Inmunoterapia en cáncer de pulmón · Inmunoterapia en cáncer de pulmón Manuel Cobo Dols Oncología Médica Hospital R.U. Málaga regional y Virgen de la Victoria Madrid 6-04-2017

Inmunoterapia en cáncer de pulmón

Manuel Cobo Dols

Oncología Médica

Hospital R.U. Málaga regional y Virgen de la Victoria

Madrid 6-04-2017

Anti PD1/PDL1 Nivolumab Pembrolizumab Atezolizumab Durvalumab Avelumab

Anti CTL4 Ipilimumab Tremelimumab

Combinación *Terapia clásicas Quimioterapia Radioterapia *Nuevas dianas *Nuevos inmunomoduladores

Contexto * 2º línea CPNM * 1º línea CPNM * Adyuvancia * Estadio III con RT * En Mutaciones (EGFR/ALK..) * Microcitico * Escamoso * Adenocarcinoma

Anti PD1/PDL1 Con biomarcador Sin biomarcador Con PDL1 Sin PDL1 Puntos de corte PDL1 Otros biomarcadores

Combinaciones - Variaciones - Permutaciones

Inmunoterapia Cáncer pulmón

Anti-PDL1/PD1 therapies in advanced NSCLC

*And approved therapy for EGFR Mut+ or ALK+ NSCLC §Tumour proportion score (TPS) ≥50%, where TPS is the proportion of viable tumour cells showing partial or complete membrane PD-L1 expression ¶Study data available

Nivolumab Pembrolizumab Atezolizumab Durvalumab

Company Bristol-Myers Squibb Merck Roche AstraZeneca

Brand name Opdivo Keytruda – –

Target PD-1 PD-1 PD-L1 PD-L1

Class mAb (IgG4) mAb (IgG4) mAb (IgG1) mAb (IgG1)

Dosing 3mg/kg q2w 2mg/kg q3w 1200mg q3w 20mg/kg q4w

Administration Intravenous infusion Intravenous infusion Intravenous infusion Intravenous infusion

Indications

/approvals in

NSCLC

US/EU: metastatic

NSCLC after prior

CT*

US: PD-L1+§

metastatic NSCLC

after prior CT*

Not yet approved Not yet approved

Pivotal trials in ≥2L

NSCLC

CheckMate 017¶,

CheckMate 057¶ KEYNOTE-010¶ POPLAR¶, OAK

Pivotal trials in 1L

NSCLC

CheckMate 026

CheckMate 227

KEYNOTE-024

KEYNOTE-042

KEYNOTE-189

IMpower 110, IMpower 111,

IMpower 130, IMpower 131,

IMpower 132, IMpower 150

NEPTUNE

MYSTIC

Diagnostic assay 28-8 22C3 SP142 SP263

of PD-L1 expression in advanced NSCLC Nivolumab Pembrolizumab Atezolizumab Durvalumab

Detection antibody 28-81 22C31 SP1422 SP2633

IHC platform Dako1 Dako1 Ventana1 Ventana3

Cell types scored

for NSCLC TC1 TC1 IC and TC1,2 TC1

Cut-off definitions

for NSCLC

PD-L1+ as ≥5% of

TCs exhibiting

positive membrane

PD-L1 staining at

any intensity

PD-L1+ as ≥50% of

viable TCs showing

partial or complete

membrane PD-L1

expression*

TC3 or IC3: ≥50% of TCs or ≥10% of ICs

TC2/3 or IC2/3: ≥5% of TCs or ICs

TC1/2/3 or IC1/2/3: ≥1% of TCs or ICs

TC0 and IC0: <1% of TCs and ICs

(Proportion of cells stained at any

intensity)

PD-L1+ as ≥25% of

TCs with

membrane PD-L1

staining

Estimated PD-L1

prevalence in

NSCLC ~46%1

~25%1 37%*

68%*

16%*

~48%4

*For the 22C3 assay, the proportion of viable tumour cells showing partial or complete membrane PD-L1 staining is termed the tumour proportion score (TPS) 1. Kerr, et al. J Thorac Oncol 2015; 2. Vansteenkiste, et al. ECC 2015; 3.Rebelatto, et al. ASCO 2015; 4. Rizvi, et al. ASCO 2015

7

PFS by Tumor Mutation Burden Tertile CheckMate 026 TMB Analysis: Nivolumab in First-line NSCLC

100

90

80

70

60

50

40

30

20

10

0

0 3 6 9 12

Months

15 18 21 24

PF

S (

%)

High

Low

Medium

Medium

n = 49 n = 47

3.6

(2.7, 6.9)

Low

n = 62

4.2

(1.5, 5.6)

9.7

(5.1, NR)

Median PFS, months

(95% CI)

High

Nivolumab Arm Chemotherapy Arm

Medium

n = 53 n = 60

6.5

(4.3, 8.6)

Low

n = 41

6.9

(5.4, NR)

5.8

(4.2, 8.5)

Median PFS, months

(95% CI)

High 100

90

80

70

60

50

40

30

20

10

0

0 3 6 9 12

Months

15 18

High

Low

Medium

21

• Data for patients with low and medium TMB were pooled in subsequent analyses

Carbone. IASLC 2015

Pt CD8+ Density, Invasive Margin Before Treatment

Predicted Probability of Response

Blinded Prediction Clinical Response (RECIST 1.1)

1 58 0.35 Progression Progression




5 2120 0.75 Response Stable

6 5466 0.98 Response Progression

7 2211 0.76 Response Response






13 5951 0.99 Response Complete response



Lo ideal:la densidad de infiltración de LT8 junto con expresión de PD-L1

P. C. Tumeh et al., Nature 2014; 515,:568 -71.

La densidad de LT CD8 en el margen de invasión del tumor fue mucho más predictiva de beneficio a Pembrolizumab

que PD-L1. .- Este dato sugiere que expresión de PD-L1 en el tumor es más poderoso como biomarcador cuando se

observa en el contexto de una respuesta de cel T activos.

Rationale for Combination strategies

• Tumors can present as either immunogenic or nonimmunogenic

• Immune system priming or depletion of immunosuppressive factors through combination therapies can boost tumor immunogenicity, and therefore, susceptibility to I-O therapy

10

CD=cluster of differentiation; I-O=immuno-oncology; PD-L1=programmed death ligand 1. Adapted from Sharma P, Allison JP. Science. 2015;348(6230):56-61.

