Repotrectinib is a novel, oral, small-molecule, multi-target tyrosine kinase inhibitor (TKI) primarily used to treat advanced solid tumors harboring specific gene mutations, particularly ROS1-positive non-small cell lung cancer (NSCLC) and NTRK gene fusion-positive solid tumors.
Indications for Repotrectinib:
1. Non-Small Cell Lung Cancer (NSCLC)
For the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer that is c-ros oncogene 1 (ROS-1) positive (designated as an orphan drug by the U.S. Food and Drug Administration for this purpose).
2. Solid Tumors
For the treatment of patients with solid tumors harboring NTRK fusions (without known acquired resistance mutations), including adults and children aged 12 years and older, who have locally advanced or metastatic disease, or who may experience serious complications after surgical resection, and whose disease has progressed after prior treatment or for whom there is no satisfactory alternative treatment (designated as an orphan drug by the U.S. Food and Drug Administration for these cancers).
Repotrectinib Dosage and Administration
I. Standard Dosage
1. Pediatric Patients
Solid Tumors
Children aged 12 years and older: Initially, 160 mg orally once daily for 14 days, then increase to 160 mg twice daily. Continue treatment until disease progression or unacceptable toxicity.
2. Adult Patients
Non-Small Cell Lung Cancer
Initially, 160 mg orally once daily for 14 days, then increase to 160 mg twice daily. Continue treatment until disease progression or unacceptable toxicity.
Solid Tumors
Initially, 160 mg orally once daily for 14 days, then increase to 160 mg twice daily. Continue treatment until disease progression or unacceptable toxicity.
II. Adverse Reactions and Dosage Adjustment
If adverse reactions occur, it may be necessary to temporarily interrupt treatment, reduce the dose, and/or permanently discontinue Repotrectinib:
1. Recommended Dosage Reduction Regimen for Repotrectinib
Original dose: 160 mg once daily: Initial dose reduction to 120 mg once daily, then to 80 mg once daily.
Original dose: 160 mg twice daily: Initial dose reduction to 120 mg twice daily, then to 80 mg twice daily.
2. Dosage Adjustment Based on Severity of Adverse Reactions
Central Nervous System Symptoms
Grade 2 (Intolerable): Discontinue use until recovery to Grade 1 or below/baseline level; upon recovery, continue at the original dose or at a reduced dose.
Grade 3 (Intolerable): Discontinue use until recovery to Grade 1 or below/baseline level; upon recovery, at a reduced dose.
Grade 4 (Intolerable): Permanent discontinuation.
Interstitial Lung Disease (ILD)/Pneumonia
Any grade: Discontinue use if ILD/pneumonia is suspected; permanently discontinue use upon diagnosis.
Hepatotoxicity
Grade 3: Discontinue use until recovery to Grade 1 or below/baseline level; continue at the original dose if recovery occurs within 4 weeks; reduce dose for recurrent Grade 3 events.
Grade 4: Discontinue use until recovery to Grade 1 or below/baseline level, then reduce dose; permanently discontinue use if no recovery occurs within 4 weeks or for recurrent Grade 4 events.
ALT/AST > 3 times ULN and total bilirubin > 1.5 times ULN (without cholestasis or hemolysis: Permanent discontinuation).
Elevated CPK
> 5 times ULN: Discontinue use until recovery to baseline or ≤ 2.5 times ULN, then resume at the original dose.
> 10 times ULN or a second > 5 times ULN: Discontinue use until recovery to baseline or ≤ 2.5 times ULN, then reduce the dose.
Hyperuricemia
Grade 3 or 4: Discontinue use until symptoms improve; resume at the original dose or reduce the dose upon recovery.
Other clinically important adverse reactions
Unacceptable Grade 2/3/4: Discontinue use until recovery to Grade 1 or below/baseline levels; if recovery occurs within 4 weeks, resume at the original dose or reduce the dose; otherwise... Permanent discontinuation of medication.
3. Special Populations
Hepatic Impairment
Patients with mild hepatic impairment (total bilirubin >1–1.5 times the upper limit of normal, or aspartate aminotransferase > the upper limit of normal) require no dose adjustment.
The recommended dose for patients with moderate (total bilirubin >1.5–3 times the upper limit of normal, with any level of aspartate aminotransferase) or severe (total bilirubin >3 times the upper limit of normal, with any level of aspartate aminotransferase) hepatic impairment has not been determined.
Renal Impairment
Patients with mild to moderate renal impairment (estimated glomerular filtration rate 30–90 mL/min) require no dose adjustment.
Patients with severe renal impairment or renal failure (estimated glomerular filtration rate <30 mL/min) and those undergoing dialysis... The recommended dose for patients has not yet been determined.
