ripretinib
Sources réglementaires consultées
Indications approuvées
- Chez l’adulte atteint d’une tumeur stromale gastro-intestinale avancée ayant reçu auparavant au moins trois inhibiteurs de kinase, dont l’imatinib.
Contre-indications
Absolues
- Hypersensibilité au riprétinib ou à ses excipients.
Mises en garde cliniques
- Mise en garde majeure · Peut provoquer une érythrodysesthésie palmo-plantaire. Suspendre puis reprendre à la même dose ou à dose réduite selon le grade, le délai de récupération et la récidive. — CIMA/AEMPS, ficha técnica QINLOCK 50 mg, registro 1211569001
- Mise en garde majeure · Peut provoquer de nouveaux cancers cutanés primitifs. Réaliser une évaluation dermatologique au début puis régulièrement ; exciser et analyser les lésions suspectes. — DailyMed, QINLOCK set_id 9f18e462-03dd-4296-a02a-a0577e3ee78d
- Mise en garde majeure · Contrôler la pression artérielle avant et pendant le traitement ; ne pas commencer si l’hypertension n’est pas contrôlée. Évaluer la fraction d’éjection avant et pendant selon la clinique et arrêter définitivement en cas de dysfonction systolique ventriculaire gauche de grade 3–4. — DailyMed, QINLOCK set_id 9f18e462-03dd-4296-a02a-a0577e3ee78d
- Mise en garde majeure · Suspendre au moins 1 semaine avant une chirurgie programmée et ne pas administrer pendant au moins 2 semaines après une chirurgie majeure ni avant cicatrisation adéquate. Limiter l’exposition aux ultraviolets pendant le traitement et pendant 1 semaine après. — DailyMed, QINLOCK set_id 9f18e462-03dd-4296-a02a-a0577e3ee78d
Interactions médicamenteuses
- ModéréeInhibiteurs puissants du CYP3A
Mécanisme: Ils augmentent l’exposition au riprétinib et à son métabolite actif.
Recommandation: En cas d’association, surveiller plus fréquemment les effets indésirables.
DailyMed, QINLOCK set_id 9f18e462-03dd-4296-a02a-a0577e3ee78dhttps://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9f18e462-03dd-4296-a02a-a0577e3ee78d
- SévèreInducteurs puissants ou modérés du CYP3A
Mécanisme: Ils réduisent l’exposition et peuvent diminuer l’activité antitumorale.
Recommandation: Éviter l’association. Si un inducteur modéré est indispensable, utiliser 150 mg deux fois par jour avec surveillance.
DailyMed, QINLOCK set_id 9f18e462-03dd-4296-a02a-a0577e3ee78dhttps://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9f18e462-03dd-4296-a02a-a0577e3ee78d
- ModéréeInhibiteurs de la BCRP
Mécanisme: Ils peuvent augmenter les concentrations de riprétinib ou de son métabolite actif.
Recommandation: Utiliser l’association avec prudence et surveiller les effets indésirables.
CIMA/AEMPS, ficha técnica QINLOCK 50 mg, registro 1211569001https://cima.aemps.es/cima/dochtml/ft/1211569001/FT_1211569001.html
- ModéréeSubstrats du CYP3A, CYP1A2 ou UGT1A à marge thérapeutique étroite
Mécanisme: Le riprétinib peut augmenter l’exposition à ces substrats.
Recommandation: Utiliser l’association avec prudence et surveiller concentration, efficacité et toxicité du substrat.
CIMA/AEMPS, ficha técnica QINLOCK 50 mg, registro 1211569001https://cima.aemps.es/cima/dochtml/ft/1211569001/FT_1211569001.html
- ModéréeSubstrats du CYP2B6 à marge thérapeutique étroite
Mécanisme: L’induction du CYP2B6 peut réduire leur exposition et leur efficacité.
Recommandation: Surveiller la réponse du substrat et coordonner un ajustement en cas de perte d’efficacité.
CIMA/AEMPS, ficha técnica QINLOCK 50 mg, registro 1211569001https://cima.aemps.es/cima/dochtml/ft/1211569001/FT_1211569001.html
Effets indésirables
Communs (≥1%)
alopécie · fatigue · nausées · douleur abdominale · constipation · myalgie · diarrhée · diminution de l’appétit · érythrodysesthésie palmo-plantaire · vomissements
Rares mais graves
mélanome · insuffisance cardiaque
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 1 semaine après. En cas de contraception hormonale systémique, ajouter une méthode barrière. Peut altérer la fertilité masculine. Ne pas allaiter pendant le traitement ni pendant 1 semaine après.