Nonimmunogenic tumor

Immunogenic tumor

CD8 T cell

CD4 T cell

CD4 T cell

CD8 T cell

CD8 T cell expressing

CD45RO

CD8 T cell expressing

PD-L1 CD8 T cell

with granzyme B

Tumor cell expressing

PD-L1

PRIMING

Immunosuppressive factors ▼

CPNCP avanzado. 2º línea

Checkmate 017 and 057: Nivolumab vs docetaxel Kaplan-Meier Estimates of OS

Nivolumab (n=135)

Docetaxel (n=137)

Events, n (%) 110 (81) 128 (93)

Median OS, mo (95% CI)

9.2 (7.3, 12.6)

6.0 (5.1, 7.3)

HR (95% CI) 0.62 (0.47, 0.80)

Nivolumab (n=292)

Docetaxel (n=290)

Events, n (%) 228 (78) 247 (85)

Median OS, mo (95% CI)

12.2 (9.7, 15.1)

9.5 (8.1, 10.7)

HR (95% CI) 0.75 (0.63, 0.91)

Checkmate 057 (non-SQ NSCLC)

Nivolumab

Docetaxel

Number of patients at risk: Nivolumab Docetaxel

100

80

60

40

20

0 0 3 6

128 89

Time (Months)

21 30 33 39 O

S (%

) 18 9 12 24 27 36

292 290

233 243

194 194

97 53

18 6

6 3

0 0

112 66

171 150

148 111

81 45

46 25

0 1

15

2-yr OS=16%

Δ13%

2-yr OS=29%

1-yr OS=51%

Δ12%

1-yr OS=39%

Checkmate 017 (SQ NSCLC)

100

80

60

40

20

0 0 3 6

51 22

Time (Months)

21 30 33 39

OS

(%)

18 9 12 24 27 36

135 137

113 104

86 69

34 14

14 6

7 4

0 0

38 17

69 46

57 33

29 11

19 9

1 1

15

Number of patients at risk: Nivolumab Docetaxel

2-yr OS=23%

2-yr OS=8%

Δ15%

1-yr OS=42%

1-yr OS=24%

Δ18%

Based on February 2016 DBL. Symbols refer to censored observations. Minimum follow-up for survival: 24.2 months. Borghaei H et al. Poster presentation at ASCO 2016. 9025.

12

Nivolumab

Docetaxel

Bhramer J, et al. NEJM 2015 Borghaei H et al. NEJM Sept 2015

NO ESCAMOSOS ESCAMOSOS

Bhramer J, et al. NEJM 2015

ESCAMOSOS

Borghaei H et al. NEJM Sept 2015

Overall survival at the 1%, 5% and 10% PD-L1 expression levels

NO ESCAMOSOS

Checkmate 057. EMA. Global de los pacientes

Presentation Number: Presentation Title – Presenting Author

3-Month Landmark Analysis of OS CheckMate 057: Nivolumab vs Docetaxel in Previously Treated NSQ NSCLC

17

Nivo (n = 232)

Doc (n = 244)

Median OS, mo

17.4 11.3

Events, n 131 179

HR (95% CI)

0.59 (0.47, 0.74)

Alive at 3 Months −

All Patients ITT Population1

Nivo (n = 292)

Doc (n = 290)

Median OS, mo

12.2 9.4

Events, n 190 223

HR (96% CI)

0.73 (0.59, 0.89)

Based on a March 18, 2015 database lock 1. Borghaei H, et al. N Engl J Med 2015;373:1627–1639.

Nivolumab

Docetaxel

OS

(%

)

Months

100

90

80

70

60

50

40

30

10

0

20

27 21 18 15 12 9 6 3 0 24

Months

100

90

80

70

60

50

40

30

10

0

20

27 21 18 15 12 9 6 3 0 24

Nivo (n = 82)

Doc (n = 87)

Median OS, mo

14.7 11.4

Events, n 51 62

HR (95% CI)

0.66 (0.45, 0.97)

Alive at 3 Months –

Patients With <1% PD-L1 Expression

Months

100

90

80

70

60

50

40

30

10

0

20

27 21 18 15 12 9 6 3 0 24

Garón et al NEJM 2015

Pembrolizumab

Herbst. Lancet 2015

Herbst. Lancet 2015

Herbst. Lancet 2015

POPLAR: randomised all-comer phase II study

*Archival or new tissue required for pre-dose testing

• Primary analysis conducted with 173 events, minimum follow-up 13 months • Interim analysis with 153 events and minimum follow-up 10 months was presented at ASCO

2015 (Spira et al. Abstract 8010)

Fehrenbacher, et al. Lancet 2016

• Metastatic or locally

advanced NSCLC (2L/3L)

• Disease progression on a

prior platinum therapy

• N=287

Primary endpoint:

• OS in ITT and PD-L1

expression subgroups

Additional endpoints:

• Estimate PFS, ORR and

DOR in ITT and PD-L1

expression subgroups

• Evaluate safety

Key inclusion criteria

Docetaxel

75mg/m2 IV q3w

until disease

progression

Atezolizumab

1200mg IV q3w

until loss of clinical

benefit R

1:1

Patients stratified by:

• PD-L1 IC expression (0 vs 1 vs 2 vs 3)*

• Histology (squamous vs non-squamous)

• Prior chemotherapy regimens (1 vs 2)

Endpoints

24

ASCO 2016

25

POPLAR: OS by PD-L1 expression

*Stratified HR; Data cut-off May 8, 2015

HR* = 0.49 (0.22, 1.07)

P value = 0.068

n = 47

Median 15.5 mo

(9.8, NE)

Median 11.1 mo

(6.7, 14.4)

HR* = 0.54 (0.33, 0.89)

P value = 0.014

n = 105

Median 15.1 mo

(8.4, NE) Median 7.4 mo

(6.0, 12.5)

HR* = 0.59 (0.40, 0.85)

P value = 0.005

n = 195

Median 15.5 mo

(11.0, NE) Median 9.2 mo

(7.3, 12.8)

HR* = 1.04 (0.62, 1.75)

P value = 0.871

n = 92

Median 9.7 mo

(6.7, 12.0)

Median 9.7 mo

(8.6, 12.0)

Atezolizumab

Docetaxel

Censored +

Fehrenbacher, et al. Lancet 2016

Phase III OAK study design

• Barlesi et al, Atezolizumab Phase III OAK Study. Lancet 207

Atezolizumab 1200 mg IV q3w

PD or loss of clinical benefit

Docetaxel 75 mg/m2 q3w

Locally Advanced or

Metastatic NSCLC

•1–2 prior lines of chemo

including at least 1 platinum

based

•Any PD-L1 status

N = 1,225 enrolleda

PD

R

1:1

Stratification factors

•PD-L1 expression

•Histology

•Prior chemotherapy

regimens

Primary Endpoints (first 850 enrolled patients):

•OS in the ITT population

•OS in patients with patients with PD-L1 expression on ≥ 1% TC or IC

Secondary Endpoints: ORR, PFS, DoR, Safety aA prespecified analysis of the first 850 patients provided sufficient power to test the co-primary

endpoints of OS in the ITT and TC1/2/3 or IC1/2/3 subgroup (≥ 1% PD-L1 expression).

