Cáncer de vejiga avanzado: Quimioterapia en segunda línea y tratamiento de mantenimiento

Transcripción

1 Cáncer de vejiga avanzado: Quimioterapia en segunda línea y tratamiento de mantenimiento Javier Puente, MD, PhD Hospital Universitario Clinico San Carlos Medical Oncology Department Complutense University Associate Professor of Medicine javierpuente.hcsc@gmail.com

2 An Evolving treatment algorithm for muc: EAU guidelines Nivolumab

3 An Evolving treatment algorithm for muc: NCCN guidelines

4 Progress and Pitfalls in randomized phase III trials in advanced bladder cancer The definition of second-line therapy The need for clear definitons of primary refractory disease, adquired resistant disease and recurrent disease after treatment The use of prognostic factors for proper stratification The analysis based on elegibility versus ITT The role of prolonged/maintenance treatment in second line vs predefined period The value of rechallenging with agents used in first-line therapy Bellmunt J, Ann Oncol 2011

5 Single Agent 2nd Line Trials Autor Molécula QT previa perioperativa como 1ª línea N RG (%) SLP (meses) MS (meses) Mc Caffrey, 1997 Docetaxel Sí NR 9,0 Papamichael, 1997 Paclitaxel NR 14 7 NR NR Vaughn, 2002 Paclitaxel No ,2 7,2 Joly, 2004 Paclitaxel No ,5 Lorusso, 1998 Gemcitabina Sí ,8 5,0 Gebbia, 1999 Gemcitabina Sí NR 13,0 Albers, 2002 Gemcitabina NR ,9 8,7 Moore, 2003 Oxaliplatino Sí, si <6m ,5 7,0 Sweeney, 2006 Pemetrexed Sí, si <12m ,9 9,6 Galsky, 2007 Pemetrexed Sí 12 8 NR NR Culine, 2006 Vinflunina NR ,0 6,6 Vaughn, 2009 Vinflunina Sí, si <12m ,8 8,2

6 2:1 N: 370 2nd LINE T4bN0M0 or TxN2-3 or M1 Progression after 1st line platinum treatment Stratify: -Center -Refractory vs Non-refractory Primary Endpoint: OS Secondary Endpoints: ORR, PFS, DCR, QoL, CB R A N D O M I S E N: 253 VFL+BSC (PS 0: 320 mg/m2, q3w; PS 0 with previous pelvic irradiation and PS 1: 280 mg/m2) N: 117 BSC with treatment upon progression permitted Bellmunt J, JCO 2009

7 Phase III trial of vinflunine+bsc vs BSC: Results in OS: ITT and Eligible population Bellmunt J, JCO 2009

8 Most common treatment-related adverse events and hematologic abnormalities Bellmunt J, JCO 2009

9 Bellmunt J, Ann Oncol 2013

10 Real World Data with Vinflunine N pacientes Tratamiento de Línea Alemania1, Francia2 Italia3 Reino Unido4 España5 Grecia PS0 31 PS1 61 PS2 8 PS0 3 PS1 84 PS2 13 PS0 28,5 PS1 71,5 72 (visceral) 74 (visceral) 1ª FIII7 QT con platino PS0 25 PS1 46 PS 2 29 PS (visceral) 57 (pulmón + hígado) 21 (hígado) Mediana ciclos VFL [rango] 5 5 [1-23] 4 [1-23] 3 [1-16] 4 [1-18] 4 [1-16] 3 [1-20] ORR (%) ,6 DCR (%) ,1 ECOG-PS/ IK (%) Afectación visceral (%) PS PS (pulmón) (pulmón) 17 (hígado) (hígado)

11 Real World Data with Vinflunine Median Overall Survival (7) Fase III VFL n=253 6,9 (1) Alemania n=77 (3) Italia n=217 8,1 (2) Francia n=134 8,2 (4) Reino Unido n=49 (5) (6) 7,7 9,1 España n=102 10, Grecia n=71 11,9 0, 3, 6, 9, 12, 15,

12 MAJA trial: vinflunine in maintenance García-Donas J, et al. Lancet Oncol 2017

13 MAJA trial: vinflunine in maintenance Brazo de tratamiento; N (%) VINFLUNINA + MTS (45) MTS (43) 63.7 [42-83] 65 [42-78] Hombre 37 (82.2%) 40 (93%) Mujer 8 (17.8%) 3 (7%) TCCU puro 38 (84.4%) 37 (86%) TCCU con cél. escamosas 7 (15.6%) 4 (9.3%) 0 (0%) 2 (4.7%) Tracto superior 7 (15.6%) 5 (11.6%) Vejiga 36 (80%) 37 (86%) Uretra 2 (4.4%) 1 (2.3%) Locorregional 9 (20%) 9 (20.9%) Metastásica 36 (80%) 34 (79.1%) < 10 g/dl 4 (8.9%) 3 (7%) 10 g/dl 41 (91.1%) 40 (93%) Mediana de edad (años) Gender Histología TCCU con adenocarcinoma Lugar primario Extensión de la enfermedad Hemoglobina García-Donas J, et al. Lancet Oncol 2017

