FDA Approves AYVAKIT (Avapritinib) for the Treatment of Adults with Unresectable or Metastatic Gastrointestinal Stromal Tumor Harboring a Platelet-derived Growth Factor Receptor Alpha Exon 18 Mutation


On January 9, 2020, the U.S. Food and Drug Administration (FDA) approved AYVAKIT (avapritinib) for
the treatment of adults with unresectable or metastatic gastrointestinal stromal tumor (GIST) harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation, including PDGFRA D842V mutations. Select patients for treatment with AYVAKIT based on the presence of a PDGFRA exon 18 mutation. The approved recommended dosage of AYVAKIT is 300 mg orally once daily on an empty stomach, at least 1 hour before and 2 hours after a meal. Additional information regarding dosage and administration as well as important warnings and precautions related to intracranial hemorrhage, central nervous system effects, and embryo-fetal toxicity can be found in the full prescribing information linked below.

Mechanism of Action (MOA), Pharmacokinetics (PK), and Pharmacodynamics (PD)

  • MOA: Avapritinib is a tyrosine kinase inhibitor.
  • General PK: Avapritinib Cmax and AUC increased proportionally over the dose range of 30 mg to 400 mg once daily (0.1 to 1.33 times the recommended dose). At the recommended dosage of 300 mg once daily, the mean (CV%) steady state Cmax of avapritinib was 813 ng/mL (52%) and the mean steady state AUC0-24h was 15400 h•ng/mL (48%). Steady state concentration of avapritinib was reached by day 15 following daily dosing and the mean accumulation ratio was 3.1 to 4.6 after repeated dosing.
  • Absorption: The median Tmax ranged from 2.0 to 4.1 hours following single doses of avapritinib 30 mg to 400 mg.
  • Effect of Food: The Cmax of avapritinib was increased by 59% and the AUC0-INF was increased by 29% when AYVAKIT was taken with a high-calorie, high-fat meal (approximately 909 calories, 58 grams carbohydrate, 56 grams fat and 43 grams protein) compared to those in the fasted state.
  • Distribution: The mean apparent volume of distribution of avapritinib is 1200 L (43%). In vitro protein binding of avapritinib is 98.8% and is independent of concentration. The blood-to-plasma ratio is 0.95.
  • Elimination: The mean plasma elimination half-life of avapritinib was 32 hours to 57 hours following single doses of avapritinib 30 mg to 400 mg. The steady state mean apparent oral clearance of avapritinib is 19.5 L/h (48%).
  • Metabolism: Avapritinib is primarily metabolized by CYP3A4 and to a lesser extent by CYP2C9 in vitro.
  • Excretion: Following a single oral dose of approximately 310 mg of radiolabeled avapritinib to healthy subjects, 70% of the radioactive dose was recovered in feces (11% unchanged) and 18% in urine (0.23% unchanged).
  • PD: Based on the data from a multi-center, single-arm, open-label clinical trial, exposure-response relationships for any Grade 3 or 4 adverse reaction were observed at higher exposures with a faster time to onset for adverse reactions with increasing avapritinib exposure.

Drug Interactions

  • Strong and Moderate CYP3A Inhibitors: Avoid coadministration of AYVAKIT with strong or moderate CYP3A inhibitors. If coadministration with a moderate CYP3A inhibitor cannot be avoided, reduce the starting dose of AYVAKIT from 300 mg orally once daily to 100 mg orally once daily. Coadministration of AYVAKIT with a strong or moderate CYP3A inhibitor increases avapritinib plasma concentrations, which may increase the incidence and severity of adverse reactions of AYVAKIT.
  • Strong and Moderate CYP3A Inducers: Avoid coadministration of AYVAKIT with strong or moderate CYP3A inducers. Coadministration of AYVAKIT with a strong or moderate CYP3A inducer decreases avapritinib plasma concentrations, which may decrease efficacy of AYVAKIT.

Use in Specific Populations

No clinically significant differences in the PK of avapritinib were observed based on age (18 to 90 years), sex, race (White, Black, or Asian), body weight (39.5 to 156.3 kg), mild to moderate (CLcr 30 to 89 mL/min estimated by Cockcroft-Gault) renal impairment, or mild (total bilirubin ≤ ULN and AST > ULN or total bilirubin > 1 to 1.5 times ULN and any AST) to moderate (total bilirubin > 1.5 to 3 times ULN and any AST) hepatic impairment. The effect of severe renal impairment (CLcr 15 to 29 mL/min), end-stage renal disease (CLcr < 15 mL/min), or severe hepatic impairment (total bilirubin > 3 times ULN and any AST) on the PK of avapritinib is unknown.

Lactation

Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with AYVAKIT and for 2 weeks following the final dose.

Efficacy and Safety

The efficacy of AYVAKIT was demonstrated in a multi-center, single-arm, open-label clinical trial in patients who were required to have a confirmed diagnosis of GIST and an ECOG performance status (PS) of 0 to 2. The major efficacy outcome measure was overall response rate based on disease assessment by independent radiological review using modified RECIST v1.1 criteria, in which lymph nodes and bone lesions were not target lesions and progressively growing new tumor nodules within a pre-existing tumor mass was progression. An additional efficacy outcome measure was duration of response. Additional information regarding the efficacy trial can be found in the full prescribing information linked below.

The most common adverse reactions (incidence ≥ 20%) are edema, nausea, fatigue/asthenia, cognitive impairment, vomiting, decreased appetite, diarrhea, hair color changes, increased lacrimation, abdominal pain, constipation, rash and dizziness.


Full prescribing information is available at https://go.usa.gov/xdqmx.

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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.