TC, tumor cells; IC, tumor-infiltrating immune cells.

(n = 850)

aStratified HR for ITT and TC1/2/3 or IC1/2/3. Unstratified HR for other subgroups. TC, tumor cells; IC, tumor-infiltrating immune cells; OS, overall survival. Barlesi et al. ESMO 2016 LBA44

Overall survival, ITT (n = 850) and PD-L1 subgroups

Atezolizumab

Docetaxel

Median 9.6 mo

(95% CI, 8.6, 11.2)

Median 13.8 mo

(95% CI, 11.8, 15.7)

Ove

rall

Su

rviv

al (%

)

Months

HR, 0.73a

(95% CI, 0.62,

0.87)

P = 0.0003 Minimum follow up = 19 months

425 363

30

5 248 218 188 157 74 28 1

425 336 26

3

195 151 123 98 51 16 0

No. at risk

Atezolizumab

Docetaxel

0.2 2

Subgroup

TC1/2/3 or IC1/2/3a

TC0 and IC0

ITTa

TC3 or IC3

TC2/3 or IC2/3

Median OS, mo

n = 425 n = 425

9.6

8.9

10.3

10.8

8.9

13.8

12.6

15.7

16.3

20.5 0.41

0.67

0.74

0.75

0.73

0.2 1

2

In favor of

docetaxel

Hazard Ratioa

In favor of

atezolizumab

Docetaxel Atezolizumab

OS HR


OS, PD-L1 EXPRESSION ON ≥ 50% TC or ≥ 10% IC

TC3 or IC3; 16% of patients

Median 8.9 mo

(95% CI, 5.6, 11.6) Median 20.5 mo

(95% CI, 17.5, NE)

HR, 0.41a

(95% CI, 0.27, 0.64)

P < 0.0001b

Months

Ove

rall

Su

rviv

al (%

)

Atezolizumab

Docetaxel

Minimum follow up = 19 months


Atezolizumab

Docetaxel

Months

HR, 0.75a

(95% CI, 0.59, 0.96)

P = 0.0205b

Median 8.9 mo

(95% CI, 7.7, 11.5)

Median 12.6 mo

(95% CI, 9.6, 15.2)

OS, PD-L1 Expression ON < 1% TC AND IC TC0 and IC0; 45% of patients

Ove

rall

Su

rviv

al (%

) Minimum follow up = 19 months


CA209-003: Nivo Monotherapy in NSCLC1

Time Since First Dose (months)

100

80

60

0

40

20

0 6 12 18 30 24 36 42 48 54 66 60

3-year OS=18% 2-year OS=24% O

S (

%)

1-year OS=42%

Checkmate 017: Squamous NSCLC2

OS

(%

)

100

80

60

40

0

20

33 27 24 21 18 15 12 9 6 3 0 30

Docetaxel

2-yr OS =23%

2-yr OS=8% Nivolumab

Time (months)

Checkmate 057: Non-squamous NSCLC2

Time (months) 27 18 15 9 6 21 12 3 0 24 30

100

80

60

40

0

20

OS

(%)

Docetaxel

2-yr OS=29%

2-yr OS=16% Nivolumab

OS

(%

)

18-mo OS=40%

100

80

60

40

20

0 0 3 6 9 12 15 18 21 24 27

Atezolizumab

Docetaxel

18-mo OS=27%

Time (months)

OAK: NSCLC3

18-mo OS=37% 18-mo OS=43% 18-mo OS=24%

Checkmate 032: SCLC5

Time (months)

OS

(%

)

27 21 18 15 12 9 6 3 0 24 0

20

40

60

100

80 Nivolumab-3 Nivolumab-1/ipilimumab-3 Nivolumab-3/ipilimumab-1

1-year OS=33% 1-year OS=43% 1-year OS=35%

KN-010: ≥1% PD-L1 NSCLC4

Pembro 2 mg/kg

Docetaxel Pembro 10 mg/kg

0 5 Time (months)

OS

(%)

0

20

40

60

80

100

10 15 20 25 30

OS plateau demonstrates long-term benefit in 2L+ lung cancer with PD1/PDL1 therapy

Nivolumab is currently not approved for SCLC. 1. Gettinger SN. J Clin Oncol. 2015;33(18):2004-2012. 2. Borghaei H et al. Poster presentation at ASCO 2016. 9025. 3. Barlesi F et al. Oral presentation at ESMO 2016. LBA44. 4. Herbst RS et al. Poster presentation at ESMO 2016. LBA48. 5. Antonia SJ et al. Oral presentation at ASCO 2016. 100.

Meta-análisis Expresión PD-L1 en Ca pulmón pretratados

Passiglia F. Oncotarget 2016. PD-L1 expression as predictive biomarker in patients with NSCLC: a pooled analysis

- - PD-L1 no se puede definir como un biomarcador clásico.

- - Expresión de PD-L1 se correlaciona con densidad eficaz

de LTc (CD8) específicos contra el inmunopeptidoma

clonal del tumor. (Se puede usar como modelo predictivo

indirecto de eficacia a inmunoterapia).

- - Expresión de PD-L1 tiene aún muchas limitaciones: - - heterogeneidad en espacio – tiempo - y tipo de tratamiento previo

- - El modelo predictivo es diferente según las diferentes neoplasias

- - Limitación tecnológica por los diferentes Ac inmunohistoquímica.

- - Expresión de PD-L1 puede ser una herramienta para

disminuir la incertidumbre respecto a la estrategia

terapéutica más adecuada en cada momento : - - PD-L1 bajo: trat anti PD1 / PD-L1 pueden ser menos eficaces que

trat clásicos.

