avapritinib
Sources réglementaires consultées
Indications approuvées
- En monothérapie chez l’adulte atteint d’une tumeur stromale gastro-intestinale non résécable ou métastatique porteuse de la mutation PDGFRA D842V.
- En monothérapie chez l’adulte atteint de mastocytose systémique avancée après au moins un traitement systémique.
- Chez l’adulte atteint de mastocytose systémique indolente avec symptômes modérés ou sévères insuffisamment contrôlés par le traitement symptomatique.
Contre-indications
Absolues
- Hypersensibilité à l’avapritinib ou à ses excipients.
Mises en garde cliniques
- Mise en garde majeure · Peut provoquer une hémorragie intracrânienne grave ou fatale. Évaluer les antécédents d’anévrisme, d’hémorragie ou d’AVC récent, les anticoagulants et la thrombopénie ; exiger une prise en charge immédiate en cas de céphalées, nausées, vomissements, troubles visuels ou modification de l’état mental. — DailyMed, AYVAKIT set_id 645c887c-8cd4-4623-8da9-ac223d71a8b9
- Mise en garde majeure · Peut provoquer des effets cognitifs, notamment troubles de la mémoire, confusion, amnésie, somnolence ou trouble de la parole. Suspendre, réduire ou arrêter selon la gravité. — DailyMed, AYVAKIT set_id 645c887c-8cd4-4623-8da9-ac223d71a8b9
- Mise en garde majeure · Peut provoquer une photosensibilité. Limiter l’exposition directe aux ultraviolets pendant le traitement et pendant 1 semaine après. — DailyMed, AYVAKIT set_id 645c887c-8cd4-4623-8da9-ac223d71a8b9
Interactions médicamenteuses
- SévèreInhibiteurs puissants ou modérés du CYP3A
Mécanisme: Ils augmentent l’exposition et la toxicité.
Recommandation: Éviter l’association. Si un inhibiteur modéré est indispensable, commencer le GIST à 100 mg/jour ou la mastocytose avancée à 50 mg/jour ; dans la mastocytose indolente, éviter l’association.
DailyMed, AYVAKIT set_id 645c887c-8cd4-4623-8da9-ac223d71a8b9https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=645c887c-8cd4-4623-8da9-ac223d71a8b9
- SévèreInducteurs puissants ou modérés du CYP3A
Mécanisme: Ils réduisent l’exposition et peuvent diminuer l’efficacité.
Recommandation: Éviter l’association.
DailyMed, AYVAKIT set_id 645c887c-8cd4-4623-8da9-ac223d71a8b9https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=645c887c-8cd4-4623-8da9-ac223d71a8b9
- ModéréeContraceptifs contenant de l’éthinylestradiol
Mécanisme: L’avapritinib peut augmenter l’exposition à l’éthinylestradiol et ses effets indésirables.
Recommandation: Préférer une méthode non hormonale ou sans œstrogène ; sinon utiliser ≤20 microgrammes d’éthinylestradiol sauf nécessité d’une dose supérieure.
DailyMed, AYVAKIT set_id 645c887c-8cd4-4623-8da9-ac223d71a8b9https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=645c887c-8cd4-4623-8da9-ac223d71a8b9
- ModéréeSubstrats du CYP3A à marge thérapeutique étroite
Mécanisme: L’avapritinib à 300 mg/jour agit comme inhibiteur faible du CYP3A et peut augmenter leur exposition.
Recommandation: Utiliser l’association avec prudence et surveiller la toxicité du substrat ; cet effet n’est pas prédit avec des doses d’avapritinib de 200 mg/jour ou moins.
CIMA/AEMPS, ficha técnica AYVAKYT 100 mg, registro 1201473001https://cima.aemps.es/cima/dochtml/ft/1201473001/FT_1201473001.html
- ModéréeSubstrats de la P-gp, BCRP, MATE1, MATE2-K ou BSEP
Mécanisme: L’inhibition in vitro de ces transporteurs peut modifier l’exposition au substrat.
Recommandation: Utiliser l’association avec prudence et surveiller l’efficacité et la toxicité du substrat.
CIMA/AEMPS, ficha técnica AYVAKYT 100 mg, registro 1201473001https://cima.aemps.es/cima/dochtml/ft/1201473001/FT_1201473001.html
Effets indésirables
Communs (≥1%)
œdème · nausées · fatigue · trouble cognitif · vomissements · diminution de l’appétit · diarrhée · larmoiement accru · douleur abdominale · constipation · éruption cutanée · vertiges · modification de la couleur des cheveux
Rares mais graves
hémorragie intracrânienne fatale
Grossesse et allaitement
Peut provoquer une toxicité embryofœtale. Vérifier la grossesse avant de commencer. Les femmes et les hommes ayant une partenaire susceptible d’être enceinte doivent utiliser une contraception efficace pendant le traitement et pendant 6 semaines après. Peut altérer la fertilité masculine et féminine. Ne pas allaiter pendant le traitement ni pendant 2 semaines après.
Bibliographie récente (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.)