Bibliographie récente (PubMed)
Gastrointestinal stromal tumor (GIST) is the most common malignant neoplasm of mesenchymal origin. GIST spans a wide clinical spectrum that ranges from tumors with essentially no metastatic potential to malignant and life-threatening spread diseases. Gain-of-function mutations in KIT or PDGFRA receptor tyrosine kinases are the crucial drivers of most GISTs, responsible for tumor initiation and evolution throughout the entire course of the disease. The introduction of tyrosine kinase inhibitors targeting these receptors has substantially improved the outcomes in this formerly chemoresistant cancer. As of today, five agents hold regulatory approval for the treatment of GIST: imatinib, sunitinib, regorafenib, ripretinib, and avapritinib. This, in turn, represents a success for a rare neoplasm. During the past two decades, GIST has become a paradigmatic model in cancer for multidisciplinary work, given the disease-specific particularities regarding tumor biology and tumor evolution. Herein, we review currently available evidence for the management of GIST. This clinical practice guideline has been developed by a multidisciplinary expert panel (oncologist, pathologist, surgeon, molecular biologist, radiologist, and representative of patients' advocacy groups) from the Spanish Group for Sarcoma Research, and it is conceived to provide, from a critical perspective, the standard approach for diagnosis, treatment, and follow-up.
To provide an accessible, comprehensive overview of past, present, imminent, and future therapies for systemic mastocytosis. Based on recent trials, the Food and Drug Administration (FDA) and European Medicines Agency (EMA) have approved two drugs for treating advanced systemic mastocytosis: avapritinib and midostaurin. The FDA also approved imatinib for selected cases of aggressive systemic mastocytosis without the D816V c-Kit mutation. Moreover, for the first time, a cytoreductive molecule, avapritinib, has been approved for patients with indolent systemic mastocytosis. Despite the considerable therapeutic progress in recent years, systemic mastocytosis is an incurable disease. In the last 20 years, the management of systemic mastocytosis has transformed from a one-size-fits-all approach, characterized by nonspecific cytoreductive drugs, to a tailored strategy focused on increasingly precise molecular targets, with the most notable example being the KIT inhibitors. Recently, the FDA and EMA have approved two drugs for treating systemic mastocytosis: avapritinib and midostaurin. Moreover, numerous trials are currently assessing the efficacy of new molecules: most are testing new-generation KIT inhibitors (ripretinib, bezuclastinib, elenestinib, masitinib, nintedanib), others focusing on Bruton's kinase (TL-895), interleukin-6 (sarilumab), sialic acid-binding immunoglobulin-like lectin-8 (lirentelimab), mTOR and CD33, among others. Real-life data are needed to confirm preliminary preclinical results.
This review discusses the current and future landscape of advanced gastrointestinal stromal tumor (GIST) treatment. It covers the role of tyrosine kinase inhibitors (TKIs), specifically imatinib, and further treatment options, such as sunitinib, regorafenib, and ripretinib, as well as avapritinib for platelet-derived growth factor receptor alpha D842V mutations. In addition, this review emphasizes individualized treatment strategies within multidisciplinary expert teams, including surgery and other locoregional therapies, together with the importance of mutation-guided approaches, particularly for wild-type GISTs. Finally, it explores the potential of next-generation KIT inhibitors, combination therapies, and other investigational approaches.
Sunitinib, a multitargeted tyrosine kinase inhibitor (TKI), is approved for advanced gastrointestinal stromal tumor (GIST) after imatinib failure. Ripretinib is a switch-control TKI approved for advanced GIST after prior treatment with three or more TKIs, including imatinib. We compared efficacy and safety of ripretinib versus sunitinib in patients with advanced GIST who were previously treated with imatinib (INTRIGUE, ClinicalTrials.gov identifier: NCT03673501). Random assignment was 1:1 to once-daily ripretinib 150 mg or once-daily sunitinib 50 mg (4 weeks on/2 weeks off) and stratified by KIT/platelet-derived growth factor α mutation and imatinib intolerance. The primary end point was progression-free survival (PFS) by independent radiologic review using modified Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included objective response rate by independent radiologic review, safety, and patient-reported outcome measures. Overall, 453 patients were randomly assigned to ripretinib (intention-to-treat [ITT], n = 226; KIT exon 11 ITT, n = 163) or sunitinib (ITT, n = 227; KIT exon 11 ITT, n = 164). Median PFS for ripretinib and sunitinib (KIT exon 11 ITT) was 8.3 and 7.0 months, respectively (hazard ratio, 0.88; 95% CI, 0.66 to 1.16; P = .36); median PFS (ITT) was 8.0 and 8.3 months, respectively (hazard ratio, 1.05; 95% CI, 0.82 to 1.33; nominal P = .72). Neither was statistically significant. Objective response rate was higher for ripretinib versus sunitinib in the KIT exon 11 ITT population (23.9% v 14.6%, nominal P = .03). Ripretinib was associated with a more favorable safety profile, fewer grade 3/4 treatment-emergent adverse events (41.3% v 65.6%, nominal P < .0001), and better scores on patient-reported outcome measures of tolerability. Ripretinib was not superior to sunitinib in terms of PFS. However, meaningful clinical activity, fewer grade 3/4 treatment-emergent adverse events, and improved tolerability were observed with ri