taletrectinib 200 MG Oral Capsule

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 )

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.

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

CONTRAINDICATIONS None. None ( 4 )

Mechanism of Action Taletrectinib is an inhibitor of tyrosine kinase ROS1, including ROS1 resistance mutations. Taletrectinib also showed inhibitory effects on tropomyosin receptor kinases (TRKs) TRKA, TRKB, and TRKC. Fusion proteins that include ROS1 domains can drive tumorigenic potential through hyperactivation of downstream signaling pathways leading to unconstrained cell proliferation. Taletrectinib inhibited growth of cancer cells expressing ROS1 fusion genes and mutations. In mice subcutaneously implanted with tumors harboring ROS1 fusions, including the G2032R mutation, administration of taletrectinib resulted in tumor growth inhibition. Taletrectinib had anticancer activity in an intracranial NSCLC xenograft model harboring a ROS1 fusion.