ripretinib
Fuentes regulatorias consultadas
Indicaciones aprobadas
- En adultos con tumor avanzado del estroma gastrointestinal que han recibido previamente tres o más inhibidores de quinasa, incluido imatinib.
Contraindicaciones
Absolutas
- Hipersensibilidad a ripretinib o a sus excipientes.
Advertencias clínicas
- Advertencia mayor · Puede causar eritrodisestesia palmoplantar. Interrumpe y reinicia a la misma dosis o reducida según grado, tiempo de recuperación y recurrencia. — CIMA/AEMPS, ficha técnica QINLOCK 50 mg, registro 1211569001
- Advertencia mayor · Puede causar nuevos cánceres cutáneos primarios. Realiza evaluación dermatológica al iniciar y periódicamente durante el tratamiento; extirpa y estudia las lesiones sospechosas. — DailyMed, QINLOCK set_id 9f18e462-03dd-4296-a02a-a0577e3ee78d
- Advertencia mayor · Controla la presión arterial antes y durante; no inicies con hipertensión no controlada. Evalúa la fracción de eyección antes y durante según clínica y suspende definitivamente ante disfunción sistólica ventricular izquierda grado 3–4. — DailyMed, QINLOCK set_id 9f18e462-03dd-4296-a02a-a0577e3ee78d
- Advertencia mayor · Suspende al menos 1 semana antes de cirugía electiva y no administres durante al menos 2 semanas después de cirugía mayor ni hasta cicatrización adecuada. Limita la exposición ultravioleta durante el tratamiento y 1 semana después. — DailyMed, QINLOCK set_id 9f18e462-03dd-4296-a02a-a0577e3ee78d
Interacciones medicamentosas
- ModeradaInhibidores potentes de CYP3A
Mecanismo: Aumentan la exposición a ripretinib y su metabolito activo.
Recomendación: Si se combinan, vigila con mayor frecuencia reacciones adversas.
DailyMed, QINLOCK set_id 9f18e462-03dd-4296-a02a-a0577e3ee78dhttps://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9f18e462-03dd-4296-a02a-a0577e3ee78d
- SeveraInductores potentes o moderados de CYP3A
Mecanismo: Reducen la exposición y pueden disminuir la actividad antitumoral.
Recomendación: Evita la combinación. Si un inductor moderado es imprescindible, aplica 150 mg dos veces al día con vigilancia.
DailyMed, QINLOCK set_id 9f18e462-03dd-4296-a02a-a0577e3ee78dhttps://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9f18e462-03dd-4296-a02a-a0577e3ee78d
- ModeradaInhibidores de BCRP
Mecanismo: Pueden aumentar las concentraciones de ripretinib o de su metabolito activo.
Recomendación: Usa la combinación con precaución y vigila reacciones adversas.
CIMA/AEMPS, ficha técnica QINLOCK 50 mg, registro 1211569001https://cima.aemps.es/cima/dochtml/ft/1211569001/FT_1211569001.html
- ModeradaSustratos de CYP3A, CYP1A2 o UGT1A con margen terapéutico estrecho
Mecanismo: Ripretinib puede aumentar la exposición a estos sustratos.
Recomendación: Usa la combinación con precaución y vigila concentración, eficacia y toxicidad del sustrato.
CIMA/AEMPS, ficha técnica QINLOCK 50 mg, registro 1211569001https://cima.aemps.es/cima/dochtml/ft/1211569001/FT_1211569001.html
- ModeradaSustratos de CYP2B6 con margen terapéutico estrecho
Mecanismo: La inducción de CYP2B6 puede reducir su exposición y eficacia.
Recomendación: Vigila la respuesta del sustrato y coordina ajustes si pierde eficacia.
CIMA/AEMPS, ficha técnica QINLOCK 50 mg, registro 1211569001https://cima.aemps.es/cima/dochtml/ft/1211569001/FT_1211569001.html
Eventos adversos
Comunes (≥1%)
alopecia · fatiga · náuseas · dolor abdominal · estreñimiento · mialgia · diarrea · disminución del apetito · eritrodisestesia palmoplantar · vómitos
Raros pero graves
melanoma · insuficiencia cardiaca
Embarazo y lactancia
Puede causar daño embriofetal. Verifica el embarazo antes de iniciar. Mujeres y hombres con parejas con capacidad gestante deben usar anticoncepción eficaz durante el tratamiento y 1 semana después. Si se usan anticonceptivos hormonales sistémicos, añade un método de barrera. Puede reducir la fertilidad masculina. No amamantes durante el tratamiento ni durante 1 semana después.
Bibliografía reciente (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