- - PD-L1 bajo: trat anti PD1 / PD-L1 + otros trat para aumentar el

“estatus inflamado” del tumor

Valor PDL1 en cáncer de pulmón

39% (1 CR, 6 PR)

CPNCP avanzado. 1º línea Monoterapia

PEMBROLIZUMAB

Reck M, et al. NEJM 2016



6

Phase 3 CheckMate 026 Study Design:

Nivolumab vs Chemotherapy in First-line NSCLC

Primary endpoint: PFS (≥5% PD-L1+)d

Secondary endpoints:

• PFS (≥1% PD-L1+)d

• OS

• ORRd

Nivolumab3 mg/kg IV Q2W

n = 271

Randomize 1:1

Key eligibility criteria:

• Stage IV or recurrent NSCLC

• No prior systemic therapy for

advanced disease

• No EGFR/ALK mutations sensitive to

available targeted inhibitor therapy

• ≥1% PD-L1 expressiona

• CNS metastases permitted if

adequately treated at least 2 weeks

prior to randomization

Chemotherapy (histology dependent)b

Maximum of 6 cycles

n = 270

Disease progression or

unacceptable toxicity

Disease

progression

Crossover

nivolumabc

(optional)

Tumor scans Q6W until

wk 48 then Q12W

aDako 28-8 validated; archival tumor samples obtained ≤6 months before enrollment were permitted; PD-L1 testing was centralizedbSquamous: gemcitabine 1250 mg/m2 + cisplatin 75 mg/m2; gemcitabine 1000 mg/m2 + carboplatin AUC 5; paclitaxel 200 mg/m2 + carboplatin AUC 6;

Non-squamous: pemetrexed 500 mg/m2 + cisplatin 75 mg/m2; pemetrexed 500 mg/m2 + carboplatin AUC 6; option for pemetrexed maintenance therapycPermitted if crossover eligibility criteria met, including progression confirmed by independent radiology reviewdTumor response assessment for PFS and ORR per RECIST v1.1 as determined by independent central review

Stratification factors at randomization:

• PD-L1 expression (<5% vs ≥5%)a

• Histology (squamous vs non-squamous)

Socinski M et al. Oral presentation at ESMO 2016

Checkmate 026: PD-L1> 5%

42

Nivolumab

Chemotherapy

Months

PFS

(%

)

24 21 18 15 12 9 6 3 27

100

80

60

40

0

20

0

All randomized patients (≥1% PD-L1+) HR = 1.17 (95% CI: 0.95, 1.43)

HR = 1.15 (95% CI: 0.91, 1.45), P = 0.2511

Months O

S (%

)

24 21 18 15 12 9 6 3 30

100

80

60

40

0

20

0 27

Nivolumab

Chemotherapy

HR = 1.02 (95% CI: 0.80, 1.30)

All randomized patients (≥1% PD-L1+) HR = 1.07 (95% CI: 0.86, 1.33)

CI=confidence interval; HR=hazard ratio; mos=months; OS=overall survival; PFS=progression-free survival; PD-L1=programmed death ligand 1. .

Nivolumab n = 211

Chemo n = 212

Median PFS, mos (95% CI)

4.2 (3.0, 5.6)

5.9 (5.4, 6.9)

1-year PFS rate, % 23.6 23.2

Nivolumab

n = 211

Chemo

n = 212

Median OS, mos

(95% CI)

14.4

(11.7, 17.4)

13.2

(10.7, 17.1)

1-year OS rate,

% 56.3 53.6

No. of patients at risk:

Nivo 211 104 71 49 35 24 6 3 1 0

Chem

o

212 144 74 47 28 21 8 1 0 0


Nivo 211 186 156 133 118 98 49 14 4 0 0

Chemo 212 186 153 137 112 91 50 15 3 1 0

Socinski M et al. Oral presentation at ESMO 2016

CheckMate 026: PFS and OS Subgroup Analyses

(All Randomized Patients)

CheckMate 026 vs. Keynote 024

Keynote 024 CheckMate 026

Tumor biopsy After metastatic diagnosis

Within 6 months

PD-L1 cut off 50% (22C3 clone) 5% (28-8 clone)

Prevalence 30% 50%

Imaging interval Q 9 weeks Q 6 weeks for first 48 weeks

Primary endpoint PFS (RECIST) PFS (IRRC)

Never smokers (PD-1) 3% 11%

Squamous histology 19% 24%

Time from diagnosis to treatment

? 2 months

Prior radiation ? 1 37.6 %

Socinski et al, ESMO 2016

Reck et al, ESMO 2016, NEJM 2016

Until loss of clinical benefit

Atezolizumab BIRCH: study design

1L = first line; 2L = second line; 3L = third line; DOR = duration of response; ECOG = Eastern Cooperative Oncology Group

IHC = immunohistochemistry; INV = investigator; IRF = Independent Review Facility; IV = intravenous; ORR = objective response rate

OS = overall survival; PD = progressive disease; PFS = progression-free survival; RECIST = Response Evaluation Criteria in Solid Tumors

Cohort 1 (1L) No prior chemo

n=142

Cohort 2 (2L) 1 prior platinum chemo

n=271

Cohort 3 (≥3L) ≥2 prior chemos (including 1 platinum)

n=254

PD

Atezolizumab dosed at 1200 mg IV q3w in all cohorts.

• Locally advanced or

metastatic NSCLC

• Tumour PD-L1

expression by IHC (TC2/3

and/or IC2/3)

• ECOG PS 0 or 1

• No brain mets

N=667

• Primary endpoint: IRF-assessed ORR per RECIST v1.1

• Secondary endpoints: – IRF-assessed PFS, DOR per RECIST v1.1

– INV-assessed ORR, PFS, DOR per RECIST v1.1 and modified RECIST

– OS

– Safety

Besse, et al. ECC 2015

Garassino et al., WCLC 2016

Overall Survival

NE, not estimable.

TC3 or IC3 = TC ≥ 50% or IC ≥ 10% PD-L1–expressing cells;

TC2 and IC2 = ≥ 5% but IC < 10% and TC < 50% PD-L1–expressing cells;

TC2/3 or IC2/3 = TC or IC ≥ 5% PD-L1–expressing cells, respectively.

Data cutoff date: August 1, 2016.

