Cáncer de vejiga avanzado - Sociedad Española de ... · Cáncer de vejiga avanzado: Quimioterapia...
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Cáncer de vejiga avanzado:Quimioterapia en segunda línea y
tratamiento de mantenimientoJavier Puente, MD, PhD
Hospital Universitario Clinico San CarlosMedical Oncology Department
Complutense UniversityAssociate Professor of [email protected]
Cáncer de vejiga avanzado:Quimioterapia en segunda línea y
tratamiento de mantenimientoJavier Puente, MD, PhD
Hospital Universitario Clinico San CarlosMedical Oncology Department
Complutense UniversityAssociate Professor of [email protected]
An Evolving treatment algorithm for mUC:EAU guidelines
NivolumabNivolumab
An Evolving treatment algorithm for mUC:NCCN guidelines
Progress and Pitfalls in randomized phaseIII trials in advanced bladder cancer
The definition of second-line therapy
The need for clear definitons of primary refractory disease, adquired resistant disease andrecurrent 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
The definition of second-line therapy
The need for clear definitons of primary refractory disease, adquired resistant disease andrecurrent 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
The definition of second-line therapy
The need for clear definitons of primary refractory disease, adquired resistant disease andrecurrent 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
AutorMolécula
QT previaperioperativa como 1ª
líneaN RG (%) SLP (meses) MS (meses)
Mc Caffrey, 1997 Docetaxel Sí 30 13 NR 9,0
Single Agent 2nd Line Trials
Mc Caffrey, 1997 Docetaxel Sí 30 13 NR 9,0
Papamichael, 1997 Paclitaxel NR 14 7 NR NR
Vaughn, 2002 Paclitaxel No 31 10 2,2 7,2
Joly, 2004 Paclitaxel No 37 5 3 6,5
Lorusso, 1998 Gemcitabina Sí 31 23 3,8 5,0
Gebbia, 1999 Gemcitabina Sí 24 29 NR 13,0
Albers, 2002 Gemcitabina NR 28 11 4,9 8,7
Moore, 2003 Oxaliplatino Sí, si <6m 18 6 1,5 7,0
Sweeney, 2006 Pemetrexed Sí, si <12m 47 28 2,9 9,6
Galsky, 2007 Pemetrexed Sí 12 8 NR NR
Culine, 2006 Vinflunina NR 51 18 3,0 6,6
Vaughn, 2009 Vinflunina Sí, si <12m 151 15 2,8 8,2
2nd LINET4bN0M0 or TxN2-3 or M1Progression after 1st lineplatinum treatmentStratify:-Center-Refractory vs Non-refractory
RANDOMISE
VFL+BSC (PS 0: 320 mg/m2, q3w; PS0 with previous pelvic irradiation
and PS 1: 280 mg/m2)
N: 370N: 253
2:1
2nd LINET4bN0M0 or TxN2-3 or M1Progression after 1st lineplatinum treatmentStratify:-Center-Refractory vs Non-refractory
RANDOMISE
BSC with treatment uponprogression permitted
Bellmunt J, JCO 2009
N: 117
Primary Endpoint: OSSecondary Endpoints: ORR, PFS, DCR, QoL, CB
Phase III trial of vinflunine+BSC vs BSC:Results in OS: ITT and Eligible population
Bellmunt J, JCO 2009
Most common treatment-related adverseevents and hematologic abnormalities
Bellmunt J, JCO 2009
Bellmunt J, Ann Oncol 2013
Alemania1, Francia2 Italia3 Reino Unido4 España5 Grecia6 FIII7N pacientes 77 134 217 38 102 71 253
Real World Data with Vinflunine
N pacientes 77 134 217 38 102 71 253
Tratamiento de 1ªLínea QT con platino
ECOG-PS/ IK (%) PS0 25PS146PS≥2 29 PS≥1 47 PS0-1 92PS2
8PS0 31PS1
61PS2 8PS0 3PS184PS2 13
PS0 28,5PS171,5
Afectación visceral (%) 58(visceral) 57(pulmón +hígado) 21(hígado) 39 (pulmón)29
(hígado)29 (pulmón)17
