RESUMEN
Febrile illnesses are common in the management of metastatic solid organ malignancies. Traditionally they occur in the setting of immunosuppression and neutropenia owing to cytotoxic therapy necessitating consideration of systemic infections. Systemic markers of inflammation, such as C-reactive protein and procalcitonin (PCT), may be used to assist in determining the aetiology of a fever in such patients. Newer anticancer therapies may cause significant noninfectious fevers and may result in a rise in inflammatory markers, despite the absence of an infection. We present a case of a critically unwell febrile patient being treated with dabrafenib and trametinib for advanced melanoma. The patient had an extreme elevation in PCT in the absence of infection. We discuss the presentation of fevers related to dabrafenib and trametinib therapy in the management of advanced melanoma, and the utility of PCT in the management of fevers in advanced solid organ malignancies.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Fiebre/inducido químicamente , Melanoma/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Antibacterianos/uso terapéutico , Humanos , Imidazoles/administración & dosificación , Imidazoles/efectos adversos , Masculino , Melanoma/sangre , Persona de Mediana Edad , Oximas/administración & dosificación , Oximas/efectos adversos , Piridonas/administración & dosificación , Piridonas/efectos adversos , Pirimidinonas/administración & dosificación , Pirimidinonas/efectos adversos , Sepsis/diagnóstico , Sepsis/tratamiento farmacológico , Neoplasias Cutáneas/sangreRESUMEN
PURPOSE: This multicenter phase II basket trial investigated the efficacy, safety and pharmacokinetics of Debio 1347, an investigational, oral, highly selective, ATP-competitive, small molecule inhibitor of FGFR1-3, in patients with solid tumors harboring a functional FGFR1-3 fusion. PATIENTS AND METHODS: Eligible adults had a previously treated locally advanced (unresectable) or metastatic biliary tract (cohort 1), urothelial (cohort 2) or other histologic cancer type (cohort 3). Debio 1347 was administered at 80 mg once daily, continuously, in 28-day cycles. The primary endpoint was the objective response rate (ORR). Secondary endpoints included duration of response, progression-free survival, overall survival, pharmacokinetics, and incidence of adverse events. RESULTS: Between March 22, 2019 and January 8, 2020, 63 patients were enrolled and treated, 30 in cohort 1, four in cohort 2, and 29 in cohort 3. An unplanned preliminary statistical review showed that the efficacy of Debio 1347 was lower than predicted and the trial was terminated. Three of 58 evaluable patients had partial responses, representing an ORR of 5%, with a further 26 (45%) having stable disease (≥6 weeks duration). Grade ≥3 treatment-related adverse events occurred in 22 (35%) of 63 patients, with the most common being hyperphosphatemia (13%) and stomatitis (5%). Two patients (3%) discontinued treatment due to adverse events. CONCLUSIONS: Debio 1347 had manageable toxicity; however, the efficacy in patients with tumors harboring FGFR fusions did not support further clinical evaluation in this setting. Our transcriptomic-based analysis characterized in detail the incidence and nature of FGFR fusions across solid tumors.
RESUMEN
Advances in cancer immunology have increased the use of immune checkpoint inhibitors in clinical practice, however not all patients respond, and treatment can have severe side-effects. Blood-based immunological biomarkers are an attractive method for predicting which patients will respond to therapy, however, reliable biomarkers for immune checkpoint blockade are lacking. This study aimed to identify patients before or early in treatment who would best respond to PD-1 inhibitors. We hypothesised that higher baseline PD-L1 and/or PD-1 on peripheral blood T cells could predict radiological response to PD-1 inhibitors. This pilot prospective cohort study assessed 26 patients with melanoma or non-small cell lung cancer, treated with pembrolizumab, nivolumab, or nivolumab/ipilimumab combined. Response was assessed by RECIST 1.1. Peripheral blood lymphocytes collected at baseline, after one cycle, 10 weeks and at discontinuation of therapy were analysed by flow cytometry. Patients with a higher proportion of PD-L1+ T cells at baseline had improved objective response to PD-1 inhibitor therapy, and patients with a lower proportion of regulatory T cells at baseline experienced more immune-related adverse events. These findings may prove useful to assist in clinical decision making. Further studies with larger cohorts are required to validate these findings.
