Taletrectinib (Monograph)

Brand name: Ibtrozi
Drug class: Antineoplastic Agents

Introduction

Taletrectinib adipate, a kinase inhibitor, is an antineoplastic agent.¹

Uses for Taletrectinib

Taletrectinib adipate has the following uses:

Taletrectinib adipate is indicated for the treatment of adult patients with locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC).¹

Taletrectinib Dosage and Administration

General

Taletrectinib adipate is available in the following dosage form(s) and strength(s):

Capsules: 200 mg of taletrectinib¹

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

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.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 taletrectinib).¹

• Continue treatment until disease progression or unacceptable toxicity.¹

• See Full Prescribing Information for dosage modification recommendations for adverse reactions.¹

Cautions for Taletrectinib

Contraindications

• None¹

Warnings/Precautions

Hepatotoxicity

Taletrectinib can cause hepatotoxicity, including drug-induced liver injury and fatal adverse reactions. ¹

In the pooled safety population, based on laboratory values, 88% of patients treated with taletrectinib experienced increased aspartate aminotransferase (AST), including 10% Grade 3 or 4.¹ Increased alanine aminotransferase (ALT) occurred in 85% of patients treated with taletrectinib, including 13% Grade 3 or 4.¹ The median time to first onset of AST or ALT elevation was 15 days (range: 3 days to 20.8 months). ¹

Increased AST or ALT each led to dose interruption in 7% of patients.¹ Increased AST and ALT leading to dose reduction occurred in 5% and 9% of patients, respectively.¹ Increased AST and ALT each led to permanent discontinuation of taletrectinib in 0.3% of patients.¹ Other liver-related adverse reactions leading to permanent discontinuation of taletrectinib were hepatotoxicity (0.6% of patients) and increased bilirubin (0.3% of patients). ¹

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 taletrectinib.¹ Fatal liver events occurred in 2 (0.6%) patients. ¹

Monitor liver function tests (AST, ALT, and bilirubin) prior to administration of taletrectinib, 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.¹ Withhold, then resume at a reduced dose upon improvement, or permanently discontinue taletrectinib based on severity. ¹

Interstitial Lung Disease/Pneumonitis

Taletrectinib can cause severe, life-threatening, or fatal interstitial lung disease (ILD) or pneumonitis. ¹

In the pooled safety population, interstitial lung disease (ILD)/pneumonitis occurred in 2.3% of patients treated with taletrectinib, including Grade 3 or 4 in 1.1% of patients.¹ The median time to first onset of ILD/pneumonitis was 3.8 months (range: 12 days to 11.8 months). ¹

ILD/pneumonitis led to dose interruption of taletrectinib in 1.1% of patients.¹ ILD/pneumonitis required dose reduction in 0.6% of patients and permanent discontinuation of taletrectinib in 0.6% of patients.¹ One fatal ILD case occurred in a patient who received 400 mg once daily dose of taletrectinib. ¹

Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis.¹ Immediately withhold taletrectinib in patients with suspected ILD/pneumonitis.¹ Withhold, then reduce the dose or permanently discontinue taletrectinib if Grade ≥2 ILD/pneumonitis is confirmed. ¹

QTC Interval Prolongation

Taletrectinib can cause QTc interval prolongation, which can increase the risk for ventricular tachyarrhythmias (e.g., torsades de pointes) or sudden death.¹ Taletrectinib prolongs the QTc interval in a concentration-dependent manner. ¹

In the pooled safety population, 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 taletrectinib and 2.6% had an increase in QTcF to >500 msec.¹ Overall, 3.4% of patients had Grade ≥3 QTc interval prolongation.¹ The median time from the first dose of taletrectinib to the onset of ECG QT prolongation was 22 days (range: 1 day to 38.7 months).¹ QTc prolongation led to dose interruption and dose reduction, each in 2.8% of patients treated with taletrectinib. ¹

Monitor ECGs and electrolytes prior to administration of taletrectinib, and then periodically thereafter as clinically indicated during treatment.¹ 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. ¹

Significant prolongation of the QTc interval may occur when taletrectinib is taken with food, strong and moderate CYP3A inhibitors, and/or drugs with a known potential to prolong QTc.¹ Administer taletrectinib on an empty stomach.¹ Avoid coadministration of taletrectinib with strong and moderate CYP3A inhibitors and/or drugs with a known potential to prolong QTc. ¹

Withhold, then resume at the same or reduced dose, or permanently discontinue taletrectinib adipate based on severity. ¹

