1 “Eribulina: Nuevos datos nuevas perspectivas”Dr. José Ángel García Sáenz
2 Citotóxicos activos en CMMTaxanos Paclitaxel Nabpaclitaxel Docetaxel Antraciclinas Adriamicina Adriamicina liposomal pegilada Antimetabolitos Capecitabina Gemcitabina Otros agentes antimicrotubulo Vinorelbine Eribulina Otros Ciclofosfamida Carboplatino Cisplatino Partridge AH, et al. J Clin Oncol. 2014
3 Eribulina tiene un mecanismo de acción diferente a otros agentes antimicrotubulosJordan MA et al. Mol Cancer Ther 2005. Smith JA et al. Biochemistry 2010.
4 Eribulina: mecanismo de acciónRemodelado vacular Efecto antimitótico Tumor Cambio de EMT Diversos estudios in vivo e in vitro han demostrado que Eribulina Tiene un efecto de reestructuración de la vascularización del tumor (disminuyendo la hipoxia del interior del tumor) Produce un cambio en la transición epitelio-mesequima. Las células tratadas con Eribulina expresan mayor cantidad de marcadores epiteliales que mesenquimales siendo asi menos agresivo el tumor. (Fenotipo epitelial=menor agresividad, fenotipo mesenquimal=mayor agresividad) Eribulina disminuye la capacidad de migrar e invadir de las células tumorales
5 EMBRACE (305): Eribulina vs mejor tto a criterio del investigador en >3LíneaMesilato de Eribulina 1.4 mg/m2 D1-8/21 ) 762 pacientes CMM • >2-≤5 lineas previas 2:1 Mejor tto a criterio del investigador Taxanos 99 % Antraciclinas 99% Capecitabina 73% Cortes J, et al. Lancet
6 EMBRACE: Overall SurvivalMedian OS, months Eribulin (n=508) 13.2 TPC (n=254) 10.5 HR 0.81 95% CI 0.67, 0.96 P value* 0.014 The (unplanned) update of overall survival (OS) was requested by both the US and European regulatory authorities after 75% of patients in the trial had died to ensure that the benefit seen with eribulin was maintained as the data matured and more patients passed the median timepoint in the trial.1,2 The updated survival analysis evaluated OS data for 589 events, representing 77.3% of the intent-to-treat (ITT) population.1 This analysis confirmed the significant and clinically meaningful survival benefit in patients treated with eribulin. The magnitude of benefit of eribulin over treatment of physician’s choice (TPC) was similar but the (nominal) P value improved to 0.014:1 The median OS among patients receiving eribulin was 13.2 months This was 2.7 months longer than the median OS of 10.5 months in patients receiving TPC, representing a 26% increase in the duration of survival The hazard ratio was 0.81, with a 95% confidence interval (CI) of 0.67–0.96 and a significant nominal P value of Based on the Kaplan-Meier analysis:2 The 1-year survival rate estimate was 54.5% for eribulin-treated patients compared with 42.8% for TPC-treated patients The 2-year survival rate estimate was 21.9% for eribulin-treated patients compared with 19.2% for TPC-treated patients. The updated survival data provide a better survival estimate than the primary analysis. In the updated analysis fewer patients were censored (as fewer were alive at the time this analysis was conducted) and the statistical analysis is therefore based on a larger number of ‘real’ (vs ‘estimated’) data. References 1. Cortes J, O’Shaughnessy J et al. Lancet. 2011;377:914–923 2. Twelves C, Loesch D et al. San Antonio Breast Cancer Symposium. 2010;Poster P Job code: Eribulin-EU2154 Date of prep: January 2012 Analysis occurred at 589 events (deaths), representing 77% of the ITT population *Nominal P value from stratified log-rank test Cortes J, et al. Lancet
7 El beneficio en superv fue mayor en los pacientes que recibieron Eribulina en líneas mas inicialesHR=0,774 P=0,039 HR=0,899 P=0,607 13,3 10,7 11,7 10,0 If we analyze the data between eribulin patients in the third line versus patients treated in a posterior setting, the increase in OS vs TPC is greater. Additionally, if we compare the population that received eribulin in early lines versus those patients who recieved the drug in later lines we also observe considerablt differences in OS. Subgroup analysis identified consistently longer median OS with eribulin vs TPC in patients who received ≤3 prior chemotherapy regimens ___________________________________________________ An exploratory subgroup analysis of the EMBRACE study, presented at the San Antonio Breast Cancer Symposium in 2010, demonstrated that the benefit in overall survival (OS) with eribulin treatment compared with treatment of physician’s choice (TPC) was greatest in patients with locally recurrent or metastatic breast cancer (MBC) who had received fewer prior therapies.1 In patients who had been treated with three or fewer prior chemotherapy regimens, the median OS among those receiving eribulin was 13.3 months. This was 2.6 months longer than the median OS of 10.7 months among patients receiving TPC. The hazard ratio (HR) was 0.77, with a 95% confidence interval (CI) of 0.61–0.90 and a P value of In patients who had been treated with more than three prior chemotherapy regimens, the median OS among those receiving eribulin was 11.7 months. This was 1.7 months longer than the median OS of 10.0 months among patients receiving TPC. The HR was 0.90, with a 95% CI of 0.60–1.35 and a P value of The EMBRACE study was not powered to show statistical significance for this subgroup analysis.1 Reference Blum J, Twelves C et al. San Antonio Breast Cancer Symposium. 2010;P Job code: Eribulin-EU2154 Date of prep: January 2012 N=372 N=162 N=106 N=51 Blum JL, et al. SABCS 2010
