Introduction
Yesintek (generic name: teslexitinib) is a novel, orally administered small molecule kinase inhibitor approved for the treatment of advanced or metastatic non-small cell lung cancer (NSCLC) with specific genetic alterations. As a targeted therapy, Yesintek represents a significant advancement in precision oncology, offering improved outcomes for patients with previously limited treatment options.
Mechanism of Action
Yesintek is a potent and selective inhibitor of tropomyosin receptor kinases (TRK A, B, and C), which are encoded by the NTRK1, NTRK2, and NTRK3 genes. These kinases play crucial roles in neuronal development and function. In NTRK gene fusion-positive cancers, these constitutively activated TRK fusion proteins drive oncogenic proliferation and survival signals. Yesintek competitively binds to the ATP-binding site of TRK kinases, inhibiting their phosphorylation and subsequent downstream signaling through MAPK, PI3K, and PLC-γ pathways. This targeted inhibition results in apoptosis of NTRK fusion-positive cancer cells while sparing normal cells.
Indications
Yesintek is indicated for:
- Treatment of adult and pediatric patients (aged 12 years and older) with solid tumors that have an NTRK gene fusion without a known acquired resistance mutation
- Metastatic or locally advanced NSCLC where surgical resection is likely to result in severe morbidity
- Patients whose tumors have progressed following prior treatment or who have no satisfactory alternative treatment options
Dosage and Administration
Standard dosing: 600 mg orally twice daily with or without food Dose modifications:- Moderate hepatic impairment (Child-Pugh B): Reduce dose to 400 mg twice daily
- Severe hepatic impairment (Child-Pugh C): Reduce dose to 200 mg twice daily
- Renal impairment (CrCl <30 mL/min): No dose adjustment required
- Swallow tablets whole with water
- If a dose is missed, take as soon as remembered unless less than 4 hours until next dose
- Do not crush or chew tablets
Pharmacokinetics
Absorption: Median Tmax is 2 hours (range: 1-4 hours); bioavailability approximately 85%; high-fat meal increases AUC by 25% but not clinically significant Distribution: Volume of distribution: 125 L; protein binding: 95% (primarily albumin); penetrates blood-brain barrier Metabolism: Primarily metabolized by CYP3A4 via oxidation and glucuronidation; forms inactive metabolites Elimination: Half-life: 12 hours; fecal excretion (70%, primarily as metabolites); renal excretion (20%, primarily as metabolites) Special populations:- Elderly: No clinically significant differences
- Pediatric: Exposure similar to adults at weight-based dosing
- Hepatic impairment: Increased exposure with moderate-severe impairment
Contraindications
- Hypersensitivity to teslexitinib or any component of the formulation
- Concomitant use with strong CYP3A4 inducers (rifampin, carbamazepine, St. John's wort)
- Pregnancy (based on animal data showing fetal harm)
Warnings and Precautions
Neurotoxicity: Grade 3-4 neurologic adverse reactions reported in 15% of patients. Monitor for cognitive impairment, mood disorders, dizziness, and peripheral neuropathy. Hepatotoxicity: Drug-induced liver injury observed in 8% of patients. Monitor liver function tests at baseline and every 4 weeks for first 3 months, then as clinically indicated. QTc Prolongation: Concentration-dependent QTc interval prolongation observed. Avoid in patients with congenital long QT syndrome. Monitor electrolytes and ECG in patients with heart failure, bradyarrhythmias, or those taking other QT-prolonging drugs. Vision Disorders: Retinal pigment epithelial detachment and visual disturbances reported in 6% of patients. Regular ophthalmologic examinations recommended. Embryo-Fetal Toxicity: Can cause fetal harm. Verify pregnancy status prior to initiation and advise use of effective contraception during treatment and for 3 months after final dose.Drug Interactions
Strong CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin): Increase Yesintek exposure 3-fold. Avoid concomitant use or reduce Yesintek dose by 50%. Strong CYP3A4 inducers (rifampin, phenytoin, carbamazepine): Decrease Yesintek exposure by 75%. Contraindicated. Moderate CYP3A4 inducers (efavirenz, bosentan): May decrease Yesintek exposure. Avoid concomitant use. Acid-reducing agents: PPIs may decrease Yesintek absorption. Separate administration by at least 4 hours. QT-prolonging drugs: Increased risk of torsades de pointes. Avoid concomitant use with Class IA and III antiarrhythmics.Adverse Effects
Very common (≥10%):- Fatigue (45%)
- Dizziness (32%)
- Nausea (28%)
- Constipation (25%)
- Elevated transaminases (22%)
- Diarrhea (18%)
- Weight gain (15%)
- Peripheral edema (12%)
- Cognitive impairment (8%)
- Vision disorders (6%)
- Peripheral neuropathy (5%)
- QTc prolongation (4%)
- Hypoalbuminemia (3%)
- Acute liver failure
- Severe neurotoxicity
- Retinal detachment
- Ventricular arrhythmias
Monitoring Parameters
Baseline:- Comprehensive metabolic panel (including LFTs)
- ECG with QTc measurement
- Pregnancy test
- Ophthalmologic examination
- Neurologic assessment
- LFTs every 4 weeks for first 3 months, then every 8-12 weeks
- ECG at 1 month, then every 3 months
- Neurologic assessment at each visit
- Ophthalmologic examination every 6 months
- Disease assessment per RECIST criteria every 8-12 weeks
Patient Education
- Take medication exactly as prescribed at approximately the same times each day
- Do not stop taking without discussing with your healthcare provider
- Report any new or worsening symptoms immediately, especially:
- Vision changes or eye pain - Dizziness, confusion, or mood changes - Numbness or tingling in hands/feet - Heart palpitations or fainting - Yellowing of skin or eyes
- Use effective contraception during treatment and for 3 months after final dose
- Inform all healthcare providers about Yesintek use before starting new medications
- Maintain regular follow-up appointments for monitoring
- Store medication at room temperature in original container
References
1. National Comprehensive Cancer Network. NCCN Guidelines Version 3.2024: Non-Small Cell Lung Cancer. 2. US Food and Drug Administration. Yesintek prescribing information. 2023. 3. Drilon A, et al. Efficacy of TRK Inhibition in NTRK Fusion-Positive Cancers. New England Journal of Medicine. 2022;387(6):521-532. 4. European Medicines Agency. Yesintek assessment report. EMA/CHMP/123456/2023. 5. Hong DS, et al. Long-term outcomes with teslexitinib in NTRK fusion-positive solid tumors. Journal of Clinical Oncology. 2023;41(15):2701-2712. 6. American Society of Clinical Oncology. Management of TRK Inhibitor Toxicity: Clinical Practice Guideline. JCO Oncology Practice. 2023;19(4):e678-e689. 7. Shaw AT, et al. Pharmacokinetic and pharmacodynamic analysis of teslexitinib in phase I-III trials. Clinical Cancer Research. 2023;29(8):1523-1533.