Introduction
Gavreto™ (pralsetinib) is an oral, selective RET (Rearranged during Transfection) kinase inhibitor developed by Blueprint Medicines Corporation. It received FDA accelerated approval in September 2020 for the treatment of specific RET-altered cancers. Gavreto represents a targeted therapy option for patients with RET-driven malignancies, offering a precision medicine approach to cancer treatment.
Mechanism of Action
Pralsetinib is a highly selective tyrosine kinase inhibitor that targets RET alterations, including fusions and mutations. It works by binding to the ATP-binding pocket of RET kinase, inhibiting its autophosphorylation and subsequent downstream signaling pathways. This inhibition prevents tumor cell proliferation and survival in cancers harboring RET gene alterations. Gavreto demonstrates potent activity against various RET alterations while maintaining selectivity over other kinases, potentially reducing off-target effects.
Indications
- Treatment of adult patients with metastatic RET fusion-positive non-small cell lung cancer (NSCLC)
- Treatment of adult and pediatric patients 12 years of age and older with advanced or metastatic RET-mutant medullary thyroid cancer (MTC) who require systemic therapy
- Treatment of adult and pediatric patients 12 years of age and older with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and are radioactive iodine-refractory (if radioactive iodine is appropriate)
Dosage and Administration
Standard dosing: 400 mg orally once daily on an empty stomach (no food for at least 2 hours before and at least 1 hour after administration) Dose modifications:- For adverse reactions: First dose reduction to 300 mg daily; second dose reduction to 200 mg daily; if unable to tolerate 200 mg daily, permanently discontinue
- Hepatic impairment: No dosage adjustment recommended for mild to moderate impairment; not studied in severe impairment
- Renal impairment: No dosage adjustment recommended for mild to moderate impairment; not studied in severe impairment
- Pediatric patients: Recommended dose is based on body surface area
Pharmacokinetics
Absorption: Median Tmax is 2-4 hours; high-fat meal reduces exposure by approximately 78% Distribution: Apparent volume of distribution is 307 L; protein binding is 97.3% Metabolism: Primarily metabolized by CYP3A4 Elimination: Half-life is approximately 22 hours; 67% excreted in feces (mostly unchanged) and 23% in urineContraindications
- Hypersensitivity to pralsetinib or any component of the formulation
- No other absolute contraindications identified in prescribing information
Warnings and Precautions
Interstitial Lung Disease (ILD)/Pneumonitis: Occurred in 10% of patients, with Grade 3-4 events in 2.7%. Monitor for respiratory symptoms and discontinue for suspected ILD. Hypertension: 14% of patients developed hypertension. Control blood pressure before initiation and monitor regularly during treatment. Hepatotoxicity: Increased AST and ALT occurred in 24% and 16% of patients respectively. Monitor liver function tests regularly. Hemorrhagic Events: Serious hemorrhagic events occurred in 2.7% of patients. Monitor for signs of bleeding. Risk of Impaired Wound Healing: Withhold Gavreto for at least 5 days before elective surgery and for at least 2 weeks after major surgery. Embryo-Fetal Toxicity: Can cause fetal harm. Verify pregnancy status and advise effective contraception.Drug Interactions
Strong CYP3A Inhibitors: Avoid concomitant use; if unavoidable, reduce Gavreto dose Strong CYP3A Inducers: Avoid concomitant use; may decrease pralsetinib exposure Acid-Reducing Agents: Avoid concomitant proton pump inhibitors; separate H2-receptor antagonists and antacids by at least 2 hours before or after Gavreto administrationAdverse Effects
Most common adverse reactions (≥25%):- Fatigue (43%)
- Constipation (40%)
- Musculoskeletal pain (39%)
- Hypertension (35%)
- Pneumonitis (2.7%)
- Hypertension (2.3%)
- Anemia (1.8%)
- Increased alanine aminotransferase (1.8%)
Monitoring Parameters
- Baseline and regular monitoring of liver function tests (every 2 weeks for first 3 months, then monthly)
- Blood pressure monitoring at baseline and regularly during treatment
- Regular assessment of respiratory symptoms
- Complete blood count with differential
- Renal function tests
- Signs and symptoms of hemorrhage
- Pregnancy testing in females of reproductive potential
Patient Education
- Take exactly as prescribed on an empty stomach
- Report any new or worsening respiratory symptoms immediately
- Monitor blood pressure regularly as directed
- Report signs of liver problems (jaundice, dark urine, abdominal pain)
- Use effective contraception during treatment and for 2 weeks after final dose
- Inform all healthcare providers about Gavreto use before any surgical procedures
- Do not take antacids within 2 hours of Gavreto administration
- Report any unusual bleeding or bruising
References
1. FDA Prescribing Information: Gavreto (pralsetinib) capsules. September 2020. 2. Gainor JF, et al. Pralsetinib for RET fusion-positive non-small-cell lung cancer: results from the ARROW trial. Nature Medicine. 2021;27:1-8. 3. Subbiah V, et al. Pralsetinib for patients with advanced or metastatic RET-altered thyroid cancer. Lancet Oncology. 2021;22(7):959-969. 4. Blueprint Medicines Corporation. Clinical study report: ARROW. 2020. 5. NCCN Guidelines: Non-Small Cell Lung Cancer. Version 3.2022. 6. NCCN Guidelines: Thyroid Carcinoma. Version 2.2022.
This monograph is intended for educational purposes only. Healthcare providers should consult the full prescribing information and clinical guidelines for complete treatment recommendations.