Martín Lázaro CHU Vigo - basesbiologicascancer.com · Lamina propria Muscularis propria Grasa...

Martín LázaroCHU Vigo

Introducción

Primera línea

Segunda línea

Guías

Conclusiones

El cáncer de vejiga se origina en las capas internas extendiéndose hasta las capas más externas de la pared de la vejiga

1. Howlader N, et al. (eds). SEER Cancer Statistics Review 1975–2013; 2. NCCN Guidelines – Bladder Cancer v1.2017; 3. Sharma S, et al. Am Fam Physician 2009;80:717-23.

2. 4. Kaufman DS, et al. Lancet 2009;374:239-49.

Cáncer de vejiga sin invasión muscular

(CVSIM)(Tis, Ta, T1)

≈51-75% de los pacientes diagnosticados cuando el

tumor es no invasivo1-4

Cáncer de vejiga con invasión muscular (CVCIM)

(T2, T3a, T3b)

≈30-42% de los pacientes con

CVCIM confinado 1,4

Enfermedad metastásica

(T4)

≈4% de pacientes

diagnosticados en estadio metastásico1,5

Localmente

avanzada (incluye T4a

N1-N3)

Uréteres

Uretra

Lamina

propria

Muscularis

propria

Grasa

perivesical

Propagación

a órganos

adyacentes

Urotelio

1. SEER Cancer Stat Fact Sheets

11% se presentan con enfermedad regional o distante

Durante los últimos 40 años las tasas de supervivencia para el cáncer de vejiga no han mejorado sustancialmente1

Supervivencia relativa a 5 años en el momento del diagnóstico1

1. SEER Stat Fact Sheets

73.0% 78.1% 78.0%

1975–1977 1985–1989 2009

El Cáncer de vejiga afecta más a hombres que a mujeres

Nuevos casos de cáncer urotelial estimados en España:5º en incidencia

17,439 3,654

Pico en 7ª década; 20%: mayores de 80 años

El bacillus Calmette-Guérin: la primera inmunoterapia para cáncer urotelial1

1. Herr HW, Morales A. J Urol 2008;179:53-6

1908 1921 1976 1990

Albert Calmette Camille Guérin

Start working together to develop a

vaccine for tuberculosis

Vacuna de BCG usada por 1vez en

humanos



1908 1921 1976 1990

Alvaro Morales

Primer studio del del BCG intravesical

para el tratamiento de cancer de vejiga

superficial



FDA aprueba el uso del tratamiento

intravesical con BCG para el tratamiento

de cancer de vejiga superficial

1908 1921 1976 1990

Racional de la inmunoterapia en el tratamiento de cáncer urotelial1

1. Zehir et al. Nat Med 2017;23:703-713

So

mati

c m

uta

tio

n b

urd

en

(mu

t/M

b)

1

5

10

50

100

200

300

500

Germ

cell

tum

our

Soft

-tis

sue s

arc

om

a

Pro

sta

te c

ancer

Thyr

oid

cancer

Bili

ary

cancer

Ovarian c

ancer

Renal cell

carc

inom

a

Pancre

atic c

ancer

Bre

ast carc

inom

a

Head a

nd n

eck

carc

inom

a

Glio

ma

Esophagogastr

ic

carc

inom

a

Endom

etr

ial cancer

Non-s

mall-

cell

lung c

ancer

Colo

recta

l cancer

Mela

nom

a

Bla

dder

cancer

FDA-Approved Checkpoint Inhibitors for UC

1. Atezolizumab [package insert]. July 2018. 2. Avelumab [package insert]. October 2017. 3. Durvalumab [package insert]. February 2018. 4. Nivolumab [package insert]. July 2018. 5. Pembrolizumab [package insert]. June 2018.

