ABSTRACT
Introduction The incidence of cutaneous melanoma has increased worldwide over the years, and an incidence of 3 cases per 100,000 men and women is estimated in Chile. Though most of the patients are diagnosed at an early stage of the disease and have a good prognosis, advanced melanoma has poor survival results. For the treatment of melanoma, the combination of dabrafenib plus trametinib has been demonstrated to improve the outcome versus dabrafenib alone, but only indirect evidence is available for its efficacy and safety compared with immunotherapy, like nivolumab. The aim of this study is to review the available evidence to report results of efficacy and safety of dabrafenib plus trametinib in comparison with nivolumab in metastatic melanoma. Methods We searched in Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews selected, reanalyzed data of primary studies, and generated a summary of the findings table using the GRADE approach. Results and conclusions We identified five systematic reviews, including seven studies overall that included one intervention of our interest, of which all were randomized trials. We only found indirect evidence comparing dabrafenib plus trametinib versus nivolumab that came from Network Meta-Analyses. We concluded that it is not possible to decide if dabrafenib plus trametinib is a better strategy for advanced melanoma treatment than nivolumab because the certainty of the evidence is very low for efficacy and safety outcomes.
Introducción La incidencia de melanoma cutáneo ha aumentado a nivel mundial con el paso de los años, estimándose en Chile una incidencia de 3 casos por 100.000 hombres y mujeres. Aunque la mayoría de los pacientes son diagnosticados en etapas tempranas de la enfermedad y tienen un buen pronóstico, el melanoma avanzado tiene malos resultados de sobrevida. Para el tratamiento del melanoma, se ha demostrado que la combinación de dabrafenib más trametinib mejora el resultado frente a dabrafenib solo, pero sólo se dispone de evidencia indirecta sobre su eficacia y seguridad en comparación con la inmunoterapia, como nivolumab. Métodos Se realizaron búsquedas en Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud, que se mantiene mediante el cribado de múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Se extrajeron los datos de las revisiones sistemáticas seleccionadas, se reanalizaron los datos de los estudios primarios y se generó una tabla de resumen de los hallazgos utilizando el enfoque GRADE. Resultados y conclusiones Se identificaron cinco revisiones sistemáticas, incluyendo siete estudios en total que incluían una intervención de nuestro interés, de los cuales todos eran ensayos aleatorizados. Se concluyó que no es posible decidir si dabrafenib más trametinib es una mejor estrategia para el tratamiento del melanoma avanzado que nivolumab porque la certeza de las pruebas es muy baja para los resultados de eficacia y seguridad.
ABSTRACT
Objective:To investigate the therapeutic effect of dabrafenib in treatment of cutaneous melanoma (CMM) and its influence on the expression of pituitary homeobox 1 (PITX1) protein.Methods:A total of 86 patients with CMM admitted to Wuhan First Hospital from November 2016 to December 2017 were selected as the research objects, and all patients were divided into the observation group and the control group according to random number table, 43 cases in each group. The control group received chemotherapy regimen, and the observation group was added with dabrafenib on the basis of the control group. Immunohistochemistry method was used to detect the expressions of PITX1 protein in both groups. The treatment effect, recurrence rate, survival, PITX1 expression positive rate and adverse reactions were compared between the two groups.Results:The treatment effective rate in the observation group was higher than that in the control group [46.51% (20/43) vs. 25.58% (11/43)], and the difference was statistically significant ( χ2 = 3.23, P = 0.043); the disease control rate in the observation group was higher than that in the control group [93.02% (40/43) vs.72.09% (31/43)], and the difference was statistically significant ( χ2 = 5.17, P = 0.023). Compared with the control group, the observation group had better overall survival and progression-free survival, lower recurrence rate, and higher PITX1 positive rate (all P < 0.05); adverse reaction rate in the observation group was lower than that in the control group [11.63% (5/43) vs. 32.56% (14/43)], and the difference was statistically significant ( χ2 = 5.47, P < 0.05). Conclusions:Dabrafenib has a better effect in the treatment of CMM, which can increase the expression level of PITX1, reduce the recurrence rate and the incidence of adverse reactions, and prolong the survival time of patients.
