What Is Repotrectinib?
Repotrectinib is a cancer medication used to treat ROS1-positive non-small cell lung cancer (NSCLC), which can be difficult to treat, particularly if it spreads to the brain. The medicine works by identifying abnormal proteins caused by genetic mutations and blocking the signals that drive cancer cell growth and proliferation.
Repotrectinib is a next-generation tyrosine kinase inhibitor (TKI) that helps halt tumor growth by shrinking cancer cells, prevents the disease from spreading, and causes minimal harm to normal cells. It remains effective against cancer cells that have developed resistance to previous treatments. Repotrectinib, while effective in controlling the disease and improving outcomes, cannot cure cancer altogether.
FDA-Approval Date
Repotrectinib was approved by the United States Food and Drug Administration (USFDA) on November 15, 2023. Various clinical trials have demonstrated that Repotrectinib has the potential to be the new standard of care for patients with ROS1 fusion-positive NSCLC.
Drug Group:
Repotrectinib, a tyrosine kinase inhibitor, is a targeted cancer therapy. This therapeutic agent inhibits the activity of ROS1 and TRK (tropomyosin receptor kinase) proteins, which are involved in the proliferation and dissemination of specific neoplasms.
How Does Repotrectinib Work?
Repotrectinib is a targeted cancer drug that inhibits tyrosine kinases (TKIs). It blocks the activity of the proteins ROS1 and TRK (tropomyosin receptor kinase), which are important for the growth and spread of some cancer cells. By inhibiting these proteins, Repotrectinib can slow tumor growth and help control cancers such as ROS1-positive non-small cell lung cancer and NTRK fusion-positive solid tumors.
Indications of Repotrectinib:
Repotrectinib is approved for treating adult patients with metastatic or locally advanced ROS1-positive non-small cell lung cancer (NSCLC).
Contraindications of Repotrectinib:
Repotrectinib should not be used in the following groups:
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Children.
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Women who are pregnant or breastfeeding.
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Patients with severe kidney or liver disorders.
Available Doses and Dose Forms:
Repotrectinib is available as capsules and is recommended at 160 mg (milligrams) to be taken once a day for 14 days, with or without food. The prescribing doctor may later increase the dose to twice daily until unacceptable toxicity or disease progression occurs. In cases of adverse reactions,
1. For ROS1-Positive Non-Small Cell Lung Cancer:
Repotrectinib may be orally administered. The recommended dosage escalation in a first course of treatment is 160 mg once daily for 1 to 14 days. Once tolerated, it may be escalated to 160 mg twice daily. Doses will be continued until the patient has progressive disease or intolerable toxicity is noted.
2. For NTRK Fusion Solid Tumor:
Repotrectinib is an orally active drug used to treat NTRK gene fusion-positive, locally advanced or metastatic, or unresectable solid tumors. A first course dose of 160 mg PO BID. Escalated course cure, once tolerated and permitted, is 160 mg PO twice daily. The drug is to be continued until the patient has progressive disease or an unacceptable toxicity is encountered.
Warnings and Precautions:
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Repotrectinib could affect the brain and nervous system. Some people may feel dizzy, have trouble with balance, feel like they're spinning, or have trouble thinking and concentrating. It can also change your mood, making you feel anxious, sad, easily upset, or unable to sleep. The doctor may change the dose or stop the medicine if any of these side effects happen. Patients who are dizzy or confused should not drive or use heavy machinery.
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The drug may also lead to lung problems such as interstitial lung disease or pneumonitis. The patients may be required to stop the drug if lung problems appear. The drug may be halted if new or worsening breathing problems occur.
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Repotrectinib may also affect the liver and the muscles. The doctor may require blood tests to monitor liver enzyme levels and the muscle enzyme CPK. If you are experiencing unusual muscle pain, weakness, or tenderness, you should inform your doctor.
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The treatment could also lead to higher uric acid levels. It might also increase the risk of fractures. The doctor might test blood uric acid levels. Additionally, the doctor may assess for bone pain or difficulty with movement.
For Patients
How Effective Is Repotrectinib?
In ROS1-positive lung cancers, the fusion proteins can drive uncontrolled tumor cell growth. Repotrectinib, a recently developed drug, targets these specific proteins, minimizes interactions, and limits the excessive growth of malignant cells.
Clinical studies have shown that the tumor reduced in size or disappeared in approximately 79% of patients within 34 months. Repotrectinib not only shrinks the tumor cells in the lungs but also in other parts, including the brain, which is the most common site for metastasis of lung cancer.
Researchers believe that Repotrectinib is effective in tumors resistant to other drugs and may have a longer duration of action than other approved treatments.
How Should Repotrectinib Be Taken?
The instructions must be followed exactly, and the medicine must be taken at about the same time each day. The dose must not be changed, skipped, or stopped without consulting the doctor. The capsules should be swallowed whole. They shouldn't be opened, chewed, crushed, or dissolved in any liquids.
What Are the Side Effects of Repotrectinib?
The side effects of Repotrectinib include:
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Nausea.
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Diarrhea.
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Change or loss of taste.
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Weakness.
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Fatigue.
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Headache.
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Tiredness.