Agent Target Schedule FDA Approval Type by Setting

Post-Platinum Frontline Cisplatin Ineligible

Atezolizumab[1] PD-L1 Q3W Accelerated Accelerated

Avelumab[2] PD-L1 Q2W Accelerated --

Durvalumab[3] PD-L1 Q2W Accelerated --

Nivolumab[4] PD-1 Q4W Accelerated --

Pembrolizumab[5] PD-1 Q3W Level 1 Accelerated

Introducción

Primera línea

Segunda línea

Guías

Conclusiones

Paciente fitRegimens N ORR (%) CR (%) MOS (mo) P

MVACCisplatin

120126

3611

133

12.58.2

<0.0002

MVACCisCa

5555

6546

3525

12.610.0

<0.05

MVACHD-MVAC

129134

5872

921

14.115.5

0.122

MVACGemcitabine + Cisplatin

205203

4650

1212

14.813.8

0.746

MVACDocetaxel + Cis

109111

5437

2313

14.29.3

0.025

MVACPaclitaxel + Carbo

4441

4028

133

14.213.8

0.41

GCGC + Paclitaxel

315312

43.655.5

11.113.5

12.815.8

0.075

Loehrer SrPJ, et al. J Clin Oncol 1992;10:1066.Logothetis CJ, et al. J Clin Oncol 1990;8:1050.Sternberg CN, et al. J Clin Oncol 2001;19:2638. Von der Maase H, et al. J Clin Oncol 2005;23:4602.Bamias A, et al. J Clin Oncol 2004;22:220.Dreicer R, et al. Cancer 2004;100:1639.Bellmunt J, et al. J Clin Oncol 2012;30(10):1107.

M-VAC vs Cis-Gem (primera línea)

Mets orunresectable

T3-T4 TCC previouslyuntreated

PS=0-2

Mtx: 30 mg/m2 d1, 15,22VBL: 3 mg/m2 d2, 15, 22ADM: 30 mg/m2 d2CDDP 70 mg/m2, cada 28 d

CDDP: 70 mg/m2 d1GEM: 1000 mg/m2 d1, 8, 15Cada 28 d

N=426

Maase von der H. J Clin Oncol. 2005 Jul 20;23(21):4602–8.

Estudio fase III: MVAC vs. CG

SLP SG

N=405

Maase von der H. J Clin Oncol. 2005 Jul 20;23(21):4602–8.

Durable Responses With Cisplatin-Based CT in UC

Cisplatin Eligible Cisplatin Ineligible

Gemcitabine + Cisplatin[1,2]

ORR: 49%CR: 12%Median OS: 14.0 mos

Dose Dense MVAC[3]


Gemcitabine + Carboplatin[4]


1. von der Maase H, et al. J Clin Oncol. 2005;23:4602-4608. 2. von der Maase H, et al. J Clin Oncol. 2000;18:3068-3077. 3. Sternberg CN, et al. Eur J Cancer. 2006;42:50-54. 4. De Santis M, et al. J Clin Oncol. 2012;30:191-199.

Ensayo Clínico Fase Control Brazo experimental n

IMvigor130 III CDDP + GMZCBDCA + GMZ

Atezolizumab + CDDP + GMZAtezolizumab + CBDCA + GMZ

Atezolizumab

1200

DANUBE III CDDP + GMZCBDCA + GMZ

Durvalumab + tremelimumabDurvalumab

525

KEYNOTE-361 III CDDP + GMZCBDCA + GMZ

Pembrolizumab + CDDP + GMZPembrolizumab + CBDCA + GMZ

Pembrolizumab

990

CheckMate 901 III CDDP + GMZCBDCA + GMZ

Nivolumab + Ipilimumab*Inelegibles: Nivolumab + CBDCA + GMZ

1045

Javelin Bladder100

III Seguimiento Avelumab 688

HCRN GU14-182 III Seguimiento Pembrolizumab 200

INMUNOTERAPIA: estudios fase III en marcha.

SELECCIÓN DE TRATAMIENTO: FIT VS UNFIT

Sonpavde G, J Clin Oncol 2012;30. abstr 285.

Galsky MD. J Clin Oncol 2013;31. abstr 4525.