14 MAJA trial: vinflunine in maintenance *NA = no aplica García-Donas J, et al. Lancet Oncol 2017

15 MAJA trial: vinflunine in maintenance Proporción de pacientes con factores pronóstico Brazo de tratamiento; N (%) VINFLUNINA + MTS (45) Proporción de pacientes con factores pronóstico MTS (43) 0 factores pronóstico 20 (44.4%) 17 (39.5%) 1 factor pronóstico 19 (42.2%) 20 (46.5%) 2 factores pronóstico 6 (13.4%) 5 (11.6%) 3 factores pronóstico 0 (0%) 1 (2.4%) Respuesta a tratamiento previo con Cisplatino-Gemcitabina Brazo de tratamiento; N (%) VINFLUNINA + MTS (45) MTS (43) RC 7 (15.6%) 7 (16.3%) RP 28 (62.2%) 23 (53.5%) EE 10 (22.2%) 13 (30.2%) García-Donas J, et al. Lancet Oncol 2017

16 MAJA trial: vinflunine in maintenance VFL 6.53 meses; IC95% ( ) Probabilidad de supervivencia libre de progresión MTS 4.2 meses; IC95% ( ) HR = 0.6; IC95% [ ] P-valor = Mediana de seguimiento de los pacientes vivos: 27.6 months (CI 95%, ) Meses García-Donas J, et al. Lancet Oncol 2017

17 MAJA trial: vinflunine in maintenance VFL 16.7 meses; IC95% ( ) Probabilidad de Supervivencia global MTS 13.2 meses; IC95% ( ) HR = 0.695; IC95% [ ] P-valor = Meses García-Donas J, et al. Lancet Oncol 2017

18 Patient selection criteria for therapies

19 Rational for chemotherapy in second-line treatment today (2017) - Chemotherapy and long survival - Disease free survival and progressions - No benefit with IO in some subgroups of patients

20 Rational for chemotherapy in second-line treatment today (2017) - Chemotherapy and long survival - Disease free survival and progressions - No benefit with IO in some subgroups of patients

21 Neoadjuvant chemotherapy in bladder cancer: Save lifes 11 ensayos. n= % de todos los pacientes incluidos en ensayos Reducción del riesgo de muerte: 16%. ABC Meta-analysis. Eur Urol 2005 BENEFICIO ABSOLUTO S.G.: 5%

22 Van der Maase, J Clin Oncol 2005

23 Sternberg Eur J Cancer 2006

24 Long term follow-up of cisplatin combinationchemotherapy of the post-mvac-era Sternberg 2006; von der Maase 2005

25 Long term survival also occurs with 2nd line therapy Bellmunt J, JCO 2009 Bellmunt J. Ann Oncol 2013

26 Patients with favorable risk achieve better outcome: in first line Bajorin D. J Clin Oncol 1999

27 Patients with favorable risk achieve better outcome: and also in second line Bellmunt J. Ann Oncol ESMO guidlines

28 Rational for chemotherapy in second-line treatment today (2017) - Chemotherapy and long survival - Disease free survival and progressions - No benefit with IO in some subgroups of patients

29 Vinflunine in second-line therapy Bellmunt J, JCO 2009 Bellmunt J. Ann Oncol 2013

30 Vinflunine in second-line therapy: better than taxanes (SECAVIN trial) Bellmunt J, Ann Oncol 2017

31 No impact in terms of PFS with IO: KEYNOTE-045-Phase III pembrolizumab vs QT SG mediana: 10.3 meses SLP mediana: 2.1 meses Bellmunt J, et al. SITC 2016

32 No impact in terms of PFS with IO: Nivolumab-CheckMate 032 Sharma P, et al. ASCO 2016

33 No impact in terms of PFS with IO: Atezolizumab-IMvigor 210 Rosenberg. ESMO 2016

34 Rational for chemotherapy in second-line treatment today (2017) - Chemotherapy and long survival - Disease free survival and progressions - No benefit with IO in some subgroups of patients

35 IMVigor 211: Phase III atezolizumab vs QT

36 OS with IO: KEYNOTE-045-Phase III pembrolizumab vs QT Bellmunt J, et al. SITC 2016

37 Overall Survival: CheckMate-057 Peters S, et al. WCLC 2016

38 Single baseline characteristics by OS with nivolumab Peters S, et al. WCLC 2016

39 PD-L1 status as a biomarker: more than a simple question..

40 IMvigor210: phase II trial with atezolizumab (cohort 2) Rosenberg JE, et al. Lancet 2016;387:1909 Loriot Y, et al. ESMO 2016; abstr 783P

41 Basal bladder cancer is associated with poor clinical outcome: p53 confers chemo-resistance Choi. Cancer Cell 2014 McConkey. Curr Opt Urol 2015

42 Molecular TCC: A novel approach to select therapy?

43 Patient selection criteria for therapies Objetive? -Prolong survival -Maintain QoL -Delay progression -Response Mutation Load, molecular profile (TCGA subtype)

44 Thank you Javier Puente, MD, PhD Hospital Universitario Clinico San Carlos Medical Oncology Department Complutense University Associate Professor of Medicine