Hyperuricemia

Taletrectinib adipate can cause hyperuricemia. ¹

In the pooled safety population, 14% of patients treated with taletrectinib experienced hyperuricemia reported as an adverse reaction, with 16% of these patients requiring urate-lowering medication without pre-existing gout or hyperuricemia.¹ Hyperuricemia Grade ≥3 occurred in one patient.¹ The median time to first onset of hyperuricemia was 2.1 months (range: 7 days to 35.8 months).¹ Hyperuricemia leading to dose interruption occurred in 0.3% of patients. ¹

Monitor serum uric acid levels prior to administration of taletrectinib and periodically during treatment.¹ Initiate treatment with urate-lowering medications as clinically indicated.¹ Withhold, then resume at the same or reduced dose, or permanently discontinue taletrectinib based on severity. ¹

Myalgia with Creatine Phosphokinase Elevation

Taletrectinib can cause myalgia with or without creatine phosphokinase (CPK) elevation. ¹

In the pooled safety population, mylagia occurred in 10% of patients treated with taletrectinib.¹ The median time to first onset of myalgia was 11 days (range: 2 days to 10 months). ¹

Concurrent myalgia with increased CPK within a 7-day time period was observed in 0.9% of patients.¹ Taletrectinib was interrupted in one patient (0.3%) with myalgia, who also presented with concurrent CPK elevation. ¹

Advise patients to report any unexplained muscle pain, tenderness, or weakness.¹ Monitor serum CPK levels during taletrectinib treatment every 2 weeks during the first month of treatment and then as clinically indicated in patients reporting unexplained muscle pain, tenderness, or weakness.¹ Withhold, then resume at the same or reduced dose upon improvement ¹

Skeletal Fractures

Taletrectinib can increase the risk of fractures.¹ ROS1 inhibitors as a class have been associated with skeletal fractures. ¹

In the pooled safety population 3.4% of patients experienced fractures including 1.4% Grade 3.¹ Some fractures occurred in the setting of an accidental fall or other predisposing factors such as osteoporosis, bone metastasis, and age-related degenerative conditions.¹ Fractures involved the ribs (1.4%), spine (0.9%), femur (0.6%), humerus (0.3%), and acetabulum (0.3%).¹ The median time to first onset of fracture was 10.7 months (range: 26 days to 29.1 months).¹ Dose interruption occurred in 0.3% of patients. ¹

Promptly evaluate patients with signs or symptoms (e.g., pain, changes in mobility, deformity) of fractures.¹ There are no data on the effects of taletrectinib on healing of known fractures and risk of future fractures. ¹

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, taletrectinib can cause fetal harm when administered to a pregnant woman. ¹

In animal reproduction studies, oral administration of taletrectinib to pregnant rats during the period of organogenesis caused structural abnormalities.¹ Oral administration of taletrectinib to pregnant rabbits during the period of organogenesis resulted in embryo-fetal mortalities and structural abnormalities.¹ Findings in both species occurred at doses resulting in exposures below or equal to the human exposure based on AUC at the recommended dose. ¹

Advise pregnant women and females of reproductive potential of the potential risk to a fetus.¹ Advise females of reproductive potential to use effective contraception during treatment with taletrectinib and for 3 weeks after the last dose.¹ Advise male patients with female partners of reproductive potential to use effective contraception during treatment with taletrectinib and for 3 weeks after the last dose. ¹

Specific Populations

Pregnancy

Based on literature reports in humans with congenital mutations leading to changes in TRK signaling, findings from animal studies, and its mechanism of action, taletrectinib can cause fetal harm when administered to a pregnant woman.¹ Limited data from case reports with taletrectinib used in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes.¹ 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.¹ Advise pregnant women of the potential risk to a fetus. ¹

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. ¹

Lactation

There are no data on the presence of taletrectinib or its metabolites in human milk or their effects on a breastfed child or on milk production.¹ Because of the potential for adverse reactions in breastfed children, advise women not to breastfeed during treatment with taletrectinib and for 3 weeks after the last dose. ¹

Females and Males of Reproductive Potential

Taletrectinib can cause fetal harm when administered to a pregnant woman. ¹

Verify the pregnancy status of females of reproductive potential prior to initiating taletrectinib. ¹

Advise females of reproductive potential to use effective contraception during treatment with taletrectinib and for 3 weeks after the last dose. ¹

Advise male patients with female partners of reproductive potential to use effective contraception during treatment with taletrectinib and for 3 weeks after the last dose. ¹

