avapritinib
Regulatory sources consulted
Approved indications
- As monotherapy for adults with unresectable or metastatic gastrointestinal stromal tumor harboring the PDGFRA D842V mutation.
- As monotherapy for adults with advanced systemic mastocytosis after at least one systemic treatment.
- In adults with indolent systemic mastocytosis and moderate or severe symptoms inadequately controlled by symptomatic treatment.
Contraindications
Absolute
- Hypersensitivity to avapritinib or its excipients.
Clinical warnings
- Major warning · It can cause serious or fatal intracranial hemorrhage. Assess aneurysm, recent hemorrhage or stroke, anticoagulants, and thrombocytopenia; require immediate care for headache, nausea, vomiting, visual changes, or altered mental status. — DailyMed, AYVAKIT set_id 645c887c-8cd4-4623-8da9-ac223d71a8b9
- Major warning · It can cause cognitive effects, including memory impairment, confusion, amnesia, somnolence, or speech disorder. Withhold, reduce, or discontinue according to severity. — DailyMed, AYVAKIT set_id 645c887c-8cd4-4623-8da9-ac223d71a8b9
- Major warning · It can cause photosensitivity. Limit direct ultraviolet exposure during treatment and for 1 week afterward. — DailyMed, AYVAKIT set_id 645c887c-8cd4-4623-8da9-ac223d71a8b9
Drug interactions
- HighStrong or moderate CYP3A inhibitors
Mechanism: They increase exposure and toxicity.
Recommendation: Avoid the combination. If a moderate inhibitor is unavoidable, start GIST at 100 mg/day or advanced mastocytosis at 50 mg/day; in indolent mastocytosis, avoid the combination.
DailyMed, AYVAKIT set_id 645c887c-8cd4-4623-8da9-ac223d71a8b9https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=645c887c-8cd4-4623-8da9-ac223d71a8b9
- HighStrong or moderate CYP3A inducers
Mechanism: They reduce exposure and may decrease efficacy.
Recommendation: Avoid the combination.
DailyMed, AYVAKIT set_id 645c887c-8cd4-4623-8da9-ac223d71a8b9https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=645c887c-8cd4-4623-8da9-ac223d71a8b9
- ModerateEthinyl estradiol-containing contraceptives
Mechanism: Avapritinib may increase ethinyl estradiol exposure and adverse reactions.
Recommendation: Prefer a nonhormonal or estrogen-free method; if not possible, use ≤20 micrograms of ethinyl estradiol unless a higher dose is necessary.
DailyMed, AYVAKIT set_id 645c887c-8cd4-4623-8da9-ac223d71a8b9https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=645c887c-8cd4-4623-8da9-ac223d71a8b9
- ModerateNarrow-therapeutic-index CYP3A substrates
Mechanism: Avapritinib 300 mg/day acts as a weak CYP3A inhibitor and may increase their exposure.
Recommendation: Use the combination cautiously and monitor substrate toxicity; this effect is not predicted at avapritinib doses of 200 mg/day or lower.
CIMA/AEMPS, ficha técnica AYVAKYT 100 mg, registro 1201473001https://cima.aemps.es/cima/dochtml/ft/1201473001/FT_1201473001.html
- ModerateP-gp, BCRP, MATE1, MATE2-K, or BSEP substrates
Mechanism: In vitro inhibition of these transporters may alter substrate exposure.
Recommendation: Use the combination cautiously and monitor substrate efficacy and toxicity.
CIMA/AEMPS, ficha técnica AYVAKYT 100 mg, registro 1201473001https://cima.aemps.es/cima/dochtml/ft/1201473001/FT_1201473001.html
Adverse events
Common (≥1%)
edema · nausea · fatigue · cognitive impairment · vomiting · decreased appetite · diarrhea · increased lacrimation · abdominal pain · constipation · rash · dizziness · hair color changes
Rare but serious
fatal intracranial hemorrhage
Pregnancy and lactation
It can cause embryo-fetal harm. Verify pregnancy before starting. Females and males with partners who can become pregnant must use effective contraception during treatment and for 6 weeks afterward. It may impair male and female fertility. Do not breastfeed during treatment or for 2 weeks afterward.