Zagouri, F. Crit Rev Oncol Hematol; 2015:93:36-49

Community Database

N=298

RISC groupN=1077

HGUCGN=327

No quimioterapia

24% 30% -

Basada en cisplatino 36% 36% 45%

Basada en carboplatino 27% 20%

55%

Sin platino 8% 14%

¿Qué pacientes con Cáncer urotelial se consideran unfit para el tratamiento con cisplatino? 1

Los pacientes con al menos uno de los siguientes hallazgos se consideran ‘unfit’

1.Galsky et al. J Clin Oncol 2011 29:2432-8

• Un estado funcional de 2, según OMS o ECOG, o un estadofunctional de Karnofsky de 60–70%

• Aclaramiento de creatinina (calculada o medida) inferior a 60 mL/min

• Pérdida de audición audiométrica de grado 2 o superior según CTCAE versión 4

• Neuropatía periférica grado 2 o superior según CTCAE versión 4

• Insuficiencia cardiaca de clase III según NYHA

Carles 2017; Bellmunt 2001; Linardou 2004; Barnias 20017; De Santis 2012; Vaughn 2002; Calabro 2009; Culine2011; Ricci 2002; Eroglu 2013

Carbo-gem; carbo-metxte-gem; carbo-paclitaxel; paclitaxel-gem; gem-epiadriamicina; gem-oxaliplatino

Primera línea “unfit”: EORTC 30986

De Santis M, et al. J Clin Oncol 2012;30(2):191.

N=238 MCaVi vs. CaG

Estudio fase III: MCaVi vs CaG RG≅30-40%

M-CAVI GC

RR 21% 36%

PFS 4.2 m 5.8 m

Severe AE 21% 9%

KEYNOTE 052: fase II

O´Donell PH, et al. J Clin Oncol 35,2017 (suppl;4502).

Primera línea “unfit”: pembrolizumab

30%: mayores de 80 años; 49% mayores de 75 años42%: PS=221%: mets hepáticas

N=370

Tasa de respuestas

O´Donell PH, et al. J Clin Oncol 35,2017 (suppl;4502).Vuky J, et al. J Clin Oncol 2018;36(suppl;abstr4524).

Respuestas según estado PD-L1

OS

Grivas, ESMO 2017

Vuky, J et al. ASCO 2018

IMvigor210 phase II study: Cohort 1

Study design and objectives

Cohort 1: no prior chemotherapy and ineligible for cisplatin-based chemotherapy

Atezolizumab 1,200mg IV q3w (n=119)

Cohort 2: PD during or following >1 platinum-containing regimenAtezolizumab 1,200mg IV q3w

(n=310)

Key Cohort 1-specific inclusion criteria include• No prior treatment for mUC (>12 months since perioperative chemotherapy)• ECOG PS 0–2• Cisplatin ineligibility based on ≥1 of the following: <60 and >30mL/min by Cockcroft-Gault formula; Grade ≥2 hearing loss; Grade ≥2 peripheral

neuropathy; and ECOG PS 2

Primary objective: ORR (IRF assessed by RECIST v1.1)Secondary objectives: PFS and DoR (IRF assessed by RECIST v1.1 and investigator assessed by modified RECIST‡); ORR, DOR and PFS (investigator assessed by RECIST v1.1); OS and 1-year OS; and safety, tolerability, PKs and ATAsExploratory objectives: potential biomarkers and biopsy measurement of tumour volume

• Locally advanced/metastatic transitional cell carcinoma of the urothelium

• FFPE tissue specimen for PD-L1 analysis by IHC (central laboratory)

N=429

PD

Until loss of clinical benefit*

Balar et al. Lancet 2017


ORR

• Responses, including CRs, were observed in all PD-L1 subgroups

– All-patient ORR has remained consistent, and with longer follow-up, additional patients with CR have been seen

• Durable clinical benefit was also observed, with a DCR (CR + PR + SD ≥24 weeks) of 30% (95% CI: 22–39) in all patients

SubgroupIC2/3(n=32)

IC1/2/3(n=80)

All patients(N=119)

IC1(n=48)

IC0(n=39)

ORR, %(95% CI)*

28(14–47)

24(15–35)

23(16–31)

21(10–35)

21(9–36)

CR rate, % 13 10 9 8 8

Balar et al. Lancet 2017

MAYORES DE 80 AÑOS (N=25):- ORR 28%- OS: 21.4 m

Balar, Lancet. 2017 Jan;389(10064):67–76.

