On 9 January 2020, the US Food and Drug Administration (FDA) approved avapritinib (AYVAKITTM, Blueprint Medicines Corporation) for adults with unresectable or metastatic gastrointestinal stromal tumour (GIST) harbouring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation, including D842V mutations.
Avapritinib is the first therapy approved for patients with GIST harbouring a PDGFRA exon 18 mutation.
Efficacy was investigated in NAVIGATOR (NCT02508532), a multicentre, single-arm, open-label trial enrolling 43 patients with GIST harbouring a PDGFRA exon 18 mutation, including 38 patients with PDGFRA D842V mutations. The trial initially enrolled patients at a starting dose of 400 mg orally once daily, which was later reduced to the recommended dose of 300 mg orally once daily due to toxicity.
Patients received avapritinib until disease progression or unacceptable toxicity. The major efficacy outcome measure was overall response rate (ORR) based on disease assessment by independent radiological review using modified RECIST v1.1 criteria. An additional efficacy outcome measure was response duration.
For patients harbouring a PDGFRA exon 18 mutation, the ORR was 84% (95% CI: 69%, 93%), with 7% complete responses (CRs) and 77% partial responses (PRs). For the subgroup of patients with PDGFRA D842V mutations, the ORR was 89% (95% CI: 75%, 97%), with 8% CRs and 82% PRs.
The median response duration was not reached with a median duration of follow-up for all patients of 10.6 months (range 0.3 to 24.9 months); 61% of the responding patients with exon 18 mutations had a response lasting 6 months or longer (31% of patients with an ongoing response were followed for less than 6 months).
The most common adverse reactions (incidence ≥ 20%) in patients who received avapritinib were oedema, nausea, fatigue/asthenia, cognitive impairment, vomiting, decreased appetite, diarrhoea, hair colour changes, increased lacrimation, abdominal pain, constipation, rash and dizziness.
The recommended avapritinib dose is 300 mg orally once daily on an empty stomach, at least one hour before and two hours after a meal.
Full prescribing information for AYVAKIT are available here.
FDA granted this application priority review and Breakthrough Therapy designation. Avapritinib also received fast track and orphan drug designations.
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