Recent literature (PubMed)
Mastocytosis is a spectrum of clonal myeloid disorders defined by abnormal growth and accumulation of mast cells in various organ systems. The disease is divided into cutaneous mastocytosis, systemic mastocytosis (SM) and mast cell sarcoma. SM is further categorized into several non-advanced and advanced forms. The prognosis of cutaneous mastocytosis and non-advanced SM is mostly favourable, whereas prognosis and survival in advanced SM and mast cell sarcoma are poor. During the past 15 years, major advances have been made in the diagnosis, prognosis and management of patients with mast cell neoplasms. Management of mastocytosis consists of symptomatic therapy, including anti-mast cell mediator drugs, and cytoreductive agents for patients with advanced disease and selected individuals with non-advanced disease, as well as recognition and prevention of comorbidities such as osteoporosis and anaphylaxis. The preclinical and clinical development of KIT-D816V-targeting drugs, such as midostaurin or avapritinib, mark a milestone in improving management, the quality of life and survival in patients with SM. These agents induce major responses or even remission in people with advanced SM and lead to rapid improvement of mediator-related symptoms and quality of life in symptomatic patients.
Systemic mastocytosis (SM) is a rare disease and has had significant discoveries in its biology, prognostication, and management in the past 2 decades. The latest update of the World Health Organization classification and the new International Consensus Classification are current standards in the diagnosis and prognostication of SM. In clinical practice, SM can be divided into 2 main categories: nonadvanced SM (nonAdvSM) and advanced SM (AdvSM). The integration of clinical signs and symptoms as well as bone marrow morphologic, immunophenotypic, and molecular results is required to diagnose SM variants. In the modern era, data with KIT inhibitors (ie, avapritinib) suggest prolongation of survival in AdvSM. Although this is encouraging progress, and we now have effective drugs for managing both patients with indolent SM and AdvSM, there are remaining challenges in SM. For example, optimal initial treatment in certain patient subsets, such as SM with an associated hematologic neoplasm (SM-AHN), remains under debate (eg, treatments targeting AHN or SM, monotherapy, or combinations). Prospective studies evaluating drugs with different mechanisms of action are needed for such patients. This review provides an updated overview of SM, including the latest methods for diagnosis, patient classification based on their prognosis, and management according to the most significant clinical trials, covering both patients with nonadvSM and AdvSM.
BACKGROUND: Indolent systemic mastocytosis (ISM) is a clonal mast-cell disease driven by the KIT D816V mutation. We assessed the efficacy and safety of avapritinib versus placebo, both with best supportive care, in patients with ISM. METHODS: We randomized patients with moderate to severe ISM (total symptom score [TSS] of ≥28; scores range from 0 to 110, with higher numbers indicating more severe symptoms) two to one to avapritinib 25 mg once daily (n=141) or placebo (n=71). The primary end point was mean change in TSS based on the 14-day average of patient-reported severity of 11 symptoms. Secondary end points included reductions in serum tryptase and blood KIT D816V variant allele fraction (≥50%), reductions in TSS (≥50% and ≥30%), reduction in bone marrow mast cells (≥50%), and quality of life measures. RESULTS: From baseline to week 24, avapritinib-treated patients had a decrease of 15.6 points (95% CI, −18.6 to −12.6) in TSS compared to a decrease of 9.2 points (−13.1 to −5.2) in the placebo group; P<0.003. From baseline to Week 24, 76/141 patients (54%; 45% to 62%) in the avapritinib group compared to 0/71 patients in the placebo group achieved a ≥50% reduction in serum tryptase level; P<0.001. Edema and increases in alkaline phosphatase were more common with avapritinib than placebo; there were few treatment discontinuations because of adverse events. CONCLUSIONS: In this trial, avapritinib was superior to placebo in reducing uncontrolled symptoms and mast-cell burden in patients with ISM. The long-term safety and efficacy of this approach for patients with ISM remain the focus of the ongoing trial. (Funded by Blueprint Medicines Corporation; ClinicalTrials.gov number, NCT03731260.)