On June 16, 2021, avapritinib was approved for the treatment of adult patients with advanced systemic mastocytosis, including patients with aggressive systemic mastocytosis, systemic mastocytosis with an associated hematological neoplasm, and mast cell leukemia.^1,2 Avapritinib is not recommended for the treatment of patients with advanced systemic mastocytosis with platelet counts < 50 × 10⁹/L.

Supporting Efficacy Data

The study was supported by findings in the multicenter, single-arm EXPLORER (ClinicalTrials.gov identifier NCT02561988) and PATHFINDER (NCT03580655) trials.² Efficacy data are from 53 evaluable patients in the trials who received oral daily doses of avapritinib of up to 200 mg.

The main efficacy outcome measure was overall response rate on the modified international working group–myeloproliferative neoplasms research and treatment–European competence network on mastocytosis criteria, as assessed by a central committee.

A response was observed in 30 patients (57%, 95% confidence interval [CI] =42%–70%), with complete remission in 28% and partial remission in 28%. Median time to response was 2.1 months. Median duration of response was 38.3 months (95% CI = 19 months to not estimable). A response was observed in 23 (58%) of 40 patients with systemic mastocytosis with an associated hematological neoplasm (33% complete and 25% partial remission), 5 (45%) of 11 with mast cell leukemia (9% complete and 36% partial remission), and 2 of 2 with aggressive systemic mastocytosis (complete and partial remission in 1 each).

How It Works

Avapritinib is a tyrosine kinase inhibitor that targets KIT D816V, platelet-derived growth factor receptor alpha (PDGFRA), and PDGFRA D842 mutants as well as multiple KIT exon 11, 11/17, and 17 mutants with half-maximal inhibitory concentrations (IC-50) < 25 nM in biochemical assays. Certain mutations in PDGFRA and KIT can result in the autophosphorylation and constitutive activation of these receptors, which can contribute to tumor and mast cell proliferation. Other potential targets for avapritinib include wild-type KIT, PDGFRB, and CSFR1.

How It Is Used

Avapritinib is not recommended for the treatment of patients with advanced systemic mastocytosis with platelet counts < 50 × 10⁹/L. The recommended dose of avapritinib in patients with advanced systemic mastocytosis is 200 mg once daily, with treatment continued until disease progression or unacceptable toxicity. Recommended dose reductions for adverse reactions are sequentially to 100, 50, and 25 mg once daily; treatment should be permanently discontinued in patients unable to tolerate 25 mg once daily.

Product labeling provides instructions on dosage modification—including dose reduction and withholding and discontinuation of treatment—for adverse reactions including intracranial hemorrhage, cognitive effects, thrombocytopenia, and other grade 3 or 4 adverse reactions. Treatment should be permanently discontinued for any-grade intracranial hemorrhage and grade 4 cognitive effects.

Concomitant use of avapritinib with strong or moderate CYP3A inhibitors (eg, ketoconazole, conivaptan, clarithromycin) should be avoided. If concomitant use with a moderate CYP3A inhibitor (eg, amiodarone, erythromycin, fluconazole) cannot be avoided, the avapritinib dose should be reduced to 50 mg once daily. Concomitant use with strong or moderate CYP3A inducers (eg, phenobarbital, phenytoin, rifampicin) should be avoided.

Safety Profile

Safety data are from 131 patients with advanced systemic mastocytosis enrolled in the EXPLORER and PATHFINDER trials who received a starting dose of avapritinib ranging from 30 mg to 400 mg once daily, including 80 who received the recommended starting dose of 200 mg once daily. Among patients receiving avapritinib, 70% were treated for ≥ 6 months and 37% for > 1 year.

The most common adverse events of any grade at all doses (incidence ≥ 20%) were edema, diarrhea, nausea, and fatigue/asthenia. The most common among the 80 patients receiving 200 mg daily were edema (79%), diarrhea (28%), nausea (24%), and fatigue/asthenia (23%). The most common grade 3 or 4 adverse events among patients receiving 200 mg daily included edema (5%), fatigue/asthenia (4%), and vomiting (3%). The most common grade 3 or 4 laboratory abnormalities among patients receiving 200 mg were decreased neutrophils (25%), decreased hemoglobin (23%), and decreased platelets (21%).

Serious adverse events occurred in 34% of patients receiving 200 mg and in 50% at all doses; the most common were anemia (5%), subdural hematoma (4%), pleural effusion, ascites, and pneumonia (3% each), and acute kidney injury, gastrointestinal hemorrhage, intracranial hemorrhage, encephalopathy, gastric hemorrhage, large intestine perforation, pyrexia, and vomiting (2% each). Adverse events led to permanent discontinuation of treatment in 10% of patients receiving 200 mg and in 15% of patients at all doses. Among those receiving 200 mg, subdural hematoma was the sole event requiring permanent discontinuation in more than one patient. Fatal adverse events occurred in 2.5% of patients receiving 200 mg and in 5.3% of patients at all doses; no specific adverse event led to death in more than one patient.

Adverse events led to dosage interruption in 60% of patients receiving 200 mg and in 67% of patients at all doses. The most common causes among patients receiving 200 mg (> 2%) were thrombocytopenia, neutropenia, decreased neutrophil count, decreased platelet count, anemia, decreased white blood cell count, cognitive disorder, increased alkaline phosphatase, and peripheral edema. Adverse events led to dose reduction in 68% of patients receiving 200 mg and 70% of patients at all doses. The most common causes among patients receiving 200 mg (> 2%) were thrombocytopenia, neutropenia, peripheral edema, decreased neutrophil count, decreased platelet count, periorbital edema, cognitive disorder, anemia, fatigue, arthralgia, increased alkaline phosphatase, and decreased white blood cell count.

Avapritinib has warnings/precautions for intracranial hemorrhage, cognitive effects (a broad spectrum of adverse reactions has been observed, including memory impairment, cognitive disorder, confusional state, amnesia, somnolence, and speech disorder), and embryofetal toxicity. Patients should be advised not to breastfeed while receiving avapritinib. 

REFERENCES

1. U.S. Food and Drug Administration: FDA approves avapritinib for advanced systemic mastocytosis. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-avapritinib-advanced-systemic-mastocytosis. Accessed July 12, 2021.

2. Ayvakit (avapritinib) tablets prescribing information, Blueprint Medicines Corporation, June 2021. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/212608s007lbl.pdf. Accessed July 12, 2021.