Repotrectinib (Monograph)

Brand name: Augtyro
Drug class: Antineoplastic Agents

Introduction

Repotrectinib, a kinase inhibitor, is an antineoplastic agent.

Uses for Repotrectinib

Repotrectinib has the following uses:

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

Repotrectinib Dosage and Administration

General

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

Capsules: 40 mg

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.

• Prior to initiating repotrectinib, discontinue strong and moderate CYP3A inhibitors for 3 to 5 elimination half-lives of the CYP3A inhibitor.

• Recommended Dosage: 160 mg orally once daily for 14 days, then increase to 160 mg twice daily, with or without food. Continue until disease progression or unacceptable toxicity.

• See Full Prescribing Information for recommendations on dosage modifications for adverse reactions.

Related/similar drugs

Opdivo, methotrexate, Keytruda, pembrolizumab, Avastin, cisplatin, Tagrisso

Cautions for Repotrectinib

Contraindications

None.

Warnings/Precautions

Central Nervous System Adverse Reactions

Repotrectinib can cause central nervous system (CNS) adverse reactions.

Among the 351 patients who received repotrectinib in the TRIDENT-1 study, a broad spectrum of CNS adverse reactions including dizziness, ataxia, and cognitive disorders occurred in 75% or patients; Grade 3 or 4 events occurred in 4% of patients.

Dizziness, including vertigo, occurred in 64% of the 351 patients; Grade 3 dizziness occurred in 2.8% of patients. The median time to onset was 6 days (1 day to 1.4 years). Dose interruption was required in 9% of patients, and 12% required dose reduction of repotrectinib due to dizziness.

Ataxia, including gait disturbance and balance disorder, occurred in 29% of the 351 patients; Grade 3 ataxia occurred in 0.3% of patients. The median time to onset was 15 days (1 day to 1.4 years). Dose interruption was required in 6% of patients, 8% required dose reduction, and one patient (0.3%) permanently discontinued repotrectinib due to ataxia.

Cognitive disorder, including memory impairment and disturbance in attention, occurred in 23% of the 351 patients. Cognitive disorders included memory impairment (13%), disturbance in attention (11%), and confusional state (2%); Grade 3 cognitive disorders 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, 1.7% required dose reduction, and 0.6% patients permanently discontinued repotrectinib due to cognitive adverse reactions.

Mood disorders occurred in 6% of the 351 patients. Mood disorders occurring in >1% of patients included anxiety (2.8%), irritability (1.1%), and depression (1.4%); Grade 4 mood disorders (mania) occurred in 0.3% of patients. Dose interruption was required in 0.3% of patients and 0.3% of patients required a dose reduction due to mood disorders.

Sleep disorders including insomnia and hypersomnia occurred in 15% of the 351 patients. Sleep disorders observed in >1% of patients were somnolence (8%), insomnia (6%), and hypersomnia (1.1%). Dose interruption was required in 0.9% of patients, and 0.3% 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 repotrectinib. Advise patients not to drive or use machines if they are experiencing CNS adverse reactions. Withhold and then resume at same or reduced dose upon improvement, or permanently discontinue repotrectinib based on severity.

Interstitial Lung Disease/Pneumonitis

Repotrectinib can cause interstitial lung disease (ILD)/pneumonitis.

Among the 351 patients treated with repotrectinib, ILD/pneumonitis (pneumonitis [2.6%] and interstitial lung disease [0.3%]) occurred in 2.9% of patients; Grade 3 ILD/pneumonitis occurred in 1.1% of patients. The median time to onset was 45 days (19 days to 0.9 years). Dose interruption was required in 1.4% of patients, 0.6% of patients required dose reduction, and 1.1% of patients permanently discontinued repotrectinib due to ILD/pneumonitis.

Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis. Immediately withhold repotrectinib in patients with suspected ILD/pneumonitis and permanently discontinue the drug if ILD/pneumonitis is confirmed.

Hepatotoxicity

Repotrectinib can cause hepatotoxicity.

Among the 351 patients treated with repotrectinib, increased alanine transaminase (ALT) occurred in 35%, increased aspartate aminotransferase (AST) occurred in 40%, including Grade 3 or 4 increased ALT in 2% and increased AST in 2.6%. The median time to onset of increased ALT or AST was 15 days (range: 1 day to 1.9 years). Increased ALT or AST leading to dose interruptions or reductions occurred in 2.8% and 1.4% of patients, respectively. Hyperbilirubinemia leading to dose interruptions occurred in 0.6%.

Monitor liver function tests, including ALT, AST and bilirubin, every 2 weeks during the first month of treatment, then monthly thereafter and as clinically indicated. Withhold and then resume at the same or reduced dose upon improvement, or permanently discontinue repotrectinib based on the severity.

Myalgia with Creatine Phosphokinase Elevation

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

Among the 351 patients treated with repotrectinib, myalgia occurred in 13% of patients, with Grade 3 in 0.6%. Median time to onset of myalgia was 19 days (range: 1 day to 2 years). Concurrent increased CPK within a 7-day window was observed in 3.7% of patients. Repotrectinib was interrupted in one patient with myalgia and concurrent CPK elevation.

Advise patients to report any unexplained muscle pain, tenderness, or weakness.

