RESUMEN
BACKGROUND: Cyclin-dependent kinases (CDK) 4/6 inhibitors have significantly improved outcomes for patients with ER+/HER2- breast cancer. Nevertheless, they differ from each other in terms of chemical, biological, and pharmacological features, as well as toxicity profiles. We aim to determine whether QTc prolongation is caused by CDK4/6i in general or if it is associated with ribociclib only. METHODS: We systematically searched PubMed, Embase, and Cochrane Library for randomized controlled trials (RCTs) comparing the prevalence of QTc prolongation as an adverse event in HR+ breast cancer patients treated with CDK4/6i vs those without CDK4/6i. We pooled relative risk (RR) and mean difference (MD) with 95% confidence interval (CI) for the binary endpoint of QT prolongation. RESULTS: We included 14 RCTs comprising 16â196 patients, of whom 8576 underwent therapy with CDK4/6i. An increased risk of QTc prolongation was associated with the use of CDK4/6i (RR = 2.35, 95% CI = 1.67 to 3.29, P < .001; I2 = 44%). Subgroup analyses revealed a significant increase in the QTc interval for the ribociclib and palbociclib cohorts. The ribociclib subgroup showed a relative risk of 3.12 (95% CI = 2.09 to 4.65, P < .001; I2 = 12%), whereas the palbociclib subgroup had a relative risk of 1.51 (95% CI = 1.05 to 2.15, P = .025; I2 = 0%). CONCLUSION: Palbociclib was associated with QTc prolongation; however, the relative risk for any grade QTc was quantitively twice with ribociclib. Furthermore, grade 3 QTc prolongations were observed exclusively with ribociclib. These results are important for guiding clinical decision-making and provide reassurance regarding the overall safety profile of this drug class.
Asunto(s)
Neoplasias de la Mama , Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la Ciclina , Síndrome de QT Prolongado , Inhibidores de Proteínas Quinasas , Femenino , Humanos , Aminopiridinas/efectos adversos , Aminopiridinas/uso terapéutico , Aminopiridinas/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Síndrome de QT Prolongado/inducido químicamente , Piperazinas/efectos adversos , Piperazinas/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/administración & dosificación , Purinas/efectos adversos , Purinas/uso terapéutico , Purinas/administración & dosificación , Piridinas/efectos adversos , Piridinas/uso terapéutico , Piridinas/administración & dosificación , Ensayos Clínicos Controlados Aleatorios como Asunto , Roscovitina/efectos adversosRESUMEN
PURPOSE: Cyclin inhibitors plus endocrine therapy represent the reference standard for hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) locally advanced or metastatic breast cancer (ABC). Efficacy results on hard end points such as overall survival come from well-designed randomized clinical trials (RCTs). However, a limitation of RCTs is the low external results validity, and their extrapolation to a broader population may not be appropriate. Real-world studies can overcome these limitations, also increasing the reliability of RCTs. MATERIALS AND METHODS: The BrasiLEEira was an observational, longitudinal, retrospective, multicenter study to evaluate the effectiveness and safety of ribociclib plus nonsteroidal aromatase inhibitors in Brazilian women age 18 years or older with HR+/HER2- ABC. The study was approved by the institutional review boards of all 11 hospitals. Data were collected anonymously from medical records using an electronic case report form designed by an independent academic research organization, which conducted the study considering all recommendations of international guidelines. The primary end point was 1-year progression-free survival (PFS) rate. Secondary end points included mortality, dose reduction, and safety. RESULTS: The mean age of 76 patients was 57 years, and 28.9% were Black/Brown. The most prevalent comorbidity was arterial hypertension (34.7%). About 26.0% had endocrine-resistant disease, and 54.1% had more than three metastatic sites. The PFS rate was 77.6%. Three patients died (3.9%). Dose reductions occurred in 37.7% of patients. The most common adverse event was neutropenia (68.4%). CONCLUSION: The high-quality evidence from the BrasiLEEira study corroborates the RCTs' findings, expanding its validity to a broader spectrum and underrepresented population who may benefit from ribociclib treatment.
