Discusion Dra Pilar Lianes - Sociedad Española de ... · •Se detecta en el 30% de fumadores y 10% de no-fumadores •Hasta ahora las terapias dirigidas no han tenido éxito en

EXPRESIÓN DE PD-1 Y SUS LIGANDOS PD-L1 y

PD-L2 en el MICROAMBIENTE INMUNE TUMORAL Y

SU RELACIÓN CON EL HÁBITO TABÁQUICO EN

PACIENTES CON CÁNCER DE PULMÓN NO

MICROCÍTICO (CPNM) KRAS MUTADO.

Dr A.Calles

Discusion

Dra Pilar Lianes

Cnmp Kras mutados

• Kras es la alteración oncogénica más frecuente en adenocarcinoma de de pulmón

• Se detecta en el 30% de fumadores y 10% de no-fumadores

• Hasta ahora las terapias dirigidas no han tenido éxito en estos pacientes

• Existe interés en conocer la expresión de PD-1 y sus ligandos en este grupo de pacientes ya que la IT podría ofrecer una oportunidad terapeútica a los mismos

Nivolumab in NSCLC Duration of response and OS

Vertical line at 96 weeks = maximum duration of continuous nivolumab therapy aResponses were assessed by modified RECIST v1.0 bAll efficacy analyses based on data collected as of September 2013

Brahmer JR, et al.

Oral presentation at ASCO 2014

NSCLC respondersa,b by histology

Time (week)

All treated subjects with NSCLC

0 16 32 48 64 80 96 112 128 144 160

Sq

uam

ou

s

no

nsq

uam

ou

s

Duration of response up to discontinuation of therapy

Ongoing response

Time to response

Response duration following discontinuation of therapy

0 6 12 18 24 30 27 21 15 9 3 33 36 42 48 54 39 45 51 57

2-year OS Rate 45% (9 patients at risk)

1-year OS Rate 56% (17 patients at risk)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

OS

Group

1 mg/kg 3 mg/kg 10 mg/kg

Por qué PD-L1 está siendo estudiado como biomarcador para la IT con PD-1/PD-L1

• Se expresa en lfcitos T,B,macrófagos, céls dendríticas y se puede sobreexpresar en la células tumorales , entre otros , del CNMP

• Se localiza en la membrana celular y /o en el citoplasma del 27-57% de los CNMP

• Su expresión se asocia con mal pronóstico en muchos tumores

• Es el único factor , por ahora, relacionado con la respuesta a IT

1. McDermott D, and Atkins M. Cancer Med. 2013;2:662–673; 2. Zou W, and Chen L. Nat Rev Immunol. 2008;8:467–477; 3. Mu C, et al. Med Oncol. 2011;28:682–688; 4. Ceeraz S, et al. Trends Immunol. 2013;34:556–563; 5. Taube J, et al. Clin Cancer Res. 2014

PD-L1 PD-L2

PD-1

T cell

APC/Tumour cell

Adapted from McDermott and Atkins 2013

and Ceeraz et al 20131,4

Ligation results in

decreased proliferation,

cytokine secretion and

cytotoxicity

Clinical Development of Inhibitors of

PD-1 Immune Checkpoint

Target Antibody Molecule Development stage

PD-1

Nivolumab (BMS-936558)

Fully human IgG4 Phase III multiple tumors (melanoma, RCC, NSCLCa,

HNSCC)

Pembrolizumab (MK-3475)

Humanized IgG4 Phase I-II multiple tumors

Phase III NSCLC/melanoma

Pidilizumab (CT-011)

Humanized IgG1 Phase II multiple tumors

PD-L1

MEDI-4736 Engineered human IgG1 Phase I-II multiple tumors

MPDL-3280A Engineered human IgG1 Phase I-II multiple tumors

Phase III NSCLC

MSB0010718C Fully human IgG1 Phase I solid tumors

Como seleccionamos los pacientes?

Responses were durable and occurred early

• 50% of patients (11/22) with ORs demonstrated response at first assessment (8 weeks)

• Responses ongoing in 45% of patients (10/22) at time of analysis

• 38% of responders (6/16) who discontinued for reasons other than PD responded for >30 weeks after last nivolumab dose; responses in 83% of patients (5/6) ongoing at the time of reporting

Brahmer J, et al. Poster presented at ASCO 2014 (Abstract 8112).

Time to and duration of

response while on treatment

Time to response

Ongoing response

Response duration following

latest reported dose of therapy

Time , weeks

0 16 32 48 64 80 96 112 128 144 160

Squamous

(n = 9)

Non-squamous

(n = 13)

CA209-003: phase 1 follow-up study, up to 5 prior lines of therapy,

stage IIIB/IV NSCLC cohort

PD-L1 Status and Gene Mutations in Tumor Panel

• KRAS mutation-positive tumors tend to have higher PD-L1 expression

• 8 (35%) PD-L1+ tumor specimens also harbored a KRAS mutation

compared with 2 (7%) PD-L1- tumor specimens

• Analysis of mutations commonly found in NSCLC (eg, EGFR,

phosphatidylinositol-4, 5-bisphosphate 3-kinase, catalytic subunit alpha

[PIK3CA], TP53) showed no association with PD-L1 status

WCLC 2013 Mercury ID: ONCHQ13NP10127; Approved 5Nov2013; Expires 5 Nov2015 11

Results (cont) Figure 6. KRAS mutation and PD-L1 status in NSCLC specimens

in tumor panel