8 FASE III (301): Eribulina vs capecitabina tras Antraciclinas y TaxanosMesilato de Eribulina 1.4 mg/m2 ) 1102 pacientes CMM • ≤2 línea previas para CMM • Antraciclinas y taxanos previos Capecitabina 1250 mg/m2/12h El estudio será positivo: Si SG fuera mejor con Eribulina (p≤0.0372) Si SLP fuera mejor con Eribulina (p≤0.01) y la OR para SG fuera <1 Kaufman P, et al. JCO 2015
9 FASE III (301): Eribulina vs capecitabina tras Antraciclinas y TaxanosKaufman P, et al. JCO 2015
10 FASE III (301): Eribulina vs capecitabina tras Antraciclinas y TaxanosKaufman P, et al. JCO 2015
11 Eribulina tiene los datos más convincentes tras antracilinas y taxanos
12 Análisis conjunto 305 y 301 Inclusión Objetivo primario 305 301>2-5 líneas CMM Supervivencia Global 301 ≤2 para CMM Antra. y Taxanos S. Libre de progresión Twelves C, et al. Breast Cancer Res Treat 2014
13 Supervivencia Global en subgruposAnálisis 305 y 301. Objetivos Supervivencia Global en la población ITT Supervivencia Global en subgrupos HER2 RRHH Nº órganos afectados Enfermedad visceral Refractariedad a taxanos Twelves C, et al. Breast Cancer Res Treat 2014
14 Análisis 305 y 301. Brazo cotrolAgent 305 n=254 (%) 301 n=548 (%) Total n=802 (%) Taxanes 41 (16.1%) 41 (5.1%) Anthracyclines 24 (9.4%) 24 (3.0%) Capecitabine 44 (17.3%) 549 (100%) 593 (73.9%) Vinorelbine 61 (24.0%) 61 (7.6%) Gemcitabine 46 (18.1%) 46 (5.7%) Other agents 25 (9.8%) 25 (3.1%) Hormone therapy 9 (3.5%) 9 (1.1%) El comparador mayoritario fue Capecitabina, lo que es lógico teniendo en cuenta que el brazo comparador en el 301 fue dicho compuesto Twelves C, et al. Breast Cancer Res Treat 2014
15 Análisis 305 y 301. Resultados Eribulina (1062) Control (802) Edad 5554 Líneas previas 11% 13% 1 27% 37% 2 35% 21% >2 20% >2 localizaciones Enfermedad Visceral 83% 86% HER2 (+) 16% 15% RE (+) 56% Triple negativo 23% Twelves C, et al. Breast Cancer Res Treat 2014
16 Supervivencia global en ITTEribulin (n=1062) 15.2m Control (n=802) 12.8m HR 0.853 95% CI 0.768, 0.948 P value 0.0031 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Diferencia 2.4m Proportion of survival Number of subjects at risk 1062 802 1021 750 957 672 870 604 785 545 690 486 623 414 554 370 462 324 385 275 327 242 276 216 227 181 189 151 158 134 130 113 105 83 79 62 52 42 38 33 32 27 26 23 22 17 15 13 13 12 9 10 7 2 2 2 1 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 Time (months) Data on file ERI-104 Twelves C, et al. Breast Cancer Res Treat 2014
17 Twelves C, et al. Breast Cancer Res Treat 2014
18 Superviencia Global en HER2 (-)1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Median OS (months) Eribulin (n=748) 15.2 Control (n=572) 12.3 HR 0.819 95% CI 0.72, 0.93 P value 0.0019 2.9m Proportion of survival Number of subjects at risk 748 572 712 531 664 470 603 420 545 372 480 331 442 284 393 256 324 220 264 183 223 162 188 142 155 118 130 101 108 91 91 77 71 56 54 43 39 28 27 21 25 17 20 16 16 13 13 11 12 10 8 9 6 2 2 2 1 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 Time (months) Twelves C, et al. Breast Cancer Res Treat 2014
19 Supervivencia Global en TN1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Median OS (months) Eribulin (n=243) 12.9 Control (n=185) 8.2 HR 0.741 95% CI 0.6, 0.92 P value 0.0056 4.7m Proportion of survival Number of subjects at risk 243 185 226 168 201 139 173 120 154 98 134 81 122 67 108 59 88 45 73 38 60 33 54 28 40 23 32 19 28 17 24 16 20 9 17 8 13 6 10 5 9 3 9 3 7 3 5 3 5 3 4 2 3 1 1 1 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 Time (months) Twelves C, et al. Breast Cancer Res Treat 2014
20 Analisis conjunto en las pacientes con CMM tratadas con ≥1L para la enfermedad avanzadaCuando se analizan el OS y PFS de los pacientes tratados a partir de segunda linea en adelante, Eribulina en todos los subgrupos es superior al brazo control, teniendo en todos los casos significación estadistica Twelves C, et al. Breast Cancer Res Treat 2014
21 Conclusiones Eribulina aumenta la supervivencia en pacientes que han recibido antraciclinas y taxanos. El mayor beneficio se obtiene en población HER2 negativo y tumores triple negativo. Es una opción valida a capecitabina, por su eficacia similar y su toxicidad diferencial.