Monitor serum CPK levels during repotrectinib treatment and monitor CPK levels every 2 weeks during the first month of treatment and as needed in patients reporting unexplained muscle pain, tenderness, or weakness. Initiate supportive care as clinically indicated. Based on severity, withhold and then resume repotrectinib at the same or reduced dose upon improvement.

Hyperuricemia

Repotrectinib can cause hyperuricemia.

Among the 351 patients treated with repotrectinib, 18 patients (5%) experienced hyperuricemia reported as an adverse reaction and 0.9% of patients experienced Grade 3 or 4 hyperuricemia. One patient without pre-existing gout required urate-lowering medication.

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

Skeletal Fractures

Repotrectinib can cause skeletal fractures.

Among 351 adult patients who received repotrectinib, fractures occurred in 2.3%. Fractures involved the ribs (0.6%), feet (0.6%), spine (0.3%), acetabulum (0.3%), sternum (0.3%), and ankles (0.3%). Some fractures occurred at sites of disease and prior radiation therapy. The median time to fracture was 71 days (range: 31 days to 1.4 years). Repotrectinib was interrupted 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 repotrectinib on healing of known fractures and risk of future fractures.

Embryo-fetal Toxicity

Based on literature reports in humans with congenital mutations leading to changes in tropomyosin receptor tyrosine kinase (TRK) signaling, findings from animal studies, and its mechanism of action, repotrectinib can cause fetal harm when administered to a pregnant woman.

Oral administration of repotrectinib to pregnant rats during the period of organogenesis resulted in fetal malformations at doses approximately 0.3 times the recommended 160 mg twice daily dose based on body surface area (BSA).

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with repotrectinib and for 2 months following the last dose, since repotrectinib can render some hormonal contraceptives ineffective. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with repotrectinib and for 4 months after the last dose.

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, repotrectinib can cause fetal harm when administered to a pregnant woman. There are no available data on repotrectinib 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. 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.

Lactation

There are no data on the presence of repotrectinib 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 repotrectinib, advise a lactating woman to discontinue breastfeeding during treatment with repotrectinib and for 10 days after the last dose.

Females and Males of Reproductive Potential

Repotrectinib can cause fetal harm when administered to a pregnant woman.

Verify the pregnancy status of females of childbearing potential prior to initiating repotrectinib.

Repotrectinib can cause embryo-fetal harm when administered to a pregnant woman.

Advise females of childbearing potential to use effective non-hormonal contraception during treatment with repotrectinib and for 2 months following the last dose. Repotrectinib can render some hormonal contraceptives ineffective.

Based on genotoxicity findings, advise male patients with female partners of childbearing potential to use effective contraception during treatment with repotrectinib and for 4 months following the last dose.

Pediatric Use

The safety and effectiveness of repotrectinib in pediatric patients with ROS1-positive NSCLC have not been established.

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.

Geriatric Use

Of the 351 patients who received repotrectinib, 21% were 65 to 75 years of age, and 7% 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.

Renal Impairment

The recommended dosage of repotrectinib has not been established in patients with severe renal impairment or kidney failure (eGFR-MDRD <30 mL/min) and patients on dialysis.

No dosage modification is recommended for patients with mild or moderate renal impairment (eGFR-MDRD 30 to 90 mL/min).

Hepatic Impairment

The recommended dosage of repotrectinib 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.

No dosage modification is recommended for patients with mild (total bilirubin >1 to 1.5 times ULN or AST > ULN) hepatic impairment.

Common Adverse Effects

The most common adverse reactions (≥20%) were dizziness, dysgeusia, peripheral neuropathy, constipation, dyspnea, ataxia, fatigue, cognitive disorders, and muscular weakness.

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.

• P-glycoprotein (P-gp) inhibitors: Avoid concomitant use.

• Strong and Moderate CYP3A Inducers: Avoid concomitant use.

• Certain CYP3A Substrates: Avoid concomitant use with CYP3A substrates, where minimal concentration changes can cause reduced efficacy.

• Hormonal contraceptives: Avoid concomitant use.

Actions

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 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.

Advice to Patients

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

• 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.

• Advise patients to inform their healthcare provider if they experience new or worsening pulmonary symptoms indicative of ILD/pneumonitis.

• Advise patients of the need for laboratory tests to monitor liver function and to immediately report symptoms of hepatotoxicity.

• Advise patients to inform their healthcare provider if they experience muscle pain.

• Advise patients to inform their healthcare provider if they experience signs or symptoms associated with hyperuricemia.

• Inform patients that bone fractures have occurred in patients taking repotrectinib and advise patients to report symptoms to their healthcare provider.

• 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.

• Advise females of reproductive potential to use effective non-hormonal contraception during treatment with repotrectinib and for 2 months after the last dose, since repotrectinib can render some hormonal contraceptives ineffective.

• Advise male patients with female partners of reproductive potential to use effective contraception during treatment with repotrectinib and for 4 months after the last dose.

• Advise females not to breastfeed during treatment with repotrectinib and for 10 days after the last dose.

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

• Advise patients to avoid grapefruit or grapefruit juice while taking repotrectinib.

• Advise patients that hormonal contraceptives can be ineffective while taking repotrectinib.

• Advise patients to swallow repotrectinib capsules whole with or without food.

• Instruct patients if they miss a dose, or vomit at any time after taking a dose of repotrectinib, not to “make it up,” but take the next dose of repotrectinib at the next scheduled time.

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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