(hígado) 72(visceral) 74(visceral)
Mediana ciclos VFL[rango] 5 5[1-23] 4[1-23] 3[1-16] 4[1-18] 4[1-16] 3[1-20]
ORR (%) 23 22 14 29 25 15 8,6
DCR (%) 53 51 - 50 66 56 41,1
6,9Fase III VFLn=253
Median Overall Survival
(7)
Real World Data with Vinflunine
7,7
8,1
8,2
9,1
Alemania n=77
Italia n=217
Francia n=134
Reino Unidon=49
(3)
(2)
(4)
(5)
(1)
10,
11,9
0, 3, 6, 9, 12, 15,
España n=102
Grecia n=71(6)
(5)
MAJA trial: vinflunine in maintenance
García-Donas J, et al. Lancet Oncol 2017
MAJA trial: vinflunine in maintenance
Brazo de tratamiento; N (%) VINFLUNINA + MTS (45) MTS (43)
Mediana de edad (años) 63.7 [42-83] 65 [42-78]
GenderHombre 37 (82.2%) 40 (93%)
GenderHombre 37 (82.2%) 40 (93%)
Mujer 8 (17.8%) 3 (7%)
Histología
TCCU puro 38 (84.4%) 37 (86%)
TCCU con cél. escamosas 7 (15.6%) 4 (9.3%)
TCCU con adenocarcinoma 0 (0%) 2 (4.7%)
Lugar primario
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%)
García-Donas J, et al. Lancet Oncol 2017
Extensión de laenfermedad
Locorregional 9 (20%) 9 (20.9%)
Metastásica 36 (80%) 34 (79.1%)
Hemoglobina< 10 g/dl 4 (8.9%) 3 (7%)
≥ 10 g/dl 41 (91.1%) 40 (93%)
MAJA trial: vinflunine in maintenance
García-Donas J, et al. Lancet Oncol 2017
*NA = no aplica
MAJA trial: vinflunine in maintenance
Proporción de pacientes con factores pronósticoBrazo de tratamiento; N (%) VINFLUNINA + MTS (45) MTS (43)
Proporción de pacientes con factores pronóstico
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%)
Brazo de tratamiento; N (%) VINFLUNINA + MTS (45) MTS (43)
Respuesta a tratamiento previo con Cisplatino-Gemcitabina
García-Donas J, et al. Lancet Oncol 2017
RC 7 (15.6%) 7 (16.3%)
RP 28 (62.2%) 23 (53.5%)
EE 10 (22.2%) 13 (30.2%)
MAJA trial: vinflunine in maintenancePr
obab
ilida
d de
sup
ervi
venc
ia li
bre
de p
rogr
esió
n
VFL 6.53 meses; IC95% (2.02 - 11.05)
MTS 4.2 meses; IC95% (1.77 – 6.64)
Prob
abili
dad
de s
uper
vive
ncia
libr
e de
pro
gres
ión
HR = 0.6; IC95% [0.37 – 0.98]P-valor = 0.037
García-Donas J, et al. Lancet Oncol 2017
Prob
abili
dad
de s
uper
vive
ncia
libr
e de
pro
gres
ión
Meses
Mediana de seguimiento de los pacientes vivos: 27.6 months (CI95%, 14.9-48.7)
MAJA trial: vinflunine in maintenance
VFL 16.7 meses; IC95% (3.1 - 30.3)
MTS 13.2 meses; IC95% (6.7 – 19.7)
HR = 0.695; IC95% [0.41 – 1.19]P-valor = 0.179
Prob
abili
dad
de S
uper
vive
ncia
glo
bal
García-Donas J, et al. Lancet Oncol 2017
Meses
Prob
abili
dad
de S
uper
vive
ncia
glo
bal
Patient selection criteria for therapies
Rational for chemotherapy in second-linetreatment today (2017)
- Chemotherapy and long survival
- Disease free survival and progressions
- No benefit with IO in some subgroups of patients
- Chemotherapy and long survival
- Disease free survival and progressions
- No benefit with IO in some subgroups of patients
Rational for chemotherapy in second-linetreatment today (2017)
- Chemotherapy and long survival
- Disease free survival and progressions
- No benefit with IO in some subgroups of patients
- Chemotherapy and long survival
- Disease free survival and progressions
- No benefit with IO in some subgroups of patients
BENEFICIO ABSOLUTOS.G.: 5%
• 11 ensayos. n=3005• 98% de todos los pacientes incluidos en ensayos• Reducción del riesgo de muerte: 16%.
