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Coordinador Científico: Dr. Fernando Rivera Hospital Universitario Marqués de Valdecilla, Santander

Organizado por: Fundación para el progreso de la oncología en Cantabria, FUPOCAN

¿Qué hay de nuevo en el tratamiento del Cáncer de Vejiga?

Guillermo Crespo Herrero Hospital Universitario de Burgos

ESQUEMA

• Introducción

• Inmunoterapia: Anti PD-1 y Anti PD-L1

2ª línea tras progresión a platino

1ª línea no candidatos a Cisplatino

• Terapias dirigidas

• Estudios en marcha

• Conclusiones

INTRODUCCION

• 5º cáncer en incidencia en España: 20.7/100.000 habitantes (9º a nivel mundial)

• 4º en ♂ y 15º en ♀

• 7º en mortalidad (6.5/100.000 habitantes)

• Urotelial (90%)

• Edad media al diagnóstico: 65 años

• Etiología: Tabaco, productos químicos, virus del papiloma humano

• Comorbilidades: Paciente frágil (muchos no candidatos a tratamiento con cisplatino)

• Sin avances destacados en los últimos 30 años

ESCENARIOS

• Cáncer Urotelial No Músculo Invasivo: Ta/T1/Tis (70-80%)

RTU / BCG intravesical

• Cáncer Urotelial Músculo Invasivo: T2-T4 (10-15%)

Cistectomía

QT neoadyuvante / adyuvante

Preservación vesical

• Cáncer Urotelial Metastásico (10-15%)

1. Funt SA, Rosenberg JE. Nat Rev Clin Oncol. 2016 2. Kamat AM et al. Lancet. 2016

CA. MUSCULO-INVASIVO: CISTECTOMIA

1. Roehrborn CG et al. J Urol. 1991;146:36-39. 2. Pagano F et al. J Urol. 1991;145:45-50. 3. Wishnow KI et al. Urology. 1992;39:12-16. 4. Waehre H et al. Cancer. 1993;15;72:3044-3051. 5. Vieweg J et al. J Urol. 1999;161:72-76. 6. Stein JP et al. J Clin Oncol. 2001;19:666-675. 7. Dalbagni G et al. J Urol. 2001;165:1111-1116. 8. Madersbacher S et al. J Clin Oncol. 2003;21:690-696. 9. Grossman HB et al. N Engl J Med. 2003;349:859-866.

M-VAC + Cystectomy vs Cystectomy Alone

CA. MUSCULO INVASIVO: QUIMIOTERAPIA NEOADYUVANTE

Grossman, NEJM 2003

ENFERMEDAD METASTASICA LINEA CANDIDATO A

CISPLATINO ESQUEMA TASA

RESPUESTA SUPERVIV (meses)

1ª SI MVAC (1)

Cis-Gem (2)

PGC (3)

40-50% 12-15

NO Carbo-Gem (4-6)

36-56% 7-9

2ª Vinflunina Paclitaxel Docetaxel

10% 5-8

1. Loehrer PJ, Sr. et al. J Clin Oncol. 1992

2. von der Maase H et al. J Clin Oncol. 2000 3. Bellmunt J et al. J Clin Oncol. 2012

4. De Santis M et al. J Clin Oncol. 2012 5. Linardou H et al. Urology. 2004

6. Nogué-Aliguer M et al. Cancer. 2003

INMUNOTERAPIA

• BCG desde 1990

• Anti PD-1 y anti PD-L1

• 2ª línea: TR 15-21%; SG < 1año

• Respuestas prolongadas

• Buena tolerancia

• Biomarcadores:

PD-L1

Carga mutacional

Subtipo genético

PD-L1

• No es requisito

• ¿Factor pronóstico / predictor?

