Ayvakit (avapritinib) - 3 indications 

Scroll down for information on each indication:

• unresectable or metastatic gastrointestinal stromal tumor; approved in January of 2020
• advanced systemic mastocytosis; approved June of 2021
• indolent systemic mastocytosis; approved May of 2023

General Information

Ayvakit (avapritinib) is a kinase inhibitor.

Ayvakit is specifically indicated for the following:

• 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
• the treatment of adult patients with advanced systemic mastocytosis (AdvSM), including patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematological neoplasm (SMAHN), and mast cell leukemia (MCL)
• for the treatment of adult patients with indolent systemic mastocytosis (ISM).

Ayvakit is supplied as a tablet for oral administration. Administer Ayvakit 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. Scroll down to see the recommended dosing/administration for each indication.

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 patient derived xenograft model of human GIST with activating KIT exon 11/17 mutations.  

Side Effects

Adverse effects associated with the use of Ayvakit for GIST may include, but are not limited to, the following:

•  edema
• nausea
• fatigue/asthenia
• cognitive impairment
• vomiting
• decreased appetite
• diarrhea
• hair color changes
• increased lacrimation
• abdominal pain
• constipation
• rash
• dizziness

Adverse effects associated with the use of Aykavit for AdvSM may include, but are not limited to, the following:

• edema
• diarrhea
• nausea
• fatigue/asthenia

Adverse effects associated with the use of Aykavit for ISM may include, but are not limited to, the following:

• eye edema
• dizziness
• peripheral edema
• flushing

Indication 1 - unresectable or metastatic gastrointestinal stromal tumor

approved in January of 2020

The recommended dosage of Ayvakit for GIST is 300 mg orally once daily.

The FDA approval of Aykavit for GIST 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. 

Indication 2- advanced systemic mastocytosis

approved June of 2021

The recommended dosage of Ayvakit for AdvSM is 200 mg orally once daily

 The FDA approval of Ayvakit for AdvSM was based on data from the Phase 1 EXPLORER trial and Phase 2 PATHFINDER trial. Treatment response was evaluated using modified IWG-MRT-ECNM criteria, with assessments based on at least 12 weeks of response duration, resolution of at least one finding of non-hematologic and hematologic organ damage, and 50 percent or greater reductions in biomarker response, mast cell burden and serum tryptase. The overall response rate (ORR) is defined as complete remission with full or partial hematologic recovery (CR/CRh), or partial remission (PR).

Ayvakit showed durable clinical efficacy in advanced SM patients across disease subtypes and regardless of prior therapy. In 53 evaluable patients who had a median follow-up of 11.6 months, the ORR was 57% and the proportion of patients with CR/CRh (28%), PR (28%) and clinical improvement (15%) is in line with previously reported results. The median duration of response was 38.3 months.

Indication 3 - indolent systemic mastocytosis

The recommended dosage of Ayvakit is 25 mg orally once daily.

The FDA approval of Ayvakit for ISM was based on data from the double-blind, placebo-controlled PIONEER trial in which patients received AYVAKIT 25 mg once daily plus best supportive care (Ayvakit ) or placebo plus best supportive care (placebo). Overall, 96 percent of patients with Ayvakit completed 24 weeks of treatment and opted to cross over to the open-label extension study. Ayvakit met the primary and all key secondary endpoints, which were evaluated from baseline to 24 weeks, and showed deepening clinical efficacy through 48 weeks of treatment. Patients treated with Ayvakit achieved rapid, durable and statistically significant reductions on all measures of pathological mast cell burden, including serum tryptase, KIT D816V variant allele fraction and bone marrow mast cells. Ayvakit achieved statistically significant and clinically meaningful benefits in overall symptoms – as measured by the ISM-SAF Total Symptom Score (TSS) – compared to placebo at 24 weeks, with improvements deepening through 48 weeks. In addition, Ayvakit showed improvements over placebo on the most severe symptom and across all individual symptoms measured. Ayvakit showed clinically meaningful improvements in multiple exploratory endpoints of quality of life.