Median duration of survival follow-up = 22.5 months

TC2/3 or IC2/3

(n = 138)

mOS (95% CI) 23.5 mo (18.1, NE)

12-mo OS rate (95% CI) 66.4% (58.1, 74.6)

TC3 or IC3

(n = 65)

mOS (95% CI) 26.9 mo (12.0, NE)

12-mo OS rate (95% CI) 61.5% (49.0, 74.0)

TC2 and IC2

(n = 73)

mOS (95% CI) 23.5 mo (18.1, NE)

12-mo OS rate (95% CI) 70.7% (59.8, 81.6)

EGFR mOS (95% CI)

Mutant 26.0 mo (20.1, 26.0)

Wild-type 20.1 mo (15.5, NE)

KRAS mOS (95% CI)

Mutant 24.1 mo (20.3, NE)

Wild-type 23.5 mo (15.5, NE)

Atezolizumab BIRCH: OS. No prior chemo

Median duration of survival follow-up = 22.5 months

TC2/3 or IC2/3

(n = 138)

mOS (95% CI) 23.5 mo

(18.1, NE)

12-mo OS rate

(95% CI)

66.4% (58.1,

74.6)

TC3 or IC3

(n = 65)

mOS (95% CI) 26.9 mo

(12.0, NE)

12-mo OS rate

(95% CI)

61.5% (49.0,

74.0)

TC2 and IC2

(n = 73)

mOS (95% CI) 23.5 mo

(18.1, NE)

12-mo OS rate

(95% CI)

70.7% (59.8,

81.6)

ATLANTIC (NCT02087423) is a Phase 2, open-label, single-arm trial

*PD-L1 expression levels assessed by immunohistochemistry (VENTANA PD-L1 [SP263] Assay); †ORR by independent central review (RECIST v1.1)

CT, chemotherapy; DCR, disease control rate; DoR, duration of response

Primary endpoint:

• ORR†

Secondary

endpoints:

• DoR, PFS, DCR,

OS

• Safety

• PK

• Immunogenicity

Durvalumab i.v. 10 mg/kg q2w up

to 12 months

• NSCLC patients

(Stage IIIB/IV)

• ≥2 prior systemic

treatment regimens

including 1 platinum-

based CT

• Recent (≤3 months)

tumour biopsy and

archived tumour tissue

block for PD-L1 testing

N=1980 screened

Cohort 1 (n=111)

EGFR mutation/ALK alteration

PD-L1 high (≥25% tumour cells)

Cohort 2 (n=265)

EGFR/ALK wild-type


and PD-L1 low/negative

Cohort 3 (n=68)

EGFR/ALK wild-type


Protocol

amendment

restricted

selection to

pts with PD-L1

high tumours*

Cohorts were independent;

Cohorts 2 and 3 enrolled sequentially

Garassino et. al IASLC 2016

Overall survival in Cohorts 2 and 3 (full analysis set)

*Median follow up for OS was 9.4 months (PD-L1 ≥25%); 9.3 months (PD-L1 <25%); and 7.0 months (PD-L1 ≥90%)

NC, not calculated; NR, not reached


PD-L1 ≥25% 149 127 97 79 66 47 14 3 1 1 0

PD-L1 <25% 94 75 56 48 32 24 16 1 0 0 0


PD-L1 ≥90% 67 53 39 19 7 0

1.0

0

Pro

port

ion a

live

0.8

0.6

0.4

0.2

0

3 6 9 30 12 15 18 21 24 27

1-year OS

47.7% (39.3–55.5)

34.5% (25.0–44.1)

1-year OS

50.8 (36.9–63.2)

Time from first dose (months)

1.0

0

Pro

port

ion a

live

0.8

0.6

0.4

0.2

0

3 6 9 12 15

Time from first dose (months)

Cohort 2 Cohort 3

Median OS (95% CI)*

PD-L1 ≥90% (n=67): NR (5.9–NC)

Median OS (95% CI)*

PD-L1 ≥25% (n=149): 10.9 (8.6–13.6)

PD-L1 <25% (n=94): 9.3 (5.9–10.8)

Garassino et. al IASLC 2016

Study design: First-line NSCLC cohort

Patients: key eligibility

criteria

• Histologically confirmed

stage IV or recurrent

NSCLC

• ECOG PS 0–1 and

estimated life expectancy ≥3

months

• No prior treatment for

metastatic or recurrent

NSCLC

• No activating EGFR

mutation or ALK

translocation

• Unselected for PD-L1

expression

Dosing

Avelumab

10 mg/kg (1h

IV) Q2W

until

confirmed

progression,

unacceptable

toxicity, or

withdrawal

Select assessments*

Best overall

response

by RECIST v1.1

Safety and

tolerability

Progression-free

survival

PD-L1 expression

* Radiological examinations performed every 6 weeks

Time to/duration of response and PFS (n=156)

Median PFS:

17.6 weeks (95% CI: 11.6, 23.6)

PFS rate at 24 weeks:

37.2% (95% CI: 28.6, 45.7)

• 28/35 patients (80%) responded by the 1st or 2nd assessment

• Response was ongoing in 24/35 (68.6%) at data cut-off


Phase 1 CheckMate 012 Study Design: First-Line Nivolumab ± Ipilimumab in NSCLC

• Updated datad presented here are based on median follow-up durations of 22 months (monotherapy) and 16 months (combination cohorts)

– Overall additional follow-up relative to previous reports: monotherapy, +~18 months;1 combination cohorts, +6 months2

Primary endpoint: safety and tolerability

Secondary endpoints: ORR (RECIST v1.1) and PFS rate at 24 weeks assessed by investigators

Exploratory endpoints: OS, efficacy by PD-L1 expression

Stage IIIB/IV NSCLC (any histology), no prior chemotherapy for advanced disease, ECOG PS 0 or 1

Nivolumab 3 mg/kg IV Q2Wa Nivolumab 3 mg/kg IV Q2W

+ Ipilimumab 1 mg/kg IV Q12Wb

Nivolumab 3 mg/kg IV Q2W +

Ipilimumab 1 mg/kg IV Q6Wb

Until disease progressionc or unacceptable toxicity

ClinicalTrials.gov number NCT01454102; aTreatment allocation not randomized; bTreatment allocation randomized; earlier cohorts evaluated other dosing schedules/regimens2 cPatients tolerating study treatment permitted to continue treatment beyond RECIST v1.1-defined progression if considered to be deriving clinical benefit dBased on a September 2016 database lock 1. Gettinger S, et al. J Clin Oncol 2016;34:2980–2987; 2. Hellmann MD, et al. Lancet Oncol 2016 Dec 5. [Epub ahead of print].