• Diferentes anticuerpos

• Diferentes definiciones: célula tumoral / componente inmune (células inmunes infiltrantes de tumor)

• Diferentes puntos de corte

• Diferentes muestras: actuales / de archivo

CARGA MUTACIONAL

Kandoth C et al. Nature. 2013

SUBTIPO GENETICO

TCGA, Nature. 2014

PEMBROLIZUMAB

PEMBROLIZUMAB

PEMBROLIZUMAB

PEMBROLIZUMAB

PEMBROLIZUMAB

PEMBROLIZUMAB

PEMBROLIZUMAB

PEMBROLIZUMAB

PEMBROLIZUMAB

PEMBROLIZUMAB

Key Eligibility Criteriaa

• mUC with progression during or following platinum-based chemotherapy – ≤ 2 prior lines of therapy

• Measurable disease per RECIST v1.1 • ECOG PS 0-1 • Evaluable sample for PD-L1 testing • TCC histology as primary component

(N = 931)

• Primary endpoint

– OS, tested hierarchically in pre-specified populations

Powles T, et al. EAS 2017

22

Atezolizumab 1200 mg q3w

R 1:1

No crossover permitted per protocol

Survival follow-up

Loss of clinical benefit

RECIST v1.1

progression

Stratification Factors • No. of risk factorsb (0 vs. 1/2/3) • Liver metastases (yes vs. no) • PD-L1 status (0/1 vs. 2/3) • Chemotherapy (vinflunine vs. taxanes)

Additional endpoints

– Efficacy: RECIST v1.1 ORR, PFS and DORc

– Safety

– PROs: EORTC QLQ-C30

Chemotherapy (investigator’s choice)

• Vinflunine q3w • Docetaxel q3w • Paclitaxel q3w

ATEZOLIZUMAB: IMvigor211


23


Key secondary endpoints:

ORR, then PFS

Primary endpoint:

OS

OS: IC2/3

OS: IC1/2/3

OS: ITT

PFS: IC2/3

PFS: IC1/2/3

PFS: ITT

ORR: IC2/3

ORR: IC1/2/3

ORR: ITT

2-sided = 0.05


24


Characteristic

ITT Population

Atezolizumab

(n = 467)

Chemotherapy

(n = 464)

Age, median (range) 67 y (33-88 y) 67 y (31-84 y)

Male 76% 78%

ECOG PS: 0 | 1 47% | 53% 45% | 55%

Tobacco use: Current | Former | Never 13% | 57% | 30% 13% | 61% | 26%

Hemoglobin < 10 g/dL 14% 16%

No. of risk factors:1 0 | 1 | 2 | 3 31% | 46% | 18% | 5% 30% | 45% | 21% | 4%

Primary tumor site:

Lower Tract (bladder | urethra) 69% | 2% 73% | 2%

Upper Tract (renal pelvis | ureter | other) 14% | 13% | 2% 11% | 13% | 2%

Metastatic disease 91% 93%

Sites of metastases:

Lymph node only | viscerala | liver 12% | 77% | 30% 14% | 77% | 28%

Prior cystectomy 43% 43%

Previous chemotherapy < 3 mo 34% 35%

Prior regimens (metastatic setting): 0 | 1 | 2 | ≥ 3b 28% | 53% | 17% | 2% 26% | 56% | 16% | 2%

PD-L1 status: IC2/3 | IC1 | IC0 25% | 43% | 32% 25% | 41% | 33%

OS Analysis: IC2/3 Population

HR = 0.87 (95% CI: 0.63, 1.21)

P = 0.41

Events/ Patients

Median OS (95% CI)

12-mo OS Rate (95% CI)

Atezolizumab 72/116 11.1 mo (8.6, 15.5) 46% (37, 56)

Chemotherapy 88/118 10.6 mo (8.4, 12.2) 41% (32, 50)

No. at Risk

Atezolizumab 116 100 85 77 71 58 51 39 27 19 11 6 0

Chemotherapy 118 100 91 82 71 61 47 32 24 15 9 5 1

80

60

0

10 12 14 16 18 20 2 4 6 8 0 24 22

20

40

Ove

rall

Surv

ival

100

Months



OS Analysis: ITT Population

Events/ Patients

Median OS (95% CI)

12-mo OS Rate (95% CI)

Atezolizumab 324/467 8.6 mo (7.8, 9.6) 39% (35, 44)