Elderly Patients
There is currently no specific dose recommendation.
III. Administration
1. Repotrectinib must be administered orally.
2. Administer at approximately the same time each day, with or without food.
3. Capsules must be swallowed whole. Do not open, chew, crush, or dissolve them before swallowing. Do not take any broken, cracked, or damaged capsules.
4. If a dose is missed, or if vomiting occurs at any time after taking the medication, skip that dose and continue taking the next dose of repotrectinib at the usual time.
IV. Pretreatment Screening
1. For patients with locally advanced or metastatic non-small cell lung cancer who are scheduled to receive repotrectinib treatment. 1. First, confirm the presence of c-ros oncogene 1 (ROS-1) rearrangement in the tumor specimen.
2. For patients with solid tumors scheduled for ripretinib treatment, confirm the presence of neurotrophic receptor tyrosine kinase (NTRK) 1/2/3 rearrangement in the tumor specimen.
3. Serum uric acid levels must be assessed before initiating ripretinib.
4. Liver function tests (including aspartate aminotransferase, alanine aminotransferase, and bilirubin) must be performed before initiating ripretinib.
5. For female patients of reproductive potential, confirm their pregnancy status.
V. Patient Monitoring
1. Monitor the patient for new or worsening pulmonary symptoms suggestive of interstitial lung disease/pneumonia.
2. Treatment first... 1. Liver function tests (including alanine aminotransferase, aspartate aminotransferase, and bilirubin) should be performed every 2 weeks for the first month, then monthly, and as needed clinically.
2. Serum creatine phosphokinase (CPK) levels should be monitored every 2 weeks during the first month of treatment; monitoring is also necessary during treatment, and should be performed as needed if the patient experiences unexplained muscle pain, tenderness, or weakness.
3. Serum uric acid levels should be monitored regularly during treatment.
Precautions for Repotrectinib
Central Nervous System Adverse Reactions
Several central nervous system adverse reactions have been reported, such as dizziness (e.g., vertigo), ataxia (e.g., gait disturbance, balance disorder), and cognitive impairment (e.g., vertigo). Memory impairment, attention deficit, confusion, mood disturbances (such as anxiety), and sleep disturbances (such as insomnia and somnolence) are common. The incidence of adverse reactions is similar in patients with and without central nervous system metastases.
Interstitial Lung Disease/Pneumonia
Interstitial lung disease (ILD)/pneumonia has been reported. Patients should be monitored for new or worsening pulmonary symptoms suggestive of ILD/pneumonia. If ILD/pneumonia is suspected, repotrectinib should be discontinued immediately. If ILD/pneumonia is diagnosed, repotrectinib should be permanently discontinued.
Hepatotoxicity
Hepatotoxicity (such as elevated alanine aminotransferase/aspartate aminotransferase, hyperbilirubinemia) has been reported. (Hepatotoxicity). If hepatotoxicity occurs, repotrectinib should be discontinued. Once symptoms improve, medication may be resumed at the same or reduced dose, or permanently discontinued depending on the severity.
Myalgia with Elevated Creatine Phosphokinase (CPK)
Myalgia with or without elevated CPK has been reported. During the first month of treatment, CPK levels should be monitored every 2 weeks. Monitoring should be performed as needed if unexplained muscle pain, tenderness, or weakness occurs. Supportive care should be provided as clinically necessary.
Hyperuricemia
Hyperuricemia has been reported. Serum uric acid levels should be monitored regularly before starting repotrectinib and during treatment. Treatment should be based on clinical needs. The patient requires uric acid-lowering therapy.
Bone Fractures
Bone fractures have been reported. Fractures involve the ribs, foot, spine, acetabulum, sternum, and ankle; some fractures occurred at the site of the lesion and at sites previously treated with radiation. There are currently no data on the effect of Repotrectinib on the healing of known fractures or on the risk of future fractures.
Fetal/Neonatal Morbidity and Mortality
Repotrectinib can cause harm to the fetus. Human data and animal reproductive studies have been conducted on congenital mutations leading to altered tropomyosin receptor tyrosine kinase (TRK) signaling. Fetal malformations have been observed in animals.
Use in Special Populations
Pregnancy Based on human data, animal studies, and the mechanism of action of repotrectinib (a congenital mutation leading to altered TRK signaling), this drug may cause harm to the fetus.
There are currently no human data on the use of repotrectinib in pregnant women. Fetal malformations have been observed in animals. Pregnant women should be informed of the potential harm to the fetus.
Lactation
It is unknown whether repotrectinib passes into human breast milk or affects milk production or breastfed infants. It is recommended that breastfeeding women discontinue breastfeeding during treatment and for 10 days after the last dose.