51

Nivo 1 + Ipi 1 Q3W

(n = 31)

Nivo 1 Q2W + Ipi 1 Q6W

(n = 40)


(n = 38)


(n = 39) Nivo 3 Q2Wa

(n = 52)

Confirmed ORR, % (95% CI) 13

(4, 30) 25

(13, 41) 39

(24, 57) 31

(17, 48) 23

(13, 37)

Confirmed DCR, % (95% CI) 55 (36, 73) 58 (41, 73) 74 (57, 87) 51 (35, 68) 50 (36, 64)

Best overall response, %

Complete response Partial response

Unconfirmed partial response

0 13 3

0 25 3

0 39 5

0 31 8

8 15 0

Stable disease Progressive disease Unable to determine

42 35 6

33 30 10

34 13 8

21 26 15

27 38 12

PFS rate at 24 wks, % (95% CI) 55 (36, 71) NC 63 (44, 76) NC 41 (27, 54)

Median PFS, mos (95% CI) 10.6 (2.1, 16.3) 4.9 (2.8, ) 8.0 (4.2, ) 8.3 (2.6, ) 3.6 (2.3, 6.6)

Median OS, mos (95% CI) NR (11.5, ) NR (8.9, ) NR NR (8.7, ) 22.6 (14.9, )

Median length of follow-up, mos (range)

16.6 (1.8–24.5)

6.2 (0.4–13.1)

8.4 (0.9–12.3)

7.7 (1.1–12.2)

14.3 (0.2–30.1)

Summary of Efficacy

52 NR: the time point at which the percent of survivors drops below 50% has not been reached due to insufficient number of events and/or follow up. aResults for Nivo 3 Q2W are reported based on a March 2015 DBL

• Median DOR was not reached in any arm

• Unconventional immune-related responses were observed in arms Nivo 3 Q2W + Ipi 1 Q12W (n = 2), Nivo 3 Q2W + Ipi 1 Q6W (n = 1) and Nivo 3 Q2W (n = 3)

. Gettinger S, et al. J Clin Oncol 2016;34:2980–2987; 2. Hellmann MD, et al. Lancet Oncol 2016


• 5 CRs (10%) were achieved in the nivolumab monotherapy cohort (1 in a patient with tumor PD-L1 expression <1%)

• 6 CRs (8%) were achieved in the nivolumab + ipilimumab cohortsa (3 in patients with tumor PD-L1 expression <1%)

43

21

57

92

23

13

28

50

0

20

40

60

80

100

Overall <1%

≥1%

≥50%

Nivo 3 + ipi 1 Q6/12W Nivo 3

Nivolumab ± Ipilimumab ORR by Tumor PD-L1 Expression

CheckMate 012: First-Line Nivolumab ± Ipilimumab in NSCLC

53

OR

R (

%)

Overall <1% ≥1% ≥50%

PD-L1 expression

n 52 77 16 19 32 46 12 13

Based on a September 2016 database lock; a3 determined radiographically per RECIST v1.1 and 3 identified by pathologic evaluation

Nivo 3 Q2W + Ipi 1 Q6/12W Nivo 3 Q2W



OS by Tumor PD-L1 Expression CheckMate 012: First-Line Nivolumab ± Ipilimumab in NSCLC

54

Based on a September 2016 database lock

All treated patients (n = 77) ≥1% PD-L1 (n = 46) ≥50% PD-L1 (n = 13)

1-year OS rate: 76%

100

80

60

40

20

0

OS

(%

)

0 6 12 18 24 30 36 42 48

100

80

60

40

20

0

0 6 12 18 24 30 36 42 48

1-year OS rate: 87%

100

80

60

40

20

0

0 6 12 18 24 30 36 42 48

1-year OS rate: 100%

Nivo 3 Q2W +

ipi 1 Q6/12W

1-year OS rate: 73%

100

80

60

40

20

0

Months

OS

(%

)

0 6 12 18 24 30 36 42 48

100

80

60

40

20

0

Months

0 6 12 18 24 30 36 42 48

1-year OS rate: 69%

100

80

60

40

20

0

Months

0 6 12 18 24 30 36 42 48

1-year OS rate: 83%

All treated patients (n = 52) ≥1% PD-L1 (n = 32) ≥50% PD-L1 (n = 12)

Nivo 3 Q2W

• Data are based on median follow-up durations of 16 months (combination cohorts) and 22 months (monotherapy) . Gettinger S, et al. J Clin Oncol 2016;34:2980–2987; 2. Hellmann MD, et al. Lancet Oncol 2016


55

Key eligibility criteria:

• Stage IV or recurrent NSCLC

• No prior systemic therapy for

advanced disease

• No EGFR/ALK mutations

sensitive to available targeted

inhibitor therapy

• CNS metastases permitted if

adequately treated ≥2 weeks

prior to randomization

Stratification factor at

randomization:

• Histology (squamous vs

non-squamous)

Randomize 1:1:1

Disease progression

or unacceptable

toxicity

PD-L1+

(≥1%)

PD-L1‒

(<1%)

Tumor

scans Q6W

until

week 48

then Q12W

Nivolumab monotherapy

240 mg Q2W

Nivolumab 3 mg/kg Q2W +

Ipilimumab 1 mg/kg Q6W

Chemotherapy

Nivolumab 360 mg Q3W + Chemotherapy

Nivolumab 3 mg/kg Q2W +

Ipilimumab 1 mg/kg Q6W

Chemotherapy

Phase 3 CheckMate 227 (NCT02477826) Study Design


* PD-L1 positivity defined as ≥25% of tumor cells with membrane staining as determined by the Ventana PD-L1 IHC assay. Combination of durvalumab and tremelimumab is currently not approved for advanced/metastatic NSCLC. 1. Clinicaltrials.gov. NCT02542293. Accessed September 08, 2016. 2. Mok T et al. Poster presentation at ESMO Asia 2015. 480TiP.

