST-II Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase 1 Based on NCI CTCAE version 5.0 2 The denominator used to calculate the rate varied from 149 to 336 based on the number of patients with a baseline value and at least one post-treatment value. Laboratory Abnormality 1 IBTROZI 2 All Grades (%) Grade 3 or 4 (%) Hematology Hemoglobin decreased 48 3.6 Lymphocytes decreased 38 4.8 Neutrophils decreased 25 5 Chemistry AST increased 87 10 ALT increased 85 13 Creatine phosphokinase increased 53 5 Cholesterol increased 41 0 Triglycerides increased 41 2.5 Creatinine increased 39 0.3 Uric acid increased 38 0 Gamma glutamyl transferase increased 36 1.8 Alkaline phosphatase increased 30 0 Calcium decreased 28 1.8 Albumin decreased 25 0.9 Bilirubin increased 24 0.6 Potassium increased 21 1.2 Sodium increased 20 0.9

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 )] , IBTROZI can cause fetal harm when administered to a pregnant woman. Limited data from case reports with IBTROZI used in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes. In animal reproduction studies, oral administration of taletrectinib to pregnant rats and rabbits during the period of organogenesis resulted in embryo-fetal mortalities and structural abnormalities at exposures that were below or equal to the human exposure based on AUC at the recommended dose ( 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, taletrectinib was administered orally to pregnant rats during the period of organogenesis from gestation day 6 to 17 at doses of 10, 30, and 100 mg/kg/day. Taletrectinib caused fetal abnormalities including abnormal ossification of the pelvis at 100 mg/kg/day (1.3 times the human exposure based on AUC at the recommended dose). In an embryo-fetal development study, taletrectinib was administered orally to pregnant rabbits during the period of organogenesis from gestation day 6 to 19 at doses of 15, 30, and 90 mg/kg/day. Maternal lethality and increased total pregnancy loss were observed at doses ≥15 mg/kg/day (≥0.04 times the human exposure based on AUC at the recommended dose). Fetal malformations, including undeveloped or no development of eyes, nose, and mouth, ventricular malformations, thoracic vascular malformations, and skull malformations were observed at 30 mg/kg/day (0.1 times the human exposure based on AUC at the recommended dose).