Biological Women and Men of Reproductive Potential
The pregnancy status of women of reproductive potential should be confirmed before initiating treatment with repotrectinib. Women of reproductive potential are advised to use effective non-hormonal contraception during treatment and for two months after the last dose. Men whose partners are women of reproductive potential are advised to use effective contraception during treatment and for four months after the last dose.
Pediatric Patients
The safety and efficacy of repotrectinib in treating locally advanced or metastatic neurotrophic tyrosine receptor kinase (NTRK)-positive solid tumors has been established in pediatric patients aged 12 years and older. For children under 12 years of age with NTRK... The safety and efficacy of repotrectinib in pediatric patients with RK gene fusion-positive solid tumors have not been established.
Elderly Patients
No clinically significant differences in efficacy or safety of repotrectinib were observed between elderly patients (≥65 years) and younger patients.
Hepatic Impairment
No clinically significant differences in the pharmacokinetics of repotrectinib were observed in patients with mild hepatic impairment (total bilirubin >1–1.5 times the upper limit of normal or aspartate aminotransferase > the upper limit of normal).
Renal Impairment
Repotrectinib was administered to patients with mild to moderate renal impairment (estimated glomerular filtration rate 30–<90 mL/min). No clinically significant differences were observed in the pharmacokinetics of repotrectinib. The effects of severe renal insufficiency, renal failure (estimated glomerular filtration rate <30 mL/min), or dialysis on the pharmacokinetics of repotrectinib are unclear or not fully elucidated.
Common Adverse Reactions
Common adverse reactions (incidence >20%)
Dizziness, dysgeusia, peripheral neuropathy, constipation, dyspnea, fatigue, ataxia, cognitive impairment, muscle weakness, nausea.
Drug Interactions
Hormonal Contraceptives (e.g., estrogen, progestin)
Reduced exposure to progestin or estrogen may decrease the effectiveness of hormonal contraceptives. Avoid concomitant use. Women of reproductive potential are advised to use effective non-hormonal contraceptives.
Itraconazole (a potent CYP3A and P-glycoprotein inhibitor)
Repotrectinib showed a 5.9-fold increase in area under the curve (AUC) and a 1.7-fold increase in peak plasma concentration. Concomitant use should be avoided. Itraconazole should be discontinued 3-5 elimination half-lives before starting repotrectinib.
Midazolam (a CYP3A substrate)
Midazolam showed a 69% decrease in area under the curve (AUC) and a 48% decrease in peak plasma concentration. For CYP3A inhibitors, even slight changes in concentration can lead to reduced efficacy. Substrate should be avoided for concurrent use unless otherwise recommended in the prescribing information for that substrate.
Rifampin (a potent CYP3A and P-glycoprotein inducer)
The area under the curve (AUC) and peak plasma concentration of Repotrectinib were reduced by 92% and 79%, respectively. Concurrent use should be avoided.
Note: Due to space limitations, please refer to the original drug package insert for detailed information. Specific medication administration should be based on your doctor's instructions.
Pharmacokinetics
Absorption.
Bioavailability.
Absolute bioavailability: 45.7%.
Peak plasma concentrations are reached approximately 2–3 hours after a single oral dose of 40–240 mg in an empty stomach.
Within the single dose range of 40–240 mg, the time... The area under the curve (AUC) and peak plasma concentration increased approximately proportionally with the dose (but non-linearly, with estimated slopes of 0.70 and 0.78, respectively).
Steady state was reached within 14 days after daily administration of 160 mg. Steady-state pharmacokinetics were time-dependent due to CYP3A4 self-induction.
Food Effects
No clinically significant differences in the pharmacokinetics of repotrectinib were observed after consuming a high-fat meal (approximately 800–1000 calories, 50% fat).
Distribution
It is unclear whether it is distributed in human breast milk.
Plasma protein binding: 95.4% (in vitro data).
Blood and Plasma Concentration ratio: 0.56 (in vitro data).
Elimination
Metabolism
Primarily metabolized by CYP3A4, followed by secondary glucuronidation.
Elimination pathway
Following a single oral dose of 160 mg of radiolabeled drug, 4.84% (0.56% of which is unchanged drug) is excreted in the urine and 88.8% (50.6% of which is unchanged drug) is excreted in the feces.
Elimination is time-dependent due to the self-induction of CYP3A4.
Half-life
The mean terminal half-life after a single dose is approximately 60.7 hours.
The terminal half-life at steady state is approximately 40.3 hours.
Storage
20–25°C; brief fluctuations between 15–30°C are permissible.
