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Avapritinib for Gastrointestinal Stromal Tumor With PDGFRA Exon 18 Mutation


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On January 9, 2020, avapritinib was approved for treatment of adults with unresectable or metastatic gastrointestinal stromal tumors (GIST) harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation, including D842V mutations.1,2 It is the first therapy approved for patients with GIST harboring a PDGFRA exon 18 mutation.

Supporting Efficacy Data

Approval was based on the finding of durable responses in the single-arm, multicenter NAVIGATOR trial (ClinicalTrials.gov identifier NCT02508532).2,3 The trial included 43 patients with GIST harboring a PDGFRA exon 18 mutation, including 38 with PDGFRA D842V mutations. Patients received avapritinib at a starting dose of 400 mg orally once daily, which was subsequently reduced to the recommended dose of 300 mg orally once daily, due to toxicity. Treatment continued until disease progression or unacceptable toxicity.

OF NOTE

Avapritinib has warnings/precautions for intracranial hemorrhage, CNS effects, and embryofetal toxicity.

The median age of patients was 64 years (range = 29–90 years), 67% were male, 67% were white, 93% had an Eastern Cooperative Oncology Group performance status of 0 or 1, 98% had metastatic disease, 53% had a largest target lesion > 5 cm, 86% had prior surgical resection, and the median number of prior kinase inhibitors received was one (range = 0–5).

Among all 43 patients, the overall response rate on independent radiologic review using modified Response Evaluation Criteria in Solid Tumors, v1.1, was 84% (95% confidence interval [CI] = 69%–93%), with a complete response in 7% of patients. Among the 38 patients with PDGFRA D842V mutations, the overall response rate was 89% (95% CI = 75%–97%), with a complete response in 8%. The median response duration was not reached (range = 1.9+ to 20.3+ months), with a median duration of follow-up for all patients of 10.6 months (range = 0.3–24.9 months); 61% of the responding patients had a response lasting for at least 6 months.

How It Works

Avapritinib is a tyrosine kinase inhibitor that targets PDGFRA and PDGFRA D842 mutants, as well as multiple KIT exon 11, 11/17, and 17 mutants. Mutations in PDGFRA and KIT can result in autophosphorylation and constitutive activation of these receptors, which can contribute to tumor cell proliferation. Other potential targets for avapritinib include wild-type KIT, PDGFRB, and CSFR1. In cell assays, avapritinib inhibited the autophosphorylation of KIT D816V and PDGFRA D842V—mutants associated with resistance to approved kinase inhibitors. Avapritinib also exhibited antitumor activity in mice with imatinib-resistant, patient-derived xenografts of human GIST with activating KIT exon 11/17 mutations.

How It Is Used

Patients must be selected for treatment with avapritinib based on the presence of a PDGFRA exon 18 mutation; a U.S. Food and Drug Administration (FDA)-approved test for the detection of exon 18 mutations is not currently available.

The recommended dosage of avapritinib is 300 mg orally once daily, with treatment continued until disease progression or unacceptable toxicity. Recommended dose reductions for adverse reactions are to 200 mg once daily and then to 100 mg once daily. Treatment should be discontinued if 100 mg once daily is not tolerated. Product labeling provides instructions for dose modification for intracranial hemorrhage, central nervous system (CNS) adverse reactions, and other grade 3 or 4 adverse reactions.

KEY POINTS

  • Avapritinib was approved for treatment of adults with unresectable or metastatic GIST harboring a PDGFRA exon 18 mutation, including D842V mutations.
  • The recommended dosage of avapritinib is 300 mg orally once daily, with treatment continued until disease progression or unacceptable toxicity.

Concomitant use of avapritinib with strong or moderate CYP3A inhibitors should be avoided. If concomitant use with a moderate CYP3A inhibitor cannot be avoided, the starting dose of avapritinib should be reduced to 100 mg orally once daily. Concomitant use with strong or moderate CYP3A inducers should be avoided.

Safety Profile

Safety data are from a total of 204 patients who received avapritinib at 300 mg or 400 mg once daily in the NAVIGATOR trial. The most common adverse events of any grade (incidence ≥ 20%) were edema (72%), nausea (64%), fatigue/asthenia (61%), cognitive impairment (48%), vomiting (38%), decreased appetite (38%), diarrhea (37%), increased lacrimation (33%), abdominal pain (31%), constipation (23%), rash (23%), dizziness (22%), and hair color changes (21%). The most common grade 3 or 4 adverse events included fatigue/asthenia, diarrhea, and cognitive impairment. The most common grade 3 or 4 laboratory abnormalities were decreased hemoglobin, decreased phosphate, and increased bilirubin.

Serious adverse events occurred in 52% of patients, with the most common being anemia, abdominal pain, pleural effusion, sepsis, gastrointestinal hemorrhage, vomiting, acute kidney injury, pneumonia, and tumor hemorrhage. Adverse events led to dose interruption in 57% of patients (due to anemia, fatigue, nausea, vomiting, hyperbilirubinemia, memory impairment, diarrhea, cognitive disorder, and abdominal pain) and to dose reduction in 49% (due to fatigue, anemia, hyperbilirubinemia, memory impairment, nausea, and periorbital edema). Adverse events led to treatment discontinuation in 16% of patients, with those requiring treatment discontinuation in more than one patient consisting of fatigue, abdominal pain, vomiting, sepsis, anemia, acute kidney injury, and encephalopathy. Fatal adverse events occurred in 3.4% of patients, with those occurring in more than one patient being sepsis and tumor hemorrhage.

Avapritinib has warnings/precautions for intracranial hemorrhage, CNS effects (including cognitive impairment, dizziness, sleep disorders, mood disorders, speech disorders, and hallucinations), 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 gastrointestinal stromal tumor with a rare mutation. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-avapritinib-gastrointestinal-stromal-tumor-rare-mutation. Accessed February 19, 2020.

2. Ayvakit (avapritinib) tablets, for oral use, Blueprint Medicines Corporation, 2020. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/212608s000lbl.pdf. Accessed February 19, 2020.

3. Heinrich MC, Jones RL, von Mehren M, et al: Clinical activity of avapritinib in ≥ fourth-line and PDGFRA exon 18 gastrointestinal stromal tumors. 2020 Gastrointestinal Cancers Symposium. Abstract 826. Presented January 23, 2020.

 


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