Asunto(s)
Inhibidores de la Aromatasa , Neoplasias de la Mama , Purinas , Femenino , Humanos , Aminopiridinas/efectos adversos , Inhibidores de la Aromatasa/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Persona de Mediana EdadRESUMEN
BACKGROUND: Patients with HER2-positive breast cancer who have received two or more previous therapies for advanced disease have few effective treatment options. The monarcHER trial aimed to compare the efficacy of abemaciclib plus trastuzumab with or without fulvestrant with standard-of-care chemotherapy of physician's choice plus trastuzumab in women with advanced breast cancer. METHODS: This phase 2, three-group, open-label trial was done across 75 hospitals, clinics, and medical centres in 14 countries. Eligible patients were women aged 18 years or older, who had hormone receptor-positive, HER2-positive advanced breast cancer with unresectable, locally advanced, recurrent or metastatic disease, Eastern Cooperative Oncology Group performance status of 0 or 1, and who had previously received at least two HER2-targeted therapies for advanced disease. Patients were randomly assigned 1:1:1 to the abemaciclib, trastuzumab, and fulvestrant (group A), abemaciclib and trastuzumab (group B), or standard-of-care chemotherapy and trastuzumab (group C). Oral abemaciclib 150 mg 12 hourly was administered on days 1-21 of a 21-day cycle, intravenous trastuzumab 8 mg/kg on cycle 1 day 1, followed by 6 mg/kg on day 1 of each subsequent 21-day cycle, and intramuscular fulvestrant 500 mg on days 1, 15, and 29 and once every 4 weeks thereafter. Standard-of-care chemotherapy was administered as specified by the product label. Randomisation was by a computer-generated random sequence by means of an interactive web-response system and stratified by number of previous systemic therapies for advanced breast cancer and measurable versus non-measurable disease. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population, first testing group A versus group C and, if this result was significant, then group B versus group C. Safety was assessed in all patients who had received at least one dose of study treatment. This trial is registered at ClinicalTrials.gov (NCT02675231) and is ongoing for long-term survival follow-up. FINDINGS: Between May 31, 2016, and Feb 28, 2018, 325 patients were screened, of whom 237 eligible patients were enrolled and randomly assigned to groups A (n=79), B (n=79), and C (n=79). Median follow-up was 19·0 months (IQR 14·7-25·1). The study met its primary endpoint, showing a significant difference at the prespecified two-sided α of 0·2 in median progression-free survival between group A (8·3 months, 95% CI 5·9-12·6) and group C (5·7 months, 5·4-7·0; HR 0·67 [95% CI 0·45-1·00]; p=0·051). No difference was observed between median progression-free survival in group B (5·7 months, 95% CI 4·2-7·2) and group C (HR 0·94 [0·64-1·38]; p=0·77). The most common grade 3-4 treatment-emergent adverse event in groups A, B, and C was neutropenia (21 [27%] of 78 patients, 17 [22%] of 77, and 19 [26%] of 72). The most common serious adverse events were: in group A, pyrexia (three [4%]), diarrhoea (two [3%]), urinary tract infection (two [3%]), and acute kidney injury (two [3%]); in group B, diarrhoea (two [3%]) and pneumonitis (two [3%]); and in group C, neutropenia (four [6%]) and pleural effusion (two [3%]). Two deaths were attributed to treatment: one due to pulmonary fibrosis in group B and one due to febrile neutropenia in group C. INTERPRETATION: The combination of abemaciclib, fulvestrant, and trastuzumab significantly improved progression-free survival versus standard-of-care chemotherapy plus trastuzumab while showing a tolerable safety profile. Our results suggest that a chemotherapy-free regimen might potentially be an alternative treatment option for patients with hormone receptor-positive, HER2-positive advanced breast cancer. FUNDING: Eli Lilly and Company.
