Pralsetinib

GAVRETO is a kinase inhibitor indicated for treatment of: Adult patients with metastatic rearranged during transfection (RET ) fusion-positive non-small cell lung cancer as detected by an FDA approved test (NSCLC). Adult and pediatric patients 12 years of age and older with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate). This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

Pralsetinib is a kinase inhibitor of wild-type RET and oncogenic RET fusions (CCDC6- RET ) and mutations ( RET V804L, RET V804M and RET M918T) with half maximal inhibitory concentrations (IC 50s ) less than 0.5 nM. In purified enzyme assays, pralsetinib inhibited DDR1, TRKC, FLT3, JAK1-2, TRKA, VEGFR2, PDGFRB, and FGFR1 at higher concentrations that were still clinically achievable at C max. In cellular assays, pralsetinib inhibited RET at approximately 14-, 40-, and 12-fold lower concentrations than VEGFR2, FGFR2, and JAK2, respectively. Certain RET fusion proteins and activating point mutations can drive tumorigenic potential through hyperactivation of downstream signaling pathways leading to uncontrolled cell proliferation.

Select patients for treatment with GAVRETO based on the presence of a RET gene fusion. The recommended dosage in adults and pediatric patients 12 years and older is 400 mg orally once daily on an empty stomach (no food intake for at least 2 hours before and at least 1 hour after taking GAVRETO).

None. None.

Boxed warning (serious infections, including opportunistic infections gavreto): may increase the risk for serious infections, including bacterial, fungal, viral and opportunistic infections, which can lead to hospitalization or death. Withhold, reduce the dose or permanently discontinue GAVRETO based on severity. Serious Infections, Including Opportunistic Infections: Monitor for signs and symptoms of infection and treat appropriately. Withhold, reduce the dose, or permanently discontinue GAVRETO based on severity. Interstitial Lung Disease (ILD)/Pneumonitis: Withhold GAVRETO for Grade 1 or 2 reactions until resolution and then resume at a reduced dose. Permanently discontinue for recurrent ILD/pneumonitis. Permanently discontinue for Grade 3 or 4 reactions. Hypertension: Do not initiate GAVRETO in patients with uncontrolled hypertension.

The following clinically significant adverse reactions are described elsewhere in the labeling: Serious Infections, Including Opportunistic Infections Interstitial Lung Disease/Pneumonitis Hypertension Hepatotoxicity Hemorrhagic Events Tumor Lysis Syndrome Risk of Impaired Wound Healing Embryo-Fetal Toxicity The most common adverse reactions (≥ 25%) were musculoskeletal pain, constipation, hypertension, diarrhea, fatigue, edema, pyrexia and cough. The most common Grade 3-4 laboratory abnormalities (≥ 2%) were decreased lymphocytes, decreased neutrophils, decreased hemoglobin, decreased phosphate, decreased leukocytes, decreased sodium, increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), decreased calcium (corrected), decreased platelets, increased alkaline phosphatase, increased potassium, decreased potassium and increased bilirubin.

Strong or moderate CYP3A inhibitors and/or P-gp inhibitors: Avoid coadministration. If coadministration cannot be avoided, reduce the dose of GAVRETO. Strong or moderate CYP3A inducers: Avoid coadministration. If coadministration cannot be avoided, increase the dose of GAVRETO.

Store at 20°C to 25°C (68°F to 77°F), excursions are permitted from 15°C to 30°C (59°F to 86°F). Protect from moisture.