Asunto(s)
Antígeno B7-H1/biosíntesis , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Inhibidores de Puntos de Control Inmunológico/farmacología , Neoplasias Pulmonares/metabolismo , Melanoma/metabolismo , Terapia Molecular Dirigida , Proteínas de Neoplasias/biosíntesis , Linfocitos T/efectos de los fármacos , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Femenino , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Ipilimumab/administración & dosificación , Ipilimumab/efectos adversos , Ipilimumab/farmacología , Estimación de Kaplan-Meier , Neoplasias Pulmonares/tratamiento farmacológico , Masculino , Melanoma/tratamiento farmacológico , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/genética , Nivolumab/administración & dosificación , Nivolumab/efectos adversos , Nivolumab/farmacología , Nivolumab/uso terapéutico , Proyectos Piloto , Supervivencia sin Progresión , Estudios Prospectivos , Linfocitos T Reguladores/efectos de los fármacosAsunto(s)
Neoplasias/enfermería , Enfermeras Practicantes/economía , Rol de la Enfermera , Enfermería Oncológica , Pautas de la Práctica en Enfermería , Autonomía Profesional , Australia , Competencia Clínica , Análisis Costo-Beneficio , Medicina Basada en la Evidencia , Humanos , Satisfacción del Paciente , Calidad de la Atención de Salud , Ensayos Clínicos Controlados Aleatorios como Asunto , Recursos HumanosAsunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Hipercalcemia/tratamiento farmacológico , Neoplasias de las Paratiroides/complicaciones , Ligando RANK/antagonistas & inhibidores , Denosumab , Resultado Fatal , Humanos , Hipercalcemia/etiología , Metástasis Linfática , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/complicaciones , Recurrencia Local de Neoplasia/diagnóstico , Neoplasias de las Paratiroides/patología , Neoplasias Pleurales/complicaciones , Neoplasias Pleurales/diagnóstico , Neoplasias Pleurales/secundario , Neoplasias de la Tiroides/secundarioRESUMEN
Tumour infiltrating lymphocytes in primary melanoma have been found to correlate with patient outcomes. A subpopulation of tumour infiltrating lymphocytes expresses the transcription factor forkhead box protein 3 (FOXP3). These are known as FOXP3+ T-regulatory cells (Tregs) and are thought to play an immune suppressive role in tumourigenesis. In most tumours, including melanoma, a high density of intratumoural FOXP3+ Tregs has been associated with poor prognosis. It is not known whether these cells also influence the response to BRAF inhibition therapy in metastatic melanoma. In the present study we retrospectively investigated the density of FOXP3+ Tregs in primary melanomas, with known subsequent metastasis, in relation to various clinicopathological parameters including BRAF and NRAS mutation status, and response to BRAF inhibitor therapy. The intratumoural density of FOXP3+ Tregs was two-fold higher in melanomas with mutant BRAF compared to those with wild type BRAF status (pâ=â0.03). In patients treated with BRAF kinase inhibitors FOXP3+ Treg density in the primary tumour was not predictive of treatment response (pâ=â0.38).
Asunto(s)
Melanoma/genética , Melanoma/inmunología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/inmunología , Linfocitos T Reguladores/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Análisis Mutacional de ADN , Femenino , Factores de Transcripción Forkhead/inmunología , Humanos , Inmunohistoquímica , Linfocitos Infiltrantes de Tumor/inmunología , Masculino , Melanoma/tratamiento farmacológico , Persona de Mediana Edad , Mutación , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas B-raf/genética , Estudios Retrospectivos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Subgrupos de Linfocitos T/inmunología , Adulto JovenRESUMEN
BRAF and MEK inhibitors are not established treatments for non-V600 mutation-positive metastatic melanoma. We carried out a retrospective analysis of efficacy and safety in four patients with BRAF K601E and one patient with L597Q mutation-positive metastatic melanoma treated with the MEK inhibitor trametinib. Three patients achieved a RECIST partial response, including the patient with an L597Q mutation. Paired biopsies available in one of the five patients showed reduced phospho-ERK signalling and this corresponded to a metabolic response on F-fluorodeoxyglucose-PET scanning. Trametinib toxicity was manageable. Trametinib has antitumour activity in patients with BRAF K601E and L597Q mutation-positive metastatic melanoma.