Based on findings in animals, taletrectinib may impair fertility in males and females.¹ The effects on animal fertility were reversible. ¹

Pediatric Use

The safety and effectiveness of taletrectinib in pediatric patients have not been established. ¹

Geriatric Use

Of the 352 patients who received taletrectinib 600 mg orally once daily, 88 (25%) patients were 65 years of age and older, and 14 (4%) patients were 75 years of age and older.¹ 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. ¹

Common Adverse Effects

The most frequently reported adverse reactions (≥20%) were: diarrhea, nausea, vomiting, dizziness, rash, constipation, and fatigue.¹

The most frequently reported Grade 3 or 4 laboratory abnormalities (≥5%) were: increased ALT, increased AST, decreased neutrophils, and increased creatine phosphokinase.¹

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

• Strong and Moderate CYP3A inhibitors: Avoid concomitant use.¹

• Strong and Moderate CYP3A inducers: Avoid concomitant use.¹

• Gastric Acid Reducing Agents: Avoid concomitant use with proton pump inhibitors (PPIs) and H2 receptor antagonists.¹ If an acid-reducing agent cannot be avoided, administer taletrectinib 2 hours before or 2 hours after taking a locally acting antacid.¹

• Drugs That Prolong the QTc Interval: Avoid concomitant use.¹

Actions

Mechanism of Action

Taletrectinib is an inhibitor of tyrosine kinase ROS1, including ROS1 resistance mutations.¹ Taletrectinib also showed inhibitory effects on tropomyosin receptor kinases (TRKs) TRKA, TRKB, and TRKC. ¹

Fusion proteins that include ROS1 domains can drive tumorigenic potential through hyperactivation of downstream signaling pathways leading to unconstrained cell proliferation.¹ Taletrectinib inhibited growth of cancer cells expressing ROS1 fusion genes and mutations. ¹

In mice subcutaneously implanted with tumors harboring ROS1 fusions, including the G2032R mutation, administration of taletrectinib resulted in tumor growth inhibition.¹ Taletrectinib had anticancer activity in an intracranial NSCLC xenograft model harboring a ROS1 fusion. ¹

Advice to Patients

• Advise patients to read the FDA-approved patient labeling (Patient Information).¹

• Advise patients of the risk of hepatotoxicity and of the need for laboratory tests to monitor liver function during treatment with taletrectinib and to immediately contact their healthcare providers if they experience symptoms of hepatotoxicity. ¹

• Inform patients of the risk of interstitial lung disease (ILD)/pneumonitis during treatment with taletrectinib and to contact their healthcare provider immediately if they experience new or worsening pulmonary symptoms indicative of ILD/pneumonitis.¹

• Inform patients of the risk of QT interval prolongation during treatment with taletrectinib and to advise patients to contact their healthcare provider immediately for any symptoms of QT interval prolongation.¹

• Advise patients of the risk of hyperuricemia during treatment with taletrectinib and to contact their healthcare provider if they experience signs or symptoms associated with hyperuricemia. ¹

• Advise patients of the risk of myalgia with creatine phosphokinase elevation during treatment with taletrectinib and to contact their healthcare provider if they experience unexplained muscle pain, tenderness, or weakness. ¹

• Inform patients of the risk of bone fractures during treatment with taletrectinib and advise patients to contact their healthcare provider immediately if they experience signs or symptoms of fracture. ¹

• Advise pregnant women and females of reproductive potential of the potential risk to a fetus.¹ Advise females to inform their healthcare provider of a known or suspected pregnancy.¹

• Advise females of reproductive potential to use effective contraception during treatment with taletrectinib and for 3 weeks after the last dose.¹

• Advise male patients with female partners of reproductive potential to use effective contraception during treatment with taletrectinib and for 3 weeks after the last dose. ¹

• Inform patients that taletrectinib can cause photosensitivity.¹ Advise patients to minimize sun exposure while taking taletrectinib and to use sun protection, including broad-spectrum sunscreen, during treatment with the drug and for at least 5 days after discontinuation. ¹

• Advise women not to breastfeed during treatment with taletrectinib and for 3 weeks after the last dose.¹

• Advise patients to inform their healthcare providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products.¹

• Advise patients to avoid grapefruit or grapefruit juice while taking taletrectinib.¹

• Advise patients to swallow taletrectinib capsules on an empty stomach, at least 2 hours before or 2 hours after food intake.¹

• Advise patients that if a dose of taletrectinib is missed or if vomiting occurs, resume the drug at its regularly scheduled time the next day.¹

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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