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Weight gain.
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Tingling sensation or numbness in the hands and feet.
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Swelling of the eyes, face, arms, and legs.
Serious side effects that require immediate medical assistance include:
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Dizziness and lack of balance.
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Mood changes such as agitation, confusion, anxiety, or depression.
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Sleep problems.
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Vision changes such as blurred vision, double vision, or light sensitivity.
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Pain in the lower back and stomach.
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Dark and bad-smelling urine.
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Trouble speaking or understanding.
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Decreased urination.
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Light-colored stools.
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Yellowish discoloration of the skin and eyes.
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Difficulty breathing.
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Lack of attention and trouble understanding.
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Muscle and joint pain.
What Must the Patient Inform the Doctor About Before Taking Repotrectinib?
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Before starting the treatment, patients must tell the doctor if they are allergic to Repotrectinib, its ingredients, or any other medications.
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Patients must inform the doctor if they have neurological disorders or lung or liver problems before initiating treatment with Repotrectinib.
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Patients must inform their healthcare provider of any other medications, herbal medicines, vitamins, nutritional supplements, or over-the-counter (OTC) medicines they are taking before taking Repotrectinib.
Dietary Considerations
Grapefruit or grapefruit juice must not be consumed by patients while taking Repotrectinib.
Missed Dose
If the patient misses a dose or vomits a dose of Repotrectinib, it must be skipped, and the next dose must be taken as scheduled. A double or extra dose must not be taken to make up for the missed dose.
Overdose
In case of an overdose of Repotrectinib or if other serious adverse effects are observed, the doctor must be consulted immediately.
Storage
Repotrectinib must be stored at room temperature, around 20 to 25 degrees Celcius (68 to 77 degrees Fahrenheit), away from excess heat and moisture.
For Doctors
Pharmacological Aspects of Repotrectinib
Mechanism of Action
Repotrectinib is a low-molecular-weight proto-oncogene tyrosine kinase inhibitor that works on the ROS1 and TRK proteins. It works by blocking the signals that make cancer cells grow and divide too quickly. Repotrectinib is an anticancer drug that binds to the active form of kinases. This stops tumor cells from growing further and works against cancers that are resistant to other drugs.
Pharmacodynamics
It is not yet clear how the amount of repotrectinib in the body affects its activity or how long its effects last.
Pharmacokinetics
After taking the recommended twice-daily dose of repotrectinib, the peak blood level reaches about 713 ng/mL, and the total drug exposure (AUC) is 7210 ng·h/mL. Taking the drug with a high-fat meal (800 to 1000 calories) does not significantly affect these levels.
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Absorption: After a single dose of 40 to 240 mg taken on an empty stomach, the highest blood levels usually appear within 2 to 3 hours.
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Distribution: About 95.4% of the drug binds to plasma proteins, and its apparent volume of distribution is 432 L.
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Metabolism: Repotrectinib is mainly metabolized by CYP3A4, followed by secondary glucuronidation.
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Excretion: The average half-life is about 50.6 hours after a single dose, and oral clearance is 15.9 L/h. After a 160 mg dose, about 4.84% is excreted in urine and 88.8% in feces.
Drug Interactions
Repotrectinib can interact with the following drugs:
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Abemaciclib.
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Acalabrutinib.
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Acyclovir.
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Albendazole.
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Allopurinol.
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Azithromycin.
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Carbamazepine.
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Chloramphenicol.
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Erythromycin.
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Fluconazole.
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Ketoconazole.
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Metronidazole.
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Mifepristone.
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Rifampin.
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Tetracycline.
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Valproic acid.
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Verapamil.
Clinical Studies
A multicenter, single-arm, open-label clinical trial (TRIDENT-1) was conducted in patients with ROS1-positive locally advanced or metastatic NSCLC to evaluate the efficacy of Repotrectinib. Patients were given an oral dose of 160 mg of Repotrectinib once daily for 14 days, and later, the dose was increased to 160 mg twice daily until unacceptable toxicity or disease progression.
Tumor assessments were performed every 8 weeks. The trial results showed an overall response rate of 79 percent in previously treated patients on platinum-based chemotherapy and around 38 percent in ROS1 inhibitor pre-treated patients.
Nonclinical Toxicology
Carcinogenicity and fertility studies have not been performed with Reportrectinib. The drug was found to be genotoxic in in vitro assays but is known not to be mutagenic in the in vitro bacterial reverse mutation (Ames) assay.
Specific Considerations
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Geriatric Use: No clinically significant differences were observed in geriatric patients compared with younger adults.
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Pediatric Population: The safety and efficacy of Repotrectinib have not been established in pediatric patients.
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Renal and Hepatic Impairment: Repotrectinib is contraindicated in patients with severe renal disorders and moderate to severe liver impairment. However, dose modification is not required in patients with mild to moderate renal disorders and mild liver impairment.
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Pregnant Women: Repotrectinib is contraindicated in pregnancy. The drug may harm the baby; hence, pregnant women are informed about the potential risk to the fetus before administration. Females of reproductive potential must use effective non-hormonal contraceptive methods during the treatment and for up to two months following the last dose of Repotrectinib.