ABSTRACT
Resumen La mutación puntual V600E del gen BRAF juega un papel fundamental en la tumorigénesis de muchos gliomas. La inhibición de su producto forma parte de terapias innovadoras emergentes en los últimos años. Conocer el rol de estos tratamientos resulta imprescindible. El objetivo del trabajo fue describir la respuesta clínico-radiológica en niños con gliomas BRAF V600E mutado tratados con inhibidores BRAF. Para ello se realizó un estudio descriptivo y retrospectivo en pacientes menores de 16 años con gliomas BRAF V600E mu tado que recibieron vemurafenib o dabrafenib en el Hospital Garrahan. Trece pacientes tratados en los últimos 7 años fueron incluidos: 9 gliomas de bajo grado y 4 de alto grado. La mediana de edad al diagnóstico fue 8.6 años (0.89-14.04) y del comienzo del inhibidor 11.62 años (3.64-15.42). Inicialmente, todos habían realizado tratamiento quirúrgico, y 12/13 recibieron previamente otra terapia: 11 quimioterapia (eventualmente hasta 4 líneas distintas) y 4 radioterapia. Con la terapia dirigida, 10 pacientes tuvieron una disminución tumoral mayor o igual al 25%, quedando evidenciada en 7 niños la mejor respuesta dentro de los 6 meses del inicio. Hubo 4 progresados intratratamiento (todos alto grado), y 2 progresados prontamente luego de suspender el inhibidor (ambos bajo grado). Cinco presentaron efectos adversos grado 3-4, con recuperación ad-integrum. Se describe una buena y sostenida respuesta clínico-radiológica, con tolerancia aceptable, en pacientes con gliomas de bajo grado BRAF V600E mutado tratados con inhibidores BRAF V600E . En contraste, la respuesta en pacientes con gliomas de alto grado fue intermedia y de poca duración, con progresión tumoral precoz.
Abstract The BRAF V600E point mutation plays a key role in the tumorigenesis of many gliomas. Inhibiting its product is part of the innovative therapies emerging in recent years. Knowing the role of these treatments is essential. The aim of this experience was to describe the clinical-radiological response of pediatric BRAF V600E mutated gliomas treated with BRAF inhibitors. To this end, a descriptive and retrospective study was performed in patients under 16 years of age with BRAF V600E gliomas, who received vemurafenib or dabrafenib at Hospital Garrahan. Thirteen patients treated in the last 7 years were included: 9 were low-grade and 4 high-grade gliomas. The median age at diagnosis was 8.6 years (0.89-14.04) and at start of targeted therapy was 11.62 years (3.64-15.42). All patients had previously a surgical procedure, and 12/13 had received another therapy prior BRAF inhibition: 11 chemotherapy (in one case, up to 4 different protocols) and 4 radiotherapy. Under targeted therapy, tumour response was obtained in 10 patients (size reduction equal to or greater than 25%), and best response was observed in the first 6 months of treatment in 7 children. Four patients progressed under treatment (all high-grade gliomas) and 2 progressed shortly after stopping the inhibitor (both low-grade gliomas). Five patients had grade 3-4 toxicity, with subsequent full recovery. A good and sustained clinical-radiological response, with acceptable tolerance, is described in patients with BRAF V600E mutated low-grade gliomas treated with BRAF V600E inhibitors. In contrast, the response in patients with high-grade gliomas was intermediate and of short duration, with early tumour progression.
Subject(s)
Humans , Child , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Proto-Oncogene Proteins B-raf/genetics , Glioma/genetics , Glioma/drug therapy , Retrospective Studies , Hospitals , MutationABSTRACT
Melanoma is one of the most aggressive cancers in the world and is responsible for the majority of skin cancer deaths. Recent advances in the field of immunotherapy using active, adoptive, and antigen-specific therapeutic approaches, have generated the expectation that these technologies have the potential to improve the treatment of advanced malignancies, including melanoma. Treatment options for metastatic melanoma patients have been dramatically improved by the FDA approval of new therapeutic agents including vemurafenib, dabrafenib, and sorafenib. These kinase inhibitors have the potential to work in tandem with MEK, PI3K/AKT, and mTOR to inhibit the activity of melanoma inducing BRAF mutations. This review summarizes the effects of the new therapeutic agents against melanoma and the underlying biology of these BRAF inhibitors.
Subject(s)
Humans , Biology , Immunotherapy , Melanoma , Mitogen-Activated Protein Kinase Kinases , Phosphotransferases , Skin NeoplasmsABSTRACT
Melanoma is one of the most aggressive cancers in the world and is responsible for the majority of skin cancer deaths. Recent advances in the field of immunotherapy using active, adoptive, and antigen-specific therapeutic approaches, have generated the expectation that these technologies have the potential to improve the treatment of advanced malignancies, including melanoma. Treatment options for metastatic melanoma patients have been dramatically improved by the FDA approval of new therapeutic agents including vemurafenib, dabrafenib, and sorafenib. These kinase inhibitors have the potential to work in tandem with MEK, PI3K/AKT, and mTOR to inhibit the activity of melanoma inducing BRAF mutations. This review summarizes the effects of the new therapeutic agents against melanoma and the underlying biology of these BRAF inhibitors.