Chemotherapy 350/464 8.0 mo (7.2, 8.6) 32% (28, 37) 80

60

0

10 12 14 16 18 20 2 4 6 8 0 24 22

20

40

Ove

rall

Surv

ival

100

Months

80

60

0

10 12 14 16 18 20 2 4 6 8 0 24 22

20

40

Ove

rall

Surv

ival

100

Months

HR = 0.85 (95% CI: 0.73, 0.99)

P = 0.038

No. at Risk

Atezolizumab 467 405 327 280 245 201 177 138 90 59 34 13 1

Chemotherapy 464 397 330 268 219 175 140 99 60 42 17 7 1



12 14

Months

Confirmed ORRa

IC2/3 IC1/2/3 ITT

Atezo (n = 113)

Chemo (n = 116)

Atezo (n = 312)

Chemo (n = 306)

Atezo (n = 462)

Chemo (n = 461)

Responders, n (%) 26 (23%) 25 (22%) 44 (14%) 45 (15%) 62 (13%) 62 (13%) 95% CI, % 16, 32 15, 30 10, 19 11, 19 11, 17 11, 17

CR, n (%) 8 (7%) 8 (7%) 11 (4%) 13 (4%) 16 (3%) 16 (3%)

Response by PD-L1 Subgroup

DOR in ITT Population

No. at Risk

Atezolizumab 62 61 56 50 42 35 23 14 9 5 2 0

Chemotherapy 62 62 59 40 28 23 16 8 5 4 0 0

Events/ Patients mDOR (95% CI)

Atezolizumab 23/62 21.7 mo (13.0, 21.7)

Chemotherapy 49/62 7.4 mo (6.1, 10.3)

80

60

0

10 12 14 16 18 20 2 4 6 8 0 22

20

40

Ob

ject

ive

Res

po

nse

100

Months



1. Powles Nature 2014.

2. Petrylak ASCO GU 2017. 3. Rosenberg Lancet 2016.

4. Loriot ESMO 2016. 5. Roche/Genentech, data on file.

Phase I Study PCD4989g2 Phase II Study IMvigor210 (cohort 2)4,5

80

60

0

30 6 12 18 24 0

20

40

Ove

rall

Surv

ival

100

Months

36

IC2/3 mOS: 11.3 mo

IC0/1 mOS: 7.6 mo

OR

R, %

b

(n = 51) (n = 43) (n = 100) (n = 210) (N = 310)

OR

R, %

c

IC2/3 mOS: 11.9 mo

All-patient mOS: 7.9 mo

IC0/1 mOS: 6.7 mo

Months

80

60

0

12 16 24 0

20

40

Ove

rall

Surv

ival

100

20 4 6

ATEZOLIZUMAB

ATEZOLIZUMAB: Imvigor 210 Cohorte 2

Rosemberg, Lancet 2016

ATEZOLIZUMAB: Imvigor 210 Cohorte 2

Rosemberg, Lancet 2016

NIVOLUMAB (CheckMate O32)


Sharma, ASCO 2016

Responses Nivolumab (N = 78)

Confirmed ORR, % (95% CI) 24.4 (15.3–35.4)

Best overall response, % 6.4

Complete response

Partial response 17.9

Stable disease 28.2

Progressive disease 38.5

Unable to determine 9.0

Confirmed ORR, % (95% CI) by PD-L1 expression 26.2 (13.9–42.0)

PD-L1 <1%

PD-L1 ≥1% 24.0 (9.4–45.1) Sólo en células tumorales


Sharma, ASCO 2016

PD-L1 <1% PD-L1 not quantifiable

–50

–25

0

25

50

75

100

Best

Red

ucti

on

Fro

m B

ase

lin

e

in T

arg

et

Lesio

n (

%)

* * * * * * *

*

PD-L1 ≥1%

* * * * –75 * * * *

–100 * * *

Patients


Sharma, ASCO 2016

Median OS,

months (95% CI)

Nivolumab 9.72 (7.26–16.16)

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

3 6 9

61 54 41 29 16 5 0

12 15 18 21

Ove

rall

Su

rviv

al

(Pro

ba

bil

ity)

