Repotrectinib – Next-Generation ROS1 and NTRK Tyrosine Kinase Inhibitor

Repotrectinib is a low-molecular-weight, highly potent, next-generation tyrosine kinase inhibitor designed for the targeted therapy of malignant neoplasms. The drug possesses combined activity against oncogenic fusions of ROS1 (proto-oncogene tyrosine-protein kinase ROS) and the TRK family (tropomyosin receptor kinases TRKA, TRKB, and TRKC). Its mechanism of action is based on competitive binding to the ATP-binding pocket of the kinase domain, which suppresses autophosphorylation and blocks downstream mitogenic signaling cascades that control the survival, division, and migration of cancer cells.

A unique structural feature of repotrectinib is its small three-dimensional size and macrocyclic configuration. This structure allows the molecule to penetrate deeply into the catalytic center of the receptor, bypassing the spatial steric hindrances created by acquired resistance mutations. The drug is highly effective against gatekeeper mutations and particularly against the challenging ROS1 G2032R solvent-front mutation, which causes tumor resistance to first-generation inhibitors (such as crizotinib). Furthermore, repotrectinib exhibits an exceptional ability to cross the blood-brain barrier and accumulate in the central nervous system, providing pronounced, long-term control over intracranial metastases. This therapeutic agent represents an advanced tool in precision oncology for treating genetically selected patient populations.

The drug is taken orally once daily for the first two weeks, followed by a transition to twice-daily dosing. Mandatory verification of ROS1 or NTRK translocations is required prior to prescription.

Wikipedia page
Repotrectinib

Indications

Repotrectinib is indicated for the treatment of adult and pediatric patients with the following tumor types:

  • ROS1-positive NSCLC: locally advanced or metastatic non-small cell lung cancer in adult patients, regardless of prior treatment with ROS1 inhibitors.
  • NTRK-fusion Solid Tumors: advanced solid tumors in adult and pediatric patients aged 2 years and older with confirmed NTRK1/2/3 gene fusions, when no alternative treatment is available or when standard therapy has failed.
  • CNS Metastases: treatment of brain tumor lesions caused by ROS1-positive or NTRK-positive cancer.

Dosage and administration

The dosing regimen of repotrectinib includes a dose-escalation phase to allow for patient adaptation and to minimize neurological toxicity.

  • Initial Dose (Days 1–14): 160 mg taken orally once daily.
  • Maintenance Dose (From Day 15 onward): 160 mg taken orally twice daily (totaling 320 mg per day), provided the drug is well tolerated.
  • Administration Method: capsules are swallowed whole, with or without food. Opening, breaking, or chewing the capsules is strictly prohibited.
  • Missed Dose: if more than 6 hours remain until the next scheduled dose, the missed dose should be taken immediately. Otherwise, skip the missed dose and resume the regular schedule.
  • Dose Modification: in case of Grade 3 or 4 adverse reactions, the dose is reduced stepwise (to 120 mg twice daily, then to 160 mg once daily).

The use of repotrectinib is limited by the following contraindications and risk factors:

  • Hypersensitivity: confirmed allergy or hypersensitivity to repotrectinib or any component of the capsule shell.
  • Pregnancy and Lactation: the drug has embryotoxic potential. Females of reproductive potential and males must use highly effective methods of contraception during therapy and for 2 months after the final dose. Breastfeeding is prohibited.
  • Drug Interactions: concomitant use with strong or moderate CYP3A4 inducers or inhibitors is not permitted, as it unpredictably alters the plasma concentration of the active substance.

The side effects of repotrectinib are largely driven by the co-inhibition of TRK receptors, which play an important role in the functioning of the nervous system:

  • Dizziness: the most frequent neurological manifestation (including ataxia and vertigo), requiring caution when moving.
  • Dysgeusia: a pronounced distortion or complete loss of taste sensations.
  • Paresthesia: a sensation of numbness, tingling, or burning in the limbs.
  • Digestive Tract: chronic constipation, nausea, vomiting, and dry mouth.
  • General Manifestations: fatigue, muscular weakness, peripheral edema, and weight gain.
  • Laboratory Alterations: transient elevation of serum hepatic transaminases (ALT/AST) and alkaline phosphatase levels.

Frequently Asked Questions

Repotrectinib is a next-generation macrocyclic tyrosine kinase inhibitor targeting ROS1, NTRK, and ALK. Its primary advantage lies in its unique, compact three-dimensional structure. Due to its small molecular size, it binds tightly to the target protein and effectively overcomes resistance mutations (specifically solvent front mutations) that render previous-generation targeted therapies ineffective.
Repotrectinib is indicated for the treatment of advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC), as well as for adult and pediatric patients with various solid tumors harboring NTRK (1, 2, or 3) gene fusions. It can be prescribed both for patients who are treatment-naive and for those whose disease has progressed on prior tyrosine kinase inhibitors.
Yes, this substance possesses an exceptional ability to cross the blood-brain barrier and accumulate within the central nervous system. Clinical data demonstrate that repotrectinib achieves high and durable anti-tumor activity against intracranial lesions (brain metastases), significantly delaying disease progression within the CNS.
Due to its high CNS penetration, repotrectinib frequently causes specific neurological effects: dizziness, taste distortion (dysgeusia), ataxia (coordination difficulties), tingling sensations (paresthesia), and cognitive changes (memory or concentration issues). All such symptoms should be reported to a physician; they are typically manageable via temporary treatment interruptions or dose reductions.
The capsules are taken once daily for the first several days (the titration phase). If well tolerated, the physician then increases the schedule to twice daily. This step-up dosing approach helps the body, particularly the nervous system, adapt to the substance. The medication can be taken with or without food and capsules must be swallowed strictly whole.

List of medicines by active substance

-5%
Repotrex 40 mg Everest
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Everest

Repotrex

Repotrectinib
40 mg 56 capsules
29034₴ 30427₴
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