NEPTUNE: Study Design1,2

Phase III, open-label, global study of durvalumab in combination with tremelimumab vs Pt-based chemotherapy in first-line treatment of advanced or metastatic NSCLC

• Primary Endpoint: OS

• Secondary Endpoints: OS, PFS, ORR, DOR, APF12, PFS2, PK,

immunogenicity, safety

N=800

Key Inclusion Criteria

• Treatment-naïve

• Evidence of Stage IV NSCLC

• No activating EGFR or ALK rearrangement

• PD-L1 positive* or negative

• ECOG PS 0 or 1

• No mixed SCLC or NSCLC NOS

• No brain metastases/spinal cord compression unless asymptomatic, treated, and stable

• No active or prior documented inflammatory bowel disease

Durvalumab 20 mg/kg Q4W + tremelimumab 1 mg/kg Q4W

n=400

SOC Pt-based doublet chemotherapy

Carboplatin + paclitaxel

NSQ: Carboplatin/cisplatin + pemetrexed SQ: Carboplatin/cisplatin + gemcitabine

n=400

R

MYSTIC: Study Design1,2

Phase III, open-label, first-line therapy study of durvalumab ± tremelimumab vs SOC in NSCLC

• Primary Endpoints: OS, PFS (combination vs SOC)

• Secondary Endpoints: PFS (combination vs SOC, mono vs SOC); HRQoL (combo

or mono vs SOC); PK (combo and mono); immunogenicity; ORR (combo vs SOC);

ORR & OS (mono vs SOC)

• Other: Safety and tolerability

Durvalumab 20 mg/kg Q4W + tremelimumab 1 mg/kg Q4W

Platinum-doublet chemotherapy Paclitaxel + carboplatin Pemetrexed + cisplatin or carboplatin Gemcitabine + cisplatin or carboplatin

Key Inclusion Criteria

• Treatment-naïve

• Evidence of Stage IV NSCLC

• No activating EGFR or ALK rearrangement

• ECOG PS ≤1

• No mixed SCLC or NSCLC NOS

• No prior immunomodulatory therapy

• No brain metastases/spinal cord compression unless asymptomatic, treated, and stable

• No active or prior documented inflammatory bowel disease

N=1092

R

1:1:1

Combination of durvalumab and tremelimumab is currently not approved for advanced/metastatic NSCLC. 1. Clinicaltrials.gov. NCT02453282. Accessed September 08, 2016. 2. Peters S et al. Poster presented at ELCC 2016.191TiP.

Durvalumab 20 mg/kg Q4W

CPNCP avanzado. 1º línea Combinación con QT

KEYNOTE-021—Cohort G: study design

Phase 2 study of pembrolizumab plus carboplatin and pemetrexed vs.

carboplatin and pemetrexed in first-line patients with non-squamous NSCLC

aRandomisation was stratified by PD-L1 TPS <1% and ≥1%.bIndefinite maintenance therapy with pemetrexed 500 mg/m2 Q3W permitted.

cClinically stable patients who were considered to be deriving clinical benefit by the investigator despite radiological evidence of disease progression could continue therapy until

progression was confirmed on imaging done at least 4 weeks later

AUC: area under the curve; ALK: anaplastic lymphoma kinase; DOR: duration of response; ECOG: Eastern Cooperative Oncology Group performance status; EGFR: epidermal growth

factor receptor; ILD: interstitial lung disease; NSCLC: non-small-cell lung cancer; ORR: objective response rate; OS: overall survival; PFS: progression-free survival; PD: progressive

disease; PD-L1: programmed death ligand 1; Q3W: every 3 weeks; RECIST: Response Evaluation Criteria In Solid Tumors; TPS: tumour proportion score.

Langer CJ, et al. Lancet Oncol 2016; http://dx.doi.org/10.1016/S1470-2045(16)30498-3.

Langer et al. Lancet Oncol 2016

KEYNOTE-021—Cohort G: progression-free survivala

ITT population

Analysis cut-off date: 08 August 2016.aRECIST v1.1 by blinded, independent central review.

CI: confidence interval; HR: hazard ratio; ITT: intention-to-treat; NR: not reached; PFS: progression-free survival; RECIST: Response Evaluation Criteria In Solid Tumors.

Langer CJ, et al. Lancet Oncol 2016; http://dx.doi.org/10.1016/S1470-2045(16)30498-3.


Analysis cut-off date: 08 August 2016. aNominal p value. CI: confidence interval; HR: hazard ratio; NR: not reached; OS: overall survival.

1. Langer CJ, et al. Lancet Oncol 2016; http://dx.doi.org/10.1016/S1470-2045(16)30498-3; 2. Langer CJ, et al. ESMO 2016 presentation.


Keynote 021. Overall Survivall

KEYNOTE-021—Cohort G: exposure and adverse event summary

As-treated populationa

Analysis cut-off date: 08 August 2016 aDefined as all patients who received at least one dose of the assigned study treatment AE: adverse event; IQR: interquartile

range.Langer CJ et al. Lancet Oncol 2016; http://dx.doi.org/10.1016/S1470-2045(16)30498-3.

Pembrolizumab +

chemotherapy

(n=59)

Chemotherapy

alone

(n=62)

Median duration of

treatment

(IQR)

8.0 months

(4.7–11.2)

4.9 months

(2.1–7.4)

Treatment-related AEs,

% Any grade Grade 3–5 Any grade Grade 3–5

Any 54 39 65 26

Serious 3 24 2 8

Leading to

discontinuation 2 8 8 5

Leading to death 0 2 0 3


Rizvi NA et al. J Clin Oncol. 2016;24(25):2969-2979.

Checkmate 012: PFS and OS, nivo + chemo

• Checkmate 012 represents the most mature data set evaluating anti–PD-1 + chemotherapy

• OS rates observed at 1 year were not maintained at 2 years

100

80

60

40

20

0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42


OS

(%)

Group Median OS,

months (range) 1-Year OS, %

2-Year OS, %

Nivo 10 mg/kg + Gem-Cis 11.6 (4.5–33.3) 50 25

Nivo 10 mg/kg + Pem-Cis 19.2 (7.6–35.1+) 87 33

Nivo 10 mg/kg + Pac-Carb 14.9 (3.2–34.2+) 60 27

Nivo 5 mg/kg + Pac-Carb NR (8.8–30.1+) 86 62

Group Median PFS,

months (range) 24-Week PFS, %

Nivo 10 mg/kg + Gem-Cis 5.7 (0.02+–14.1) 51

Nivo 10 mg/kg + Pem-Cis 6.8 (0.9+–24.6+) 71

Nivo 10 mg/kg + Pac-Carb 4.8 (0.7–28.7+) 38

Nivo 5 mg/kg + Pac-Carb 7.1 (0.02+–24.8+) 51

20

0 3 6 9 12 15 18 21 24 27 30


PFS

(%

)