Neoadjuvant chemotherapy in bladdercancer: Save lifes• 11 ensayos. n=3005• 98% de todos los pacientes incluidos en ensayos• Reducción del riesgo de muerte: 16%.
ABC Meta-analysis. Eur Urol 2005
Van der Maase, J Clin Oncol 2005
Sternberg Eur J Cancer 2006
Long term follow-up of cisplatin combination-chemotherapy of the post-MVAC-era
Sternberg 2006; von der Maase 2005
Long term survival also occurs with 2nd line therapy
Bellmunt J, JCO 2009Bellmunt J. Ann Oncol 2013
Patients with favorable risk achieve betteroutcome: in first line…
Bajorin D. J Clin Oncol 1999
Patients with favorable risk achieve betteroutcome: and also in second line
Bellmunt J. Ann Oncol ESMO guidlines
Rational for chemotherapy in second-linetreatment today (2017)
- Chemotherapy and long survival
- Disease free survival and progressions
- No benefit with IO in some subgroups of patients
- Chemotherapy and long survival
- Disease free survival and progressions
- No benefit with IO in some subgroups of patients
Vinflunine in second-line therapy
Bellmunt J, JCO 2009Bellmunt J. Ann Oncol 2013
Vinflunine in second-line therapy: better than taxanes(SECAVIN trial)
Bellmunt J, Ann Oncol 2017
● SG mediana: 10.3 meses● SLP mediana: 2.1 meses
No impact in terms of PFS with IO:KEYNOTE-045-Phase III pembrolizumab vs QT
Bellmunt J, et al. SITC 2016
No impact in terms of PFS with IO:Nivolumab-CheckMate 032
Sharma P, et al. ASCO 2016
No impact in terms of PFS with IO:Atezolizumab-IMvigor 210
Rosenberg . ESMO 2016
Rational for chemotherapy in second-linetreatment today (2017)
- Chemotherapy and long survival
- Disease free survival and progressions
- No benefit with IO in some subgroups of patients
- Chemotherapy and long survival
- Disease free survival and progressions
- No benefit with IO in some subgroups of patients
IMVigor 211: Phase III atezolizumab vs QT
OS with IO:KEYNOTE-045-Phase III pembrolizumab vs QT
Bellmunt J, et al. SITC 2016
Overall Survival: CheckMate-057
Peters S, et al. WCLC 2016
Single baseline characteristics by OS with nivolumab
Peters S, et al. WCLC 2016
PD-L1 status as a biomarker:more than a simple question..
IMvigor210: phase II trial with atezolizumab (cohort 2)
Rosenberg JE, et al. Lancet 2016;387:1909Loriot Y, et al. ESMO 2016; abstr 783P
Basal bladder cancer is associated with poor clinicaloutcome: p53 confers chemo-resistance
Choi. Cancer Cell 2014McConkey. Curr Opt Urol 2015
Molecular TCC:A novel approach to select therapy?
Patient selection criteria for therapiesObjetive?
-Prolong survival-Maintain QoL
-Delay progression-Response
Objetive?-Prolong survival
-Maintain QoL-Delay progression
-Response
Mutation Load, molecularprofile (TCGA subtype)
Mutation Load, molecularprofile (TCGA subtype)
Thank you
Javier Puente, MD, PhDHospital Universitario Clinico San Carlos
Medical Oncology DepartmentComplutense University
Associate Professor of [email protected]
Javier Puente, MD, PhDHospital Universitario Clinico San Carlos
Medical Oncology DepartmentComplutense University
Associate Professor of [email protected]