Asunto(s)
Aminopiridinas/administración & dosificación , Antineoplásicos Inmunológicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bencimidazoles/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Antagonistas del Receptor de Estrógeno/administración & dosificación , Fulvestrant/administración & dosificación , Receptor ErbB-2/antagonistas & inhibidores , Receptores de Estrógenos/efectos de los fármacos , Trastuzumab/administración & dosificación , Anciano , Aminopiridinas/efectos adversos , Antineoplásicos Inmunológicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Argentina , Australia , Bencimidazoles/efectos adversos , Brasil , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Progresión de la Enfermedad , Antagonistas del Receptor de Estrógeno/efectos adversos , Europa (Continente) , Femenino , Fulvestrant/efectos adversos , Humanos , Persona de Mediana Edad , América del Norte , Supervivencia sin Progresión , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , República de Corea , Transducción de Señal , Factores de Tiempo , Trastuzumab/efectos adversosRESUMEN
Se presentan los resultados obtenidos con la amrinoma (A), un cardiotónico no digitálico y sin efectos adrenérgicos, en la insuficiencia cardíaca grave (IC), refractaria (R) y/o con intolerancia (I) a otras drogas. En dosis de 300-600mg/día per os fue utilizada en 10 pacientes (p). Todos estaban en clase funcional (CF) IV (NYHA) y 2 p dependientes de medicación EV (nitroprusiato y/o dopamina). Cinco p tenían miocardiopatía dilatada, 2 valvulopatía aórtica, 1 cardiopatía coronaria y 2 valvulopatía mitral. Todos los p tenían cardiomegalia (Rx). Los valores medios de DDVI y FA, determinados por ecocardiogramas modo M, fueron de 7,36 + ou - 0.84 cm y 17,18 + ou - 7%, respectivamente; la FEVI media (por centellografía con Tc99m) era de 13,66 + ou - 3,16%. El seguimiento hasta el deceso o cierre del estudio osciló entre 3 y 12 meses (media 7,7 meses/p). Nueve p mostraron mejoría clínica y Rx ostensibles, pasando a CF grado II 2 p y grado III 7 p. El restante no cambió su CF. El análisis estadístico de las variaciones (bi o trimestrales) de DDVI, FA y FEVI no mostró diferencias significativas. Los efectos secundarios fueron leves (plaquetopenia transitoria, anorexia, náuseas) y no obligaron a suspender la A. Siete p fallecieron en forma brusca. Se concluye que en p con IV la A: 1) mejora la CF de manera sostenida; 2) no ocasiona efectos secundarios trascendentes, y 3) no parece aumentar la supervivencia de los p con IC en CF IV
Asunto(s)
Adulto , Persona de Mediana Edad , Humanos , Masculino , Femenino , Aminopiridinas/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Aminopiridinas/efectos adversos , Ecocardiografía , Electroencefalografía , Frecuencia Cardíaca/efectos de los fármacos , Presión Arterial/efectos de los fármacosRESUMEN
Se presentan los resultados obtenidos con la amrinoma (A), un cardiotónico no digitálico y sin efectos adrenérgicos, en la insuficiencia cardíaca grave (IC), refractaria (R) y/o con intolerancia (I) a otras drogas. En dosis de 300-600mg/día per os fue utilizada en 10 pacientes (p). Todos estaban en clase funcional (CF) IV (NYHA) y 2 p dependientes de medicación EV (nitroprusiato y/o dopamina). Cinco p tenían miocardiopatía dilatada, 2 valvulopatía aórtica, 1 cardiopatía coronaria y 2 valvulopatía mitral. Todos los p tenían cardiomegalia (Rx). Los valores medios de DDVI y FA, determinados por ecocardiogramas modo M, fueron de 7,36 + ou - 0.84 cm y 17,18 + ou - 7%, respectivamente; la FEVI media (por centellografía con Tc99m) era de 13,66 + ou - 3,16%. El seguimiento hasta el deceso o cierre del estudio osciló entre 3 y 12 meses (media 7,7 meses/p). Nueve p mostraron mejoría clínica y Rx ostensibles, pasando a CF grado II 2 p y grado III 7 p. El restante no cambió su CF. El análisis estadístico de las variaciones (bi o trimestrales) de DDVI, FA y FEVI no mostró diferencias significativas. Los efectos secundarios fueron leves (plaquetopenia transitoria, anorexia, náuseas) y no obligaron a suspender la A. Siete p fallecieron en forma brusca. Se concluye que en p con IV la A: 1) mejora la CF de manera sostenida; 2) no ocasiona efectos secundarios trascendentes, y 3) no parece aumentar la supervivencia de los p con IC en CF IV (AU)