40

60

80

100

0

Nivo 10 mg/kg + Gem-Cis Nivo 10 mg/kg + Pem-Cis Nivo 10 mg/kg + Pac-Carb Nivo 5 mg/kg + Pac-Carb

Nivo 10 mg/kg + Gem-Cis Nivo 10 mg/kg + Pem-Cis Nivo 10 mg/kg + Pac-Carb Nivo 5 mg/kg + Pac-Carb

GP28328: a phase Ib study of first-line atezolizumab plus chemotherapy in NSCLC

DLTs = dose-limiting toxicities; DOR = duration of response; IV = intravenous; 3w= every 3 weeks ORR = objective response rate PFS = progression-free survival NCT01633970

• Locally advanced or metastatic

NSCLC

• Histologically or cytologically

confirmed stage IIIB or IV disease

• ECOG PS 0–1

• No prior chemotherapy for

advanced disease

Atezolizumab IV q3w + carboplatin q3w + pemetrexed q3w

(n≤25)

Atezolizumab IV q3w + carboplatin q3w + paclitaxel q3w

(n≤25)

Atezolizumab IV q3w + carboplatin q3w + nab-paclitaxel q1w

(n≤25)

Endpoints • Safety (including DLTs)

Secondary endpoints • Pharmacokinetics • Best overall response • ORR • DOR • PFS

Loss of clinical benefit

Camidge, et al. WCLC 2015; Giaccone, et al. ECC 2015

Camidge DR et al. WCLC 2015

Summary of ongoing phase III studies with in NSCLC

Phase III 1L in non-squamous NSCLC

Atezolizumab + carbo/pac ± bev Combo

Phase III 1L in non-squamous NSCLC

Atezolizumab + carbo/nab-pac Combo

Phase III 1L in squamous NSCLC

Atezolizumab + carbo/pac or carbo/nab-pac Combo

Combo Phase III 1L in non-squamous NSCLC

Atezolizumab + carbo or cis/pem

CPNCP local / localmente avanzado

71

Alliance Foundation Trial (AFT-16)

Chemoradiation in Stage III Unresectable NSCLC

*Chemo/RT= carboplatin (AUC2) + paclitaxel 50 mg/m2 IV weekly x6 cycles +60 Gy qd x 30fxn § Consolidation chemotherapy = carboplatin AUC6 + paclitaxel 200 mg/m2 IV q21 days x 2 cycels

ORR=objective response rate; PD=progressive disease; RT=radiotherapy; QoL=quality of life

Phase II/III trial of induction immunotherapy with atezolizumab for patients with unresectable stage IIIA

and IIIB NSCLC eligible for chemoradiotherapy with curative intent and whose tumors express PD-L1

Phase III Objectives and Endpoints:

1. Primary endpoint: OS

2. Secondary endpoint: PFS, safety, QoL

Chemo/RT + Consolidation Adjuvant Immunotherapy

Chemo/RT +

Conoslidation

4 total cycles of

Atezolizumab induction

Alliance Standard

Chemo/RT* regimen

Alliance Standard Chemo

Consolidation§

Atezolizumab

1200mg q3w for 1

year

NSCLC

Stage

IIIA &

IIIB

PDL1+

Primary Endpoints: ORR following induction, PFS following induction + chemo/RT

R A

N D

O M

I Z

E

2:1

Atezolizumab

1200 mg IV

q3w

x4 cycles

Induction

Immunotherapy

Study Design & Endpoints NEOADJUVANT NIVOLUMAB IN NSCLC

Newly diagnosed resectable

stage I (>2cm)/II/IIIA NSCLC

Nivolumab 3mg/kg IV on

Day-28 & Day-14

Surgical resection on Day 0

Standard of care postoperative

treatment

Safety follow up for 30 days after

surgery

TUMOR

BIOPSY

BLOOD

DRAWS

VIABLE TUMOR

TILS

LYMPH NODE

CELLS

BLOOD DRAW

Ongoing Adjuvant PD-1/PD-L1 trials

CPNCP avanzado. Mutaciones

FUTURO

Greil et al. Cell Communication and Signaling (2017) 15:5

Dentro del complejo mundo inmuno-oncologico, necesitaremos biomarcadores que nos orienten a decidir cuáles de todos los nuevos fármacos será eficaz

IASLC 2016

Ann Oncol 2016

Inmunoterapia Cáncer pulmón. PREGUNTAS Con respecto a inmunoterapia con antiPD1/PDL1 en segunda línea de CPNCP, cuál de las siguientes preguntas es Verdadera 1.- El fármaco de elección es Nivolumab frente a los otros dos, pembrolizumab y atezolizumab 2.- la inmunohistoquímica con PD-L1 tiene demasiados inconvenientes clínicos y no se aconseja realizar para tomar una decisión de la mejor terapia a administrar 3.- Para la indicación de pembrolizumab en segunda línea, sólo se deberían considerar los que tienen un porcentaje de PD-L1 en inmunohistoquímica > 50% 4.- El Anticuerpo de inmunohistoquímica de PD-L1 asociado a atezolizumab es: el test de Ventana SP 142, y considera tanto células tumorales como inflamatorias.

Inmunoterapia Cáncer pulmón. PREGUNTAS Con respecto a inmunoterapia con antiPD1/PDL1 en primera línea de CPNCP, cuál de las siguientes preguntas es Verdadera 1.- Los pacientes con mutación de EGFR tienen el mismo beneficio que los pacientes WT para la inmunoterapia, porque suelen tener más expresión de PD-L1 2.- El único fármaco recomendado por las agencias regulatorias en primera línea, es Pembrolizumab en monoterapia cuando la expresión de PD-L1 > 50% 3.- La combinación de un anti PD1/PD-L1 + antiCTL4 sería la opción más recomendable en primera línea en paciente con alta expresión en inmunohistoquímica de PD-L1 4.- El beneficio de nivolumab en monoterapia frente a quimioterapia en primera línea de CPNM en paciente con nivel de expresión de PD-L1 > 50%, fue similar al del ensayo con pembrolizumab

Documents

Inmunoterapia en cáncer de pulmón · Inmunoterapia en cáncer de pulmón Manuel Cobo Dols Oncología Médica Hospital R.U. Málaga regional y Virgen de la Victoria Madrid 6-04-2017