SGm: 16.3 meses(ASCO 2018)

41%

Pembrolizumab: CPS>10Atezolizumab: PD-L1 (IC): >5%

Introducción

Primera línea

Segunda línea

Guías

Conclusiones

T4bN0M0 orTxN2-3 o

M1

Progresión tras tratamiento de 1ª línea

con platino

RANDOMIZACION

Vinflunina (PS 0: 320mg/m², c3s; PS 0 con

irradiación pélvica previa y PS1: 280mg/m² y

escalado posterior a 320 mg/m²) +

tratamiento sintomático

Tratamiento sintomático (BSC)

2:1

Bellmunt et al; J Clin Oncol 2009; 27: 4454–4461

Objetivo principal: supervivencia global

N=370

Intent-to-treat population Eligible population

Supervivencia Global

Bellmunt et al; Ann Oncol 2013; doi:10.1093/annonc/mdt007


Resultados

Bellmunt et al; Ann Oncol 2013; doi:10.1093/annonc/mdt007



Study design and objectives

Key Cohort 2-specific inclusion criteria include• Progression during or following platinum• Creatinine clearance ≥30mL/min• ECOG PS 0–1

Co-primary objectives: ORR (IRF-assessed by RECIST v1.1 and investigator-assessed by modified RECIST‡)Secondary objectives: PFS and DoR (IRF-assessed by RECIST v1.1 and investigator assessed by modified RECIST‡); ORR, DOR and PFS (investigator-assessed by RECIST v1.1); OS and 1-year OS; safety, tolerability, PK and ATAsExploratory objectives: potential biomarkers and biopsy measurement of tumour volume

1. Necchi et al. ESMO 2017; 2. Necchi et al. Annals of Oncol 2017; 3. Pérez-Gracia et al. ASCO GU 2017

Cohort 1: no prior chemotherapy and ineligible for cisplatin-based chemotherapy

Atezolizumab 1,200mg IV q3w (n=119)

Cohort 2: PD during or following >1 platinum-containing regimenAtezolizumab 1,200mg IV q3w

(n=310)

• Locally advanced/metastatic transitional cell carcinoma of the urothelium

• FFPE tissue specimen for PD-L1 analysis by IHC (central laboratory)

N=429

PD

Until loss of clinical benefit*


ORR

Loriot et al. ESMO 2016

• Median treatment duration was 12 weeks (range, 0–104)– A total of 137 patients were treated beyond RECIST v1.1 progression

• Responses, including CRs, were observed in all PD-L1 subgroups, with higher ORRs observed with higher IC status

• Additional PRs and CRs have occurred with further follow-up• Durable clinical benefit was also observed, with a DCR (IRF RECIST v1.1 CR + PR + SD ≥24

weeks) of 21% (95% CI: 17–26) in all patients

IC2/3(n=100)

IC1/2/3(n=207)

Allpatients (N=310)

IC1(n=107)

IC0(n=103)

ORR per IRF RECIST v1.1*, %(95% CI)

28

(19–38)

19

(14–25)

16

(12–20)

11

(6–19)

9

(4–16)

CR rate per IRF RECIST v1.1, % (95% CI)

14

(8–22)

8

(5–13)

7

(4–9)

3

(1–8)

2

(0–7)

ORR per iRECIST‡, % (95% CI)

29

(20–39)

24

(18–30)

20

(15–25)

19

(12–27)

12

(6–19)


OS (total population)

0

20

40

60

80

100

OS

(%)

0 4 8 12

Time (months)

16 20 24

IC0/1

(n=210)

IC2/3

(n=100)

All patients

(N=310)

Median OS, months(95% CI)

6.7(5.4–8.0)

11.9(9.0–NE)

7.9 (6.7–9.3)

