General Information

Ayvakit (avapritinib) is a kinase inhibitor.

Ayvakit is specifically indicated for the treatment of adults with unresectable or metastatic GIST harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation, including PDGFRA D842V mutations.

Ayvakit is supplied as a tablet for oral administration. The 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. Continue treatment until disease progression or unacceptable toxicity. Do not make up for a missed dose within 8 hours of the next scheduled dose. Do not take an additional dose if vomiting occurs after Ayvakit, but continue with the next scheduled dose.

Clinical Results

FDA Approval

The FDA approval of Aykavit was based on efficacy results from the Phase 1 NAVIGATOR clinical trial, as well as combined safety results from multiple clinical trials for avapritinib. Patients received Ayvakit 300 mg or 400 mg orally once daily until disease progression or unacceptable toxicity. The trial initially enrolled patients at a starting dose of 400 mg, which was later reduced to the recommended dose of 300 mg due to toxicity. As there was no apparent difference in overall response rate (ORR) between patients who received 300 mg daily compared to those who received 400 mg daily, these patients were pooled for the efficacy evaluation. The major efficacy outcome measure was ORR 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 (DOR). In patients with PDGFRA exon 18 mutant GIST, AYVAKIT had an overall response rate (ORR) of 84 percent, and a median duration of response (DOR) was not reached.

Mechanism of Action

Ayvakit (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 with half maximal inhibitory concentrations (IC50s) less than 25 nM. Certain mutations in PDGFRA and KIT can result in the 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 in vitro cellular assays, avapritinib inhibited the autophosphorylation of KIT D816V and PDGFRA D842V, mutants associated with resistance to approved kinase inhibitors, with IC50 of 4 nM and 30 nM, respectively. Avapritinib also had anti-tumor activity in mice implanted with an imatinib-resistant patientderived xenograft model of human GIST with activating KIT exon 11/17 mutations.