Months 0

No. of patients at risk

78

45.6%


Sharma, STIC 2016


Sharma, STIC 2016

NIVOLUMAB (CheckMate 125)

Galsky, ESMO 2016

Outcome, % All

N=265b

Confirmed ORR by BIRCa 19.6

95% CI 15.0–24.9

Best overall response

Complete response 2.3

Partial response 17.4

Stable disease 22.6

Progressive disease 39.2

Unable to determine 18.5 aBy RECIST v1.1 b265 of 270 patients were evaluated for efficacy, as 5 patients had insufficient follow-up

Confirmed ORR in patients with PD-L1 <5% was 15.8% (95% CI, 10.8–21.8)

PD-L1 <1%

n=143

PD-L1 ≥1%

n=122

PD-L1 ≥5%

n=81

16.1 23.8 28.4

10.5–23.1 16.5–32.3 18.9–39.5

<1 4.1 4.9

15.4 19.7 23.5

17.5 28.7 28.4

46.9 30.3 25.9

19.6 17.2 17.3

NIVOLUMAB (CheckMate 125)

Galsky, ESMO 2016

All treated patients

No. at Risk

PD-L1 <1%

PD-L1 ≥1%

PD-L1 ≥1%

Median OS, Months (95% CI)a

All treated 8.74 (6.05–NR)

PD-L1 <1% 5.95 (4.30–8.08)

PD-L1 ≥1% 11.30 (8.74–NR)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 3 6 9 12 15

Ove

rall

Su

rviv

al (P

rob

ab

ilit

y)

Months

PD-L1 <1%

265 198 148 63 5 0 143 101 69 26 2 0

122 97 79 37 3 0

• Basal 1 and luminal 2 have higher response rates vs the other 2 subtypes

• Interferon-γ genes are enriched in responders vs those with progressive disease (P<0.01)

Association between UC molecular subtype, 25-gene

interferon-γ signature, and response to nivolumab

P<0.001

CR/PR/SD PD

Response

2

1

0

-1

-2

Sig

natu

re s

co

re

Signature score, 25-gene interferon-γ signature expression aBasal 2 CR, 0%; luminal 1 CR,1.5%; luminal 2 CR, 1.8%

Molecular Subtype

16,6 25,4

21,7

15,1

22,7

30,9 39,1

24,2

59,1 41,8

30,4

60,6

0%

25%

50%

75%

100%

Cluster 1 (Luminal1) n=66

Cluster 2 (Luminal2) n=55

Cluster 3 (Basal 1)n=23

Cluster 4 (Basal 2)n=33

Complete

Responsea

Partial

Response

Stable

Disease

Progressive

Disease

50

25

0

75

100

Perc

en

tag

e

Luminal 2

(Cluster 2)

n=55

Basal 1

(Cluster 3)

n=23

Basal 2

(Cluster 4)

n=33

Luminal 1

(Cluster 1)

n=66

8.7

Galsky, ESMO 2016

Powles, ASCO GU 2017

DURVALUMAB (1108)

DURVALUMAB (1108)

Powles, ASCO GU 2017

AVELUMAB (JAVELIN)

Apolo, ASCO 2017

AVELUMAB

Apolo, ASCO 2017

1. Rosenberg JE, et al. Lancet. 2016;387:1909-1920.

2. Patel M, et al. ASCO GU 2017. Abstract 330.

3. Powles T, et al. ASCO GU 2017. Abstract 286.

4. Sharma P, et al. Lancet Oncol. 2017;18:312-322.

5. Bellmunt J, et al. N Engl J Med. 2017;376:1015-1026

INMUNOTERAPIA TRAS PLATINO: TASA DE RPTAS

INMUNOTERAPIA TRAS PLATINO: SUPERVIV. 12 M

1. Rosenberg JE, et al. Lancet. 2016;387:1909-1920.

2. Patel M, et al. ASCO GU 2017. Abstract 330.

3. Powles T, et al. ASCO GU 2017. Abstract 286.

4. Sharma P, et al. Lancet Oncol. 2017;18:312-322.

5. Bellmunt J, et al. N Engl J Med. 2017;376:1015-1026

PEMBROLIZUMAB: KEYNOTE-052







IMvigor210 Study: Cohort 1

ATEZOLIZUMAB: Imvigor 210

Patients n Complete response

Partial response

Objective response rate, n (% [95% CI])*

Median duration of response (95% CI)

All Patients 119 11 16 27 (23% [16-31]) NE (14.1-NE)

IC2/3 32 4 5 9 (28% [14-47]) NE (11.1-NE)

IC1/2/3 80 8 11 19 (24% [15-35]) NE (NE)

IC1 48 4 6 10 (21% [11-35]) NE (NE)

IC0 39 3 5 8 (21% [9-37]) NE (12.8-NE)

Balar, et al. IMvigor210 Lancet 2016.



Overall survival in patients treated with atezolizumab



Responses across TCGA subtypes Overall survival by TCGA subtype



Mutation load vs response Mutation load vs response, disaggregated by subtype or PD-L1 score

Predictors of response by mutation load



Overall survival vs mutation load (binned into quartiles)


TERAPIAS DIRIGIDAS

• FGFR3: Infigratinib

• ErbB/HER: Afatinib

ESTUDIOS EN MARCHA

Anti PD-1/PD-L1 en combinación con …

• Inmunoterapia (CTLA-4, IDO, LAG-3,…)

• Quimioterapia

• Terapias dirigidas

• Radioterapia

Adyuvancia

Neoadyuvancia

Mantenimiento

Enfermedad No Músculo Invasiva

Pembrolizumab + epacadostat

IMvigor 130

ADYUVANCIA

ABACUS: Phase II study of Tecentriq prior to surgery in operable transitional cell carcinoma of the bladder

»Confirmed transitional cell

carcinoma (T2T4a)

»Radiological N0 or M0

disease

N = 85

Chemothera

py

Cystectomy

Tecentriq

1200 mg q3w

(2 cycles)

Po

st-

op

era

tive

ca

re

Surveillance

Pre-operative

care

3 weeks prior to surgery

58 weeks after study entry

NEOADYUVANCIA

JAVELIN BLADDER 100: “MANTENIMIENTO”

WO29635: Phase Ib study of Tecentriq + BCG

Expansion Cohort B

Tecentriq 1200 mg q3w

BCG-refractory/intolerant

Dx + population

n = 12

Cohort 2

BCG 2/3 dose qw x 6


BCG-refractory/resistant

Cohort 1

BCG full dose qw x 6


BCG-refractory/resistant

De-escalation

6 x weekly intravesical instillations of

BCG at full dose for induction in

Cohort 1 and Cohort A with 3-fold

de-escalation for DLT to minimum of

1/30 dose (67% dose de-escalation.

Full dose → 1/3 → 1/10 → 1/30)

Expansion

Expansion Cohort A BCG qw x 6


BCG-naive NMIBC

n = 30

If DLT 6 x weekly intravesical instillations of BCG at

full dose for induction in Cohort 1 and Cohort

A with 3-fold de-escalation for DLT to

minimum of 1/30 dose (67% dose de-

escalation. Full dose → 1/3 → 1/10 → 1/30)

» Non-muscle

invasive

bladder

cancer

» BCG-naive

N = 48

3

3

ENFERMEDAD NO-MUSCULO-INVASIVA

CONCLUSIONES

• La inmunoterapia con fármacos anti PD-1 y anti PD-L1 ha supuesto una revolución en el tratamiento del cáncer de vejiga

• Está indicada en 2ª línea tras progresión a platino y en 1ª línea en pacientes no candidatos a cisplatino

• Su perfil de toxicidad es muy favorable

• Necesitamos biomarcadores (PD-L1, Carga mutacional, Subtipo genético) para seleccionar a los pacientes que se benefician (TR 20%)

• Necesitamos combinaciones y nuevos enfoques para beneficiar a un grupo más numeroso de pacientes

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Presentación de PowerPointoncopromesas-oncosaurios.com/wp-content/uploads/...2ª línea tras progresión a platino 1ª línea no candidatos a Cisplatino • Terapias dirigidas •