12-month OS rate, %(95% CI)

31(24–37)

50(40–60)

37(31–42)

With a 12-month OS rate of 37% and a median OS of 7.9 months, atezolizumab compares favourably with historical controls

Loriot et al. ESMO 2016

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)

IMvigor211 Study Design

• Primary endpoint

– OS, tested hierarchically in pre-specified populations

42

Atezolizumab 1200 mg q3w

R1:1

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

Powles et al. Lancet 2017

IMvigor211 Study Design43


Objetivo primario: Objetivos secundarios:

SG• determinada de una manera sucesiva (procedimiento

jerárquico de secuencia fija) en las poblaciones de estudio definidas por la expresión de PD-L1

• Eficacia: RECIST v1.1 TRG, SLP y DORc

• Seguridad• PROs: EORTC QLQ-C30

SG: IC 2/3

SG: IC 1/2/3

SG: ITT

TRG: IC 2/3

TRG: IC 1/2/3

TRG: ITT

SLP: IC 2/3

SLP: IC 1/2/3

SLP: ITT

2-sided α = 0,05

IMvigor211 phase III randomised study

OS: IC2/3

Median OS,months (95% CI) HR (95% CI) p

Atezolizumab (n=116) 11.1 (8.6–15.5) 0.87 (0.63–1.21)

0.41Chemotherapy (n=118) 10.6 (8.4–12.2)

Time (months)

OS

(%)

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

0

20

40

60

80

100

46.4%

41.2%



OS: ITT


39.2%

32.4%

Time (months)

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

0

20

40

60

80

100

Median OS,months (95% CI) HR (95% CI) p

Atezolizumab (n=467) 8.6 (7.8–9.6) 0.85 (0.73–0.99)

0.038Chemotherapy (n=464) 8.0 (7.2–8.6)

OS

(%)

Powles T et al. EAS 2017, IMvigor 211

Respuesta población ITT

Eventos/pacientes MDoR (IC 95%)

Atezolizumab 23/62 21,7 m (13,0;21,7)

Quimioterapia 49/627,4 m

(6,1;10,3)

Pacientes

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

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

Re

sp

ue

sta

Ob

jeti

va

(%

)

Meses

80

60

0

10 12 14 16 18 202 4 6 8 22

20

100

0

40

DoR en la población ITT


Adverse events (Grade 3–4)

Powles T et al. EAS 2017, IMvigor 211

International, randomized, open-label phase III study

Primary endpoints: OS, PFS

Secondary endpoints: ORR, DoR, safety

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

Adult patients with predominantly transitional cell UC of the renal pelvis,

ureter, bladder, or urethra; PD after

1-2 lines of platinum-based CT or recurrence < 12 mos after

perioperative platinum-based CT; ECOG PS 0-2

(N = 542)

Treatment continued for 2 yrs or until PD,

unacceptable toxicity, or withdrawal of

consent

Pembrolizumab 200 mg IV Q3W

(n = 270)

Paclitaxel 175 mg/m2 IV Q3W or Docetaxel 75 mg/m2 IV Q3W orVinflunine 320 mg/m2 IV Q3W

(n = 272)

Stratified by ECOG PS (0/1 vs 2), Hg (< 10 vs ≥ 10 g/dL),

liver mets (yes vs no), and time since last CT (< vs ≥ 3 mos)

KEYNOTE-045: Study Design

KEYNOTE-045: OS

44.4%30.3% 33.2%

19.7%

Median OS, Mos (95% CI)10.3 (8.0-12.3)

7.4 (6.3-8.3)

0 4 8 12 16 20 24 28 320

20

40

60

80

OS

(%)

Mos

100

de Wit R, et al. ESMO 2017. Abstract LBA37_PR.

Data cutoff: May 19, 2017

HR: 0.70 (0.57-0.86; P = .0003)

OS data: in CPS≥10% only PFS

Bellmunt J, et al. N Engl J Med 2017; 376(11):1015.

KEYNOTE-045: ORR

de Wit R, et al. ESMO 2017. Abstract LBA37_PR.

