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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













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


Most common treatment-related adverseevents and hematologic abnormalities


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


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%)


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%)



*NA = no aplica


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


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


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)


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


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




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

Vinflunine in second-line therapy

Bellmunt J, JCO 2009Bellmunt J. Ann Oncol 2013

Vinflunine in second-line therapy: better than taxanes(SECAVIN trial)


● 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

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]

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