21.1%

11.0%

PRCR

7.8%

13.3%

Pembrolizumab(n = 270)

Chemotherapy(n = 272)

2.9%

8.1%

OR

R (

%, 9

5%

CI)

All Patients

20.3%

6.7%

6.8%

13.5%

Pembrolizumab(n = 74)

Chemotherapy(n = 90)

2.2%

4.4%

OR

R (

%, 9

5%

CI)

PD-L1 Positive (CPS ≥ 10)

0

5

10

15

20

25

30

35

0

5

10

15

20

25

30

35

Duración de la respuesta

Bellmunt J, et al. N Engl J Med 2017; 376(11):1015. Bellmunt J, et al. J Clin Oncol 2018;36(suppl 6S):abstr410.

CheckMate 032

Rosenberg, ESMO 2018

N=274

Imvigor211

KEYNOTE045

CheckMate275

JAVELINbladder

NCT01693562

Fármaco Atezolizumab Pembrolizumab Nivolumab Avelumab Durvalumab

Diseño Fase III Fase III Fase II Fase I/II Fase I/II

Tamaño 931 542 238 249 191

Comparador QT(VFL/taxanos)

QT(VFL/taxanos)

- - -

RG 23% (IC2/3) 21.1% 20% 17% 17.8%

SLP 2.3 m 2.1 m 2.0 m 1.5 m 1.5 m

SG 11.1 meses (IC2/3)

10.3 meses 8.57 meses - -

Sv a 2 años % 31 (44 en +)-en fase I-

27 37Patel MR, et al. Lancet Oncol 2018;19:51.

Powles T, et al. JAMA Oncol 2017;3(9):e172411.Rosenberg JE, et al. Lancet 2016;387:1909.

Sharma P, et al. Lancet Oncol 2017;18(3):312.Powles T, et al. Lancet 2018;391(10122):748.

Bellmunt J, et al. N Engl J Med 2017;376(11):1015.

CheckMate 032

Sharma P. J Clin Oncol. 2019 May 17;:JCO.19.00538–19.

TCGA y respuesta a inmunoterapia

Sharma

Rosenberg

TCGA 2017 y respuesta a inmunoterapia en el Imvigor 210

Kim J, et al. The Cancer Genome Atlas Expression Subtypes Stratify Response to Checkpoint Inhibition in AdvancedUrothelial Cancer and Identify a Subset of Patients with High Survival Probability. European Urology; 2019;6:1–4.

Rassy EE. Immunotherapy. 2018 Jun;10(8):657–63.

A network meta-analysis of the PD(L)-1 inhibitors in the salvage treatment of urothelial bladder cancer

INMUNOTERAPIA: estudios de combinación en marcha.

Sharma P, et al. Lancet Oncol 2016;17:1590.

Nadal R, et al. J Clin Oncol 2018;36(suppl_abstr4528).

Petrylack DP, et al. J Clin Oncol 2016;34(13):1500.

Parikh M, et al. J Clin Oncol 2018;36(suppl 6S;abstr525).

Smith DC, et al. J Clin Oncol 2017;35(suppl_abstr4503).

Introducción

Primera línea

Segunda línea

Guías

Conclusiones

ESMO: obsoletas (2014)

Bellmunt, J. Ann Oncol 23014

SEOM (2019)

UNFIT 1st LINE

2nd LINE

Introducción

Primera línea

Segunda línea

Guías

Conclusiones

Inmunoterapia: tratamiento estándar en

segunda líneaRespuestas duraderas

En primera línea enpacientes unfit:

Selección por PD-L1

Necesidad de biomarcadores

KEYNOTE-045 IMvigor 211

Pembro % Chemo % Atezo % Chemo %

Hemoglobina >10 g/dl 81 82 86 84

PS 0 44 39 47 45

Mets hepáticas 33.7 34.9 30 28

Tpo desde QMT < 3m 38 38 34 35

Pelvis renal 38% 29%

N factores de riesgo012

3-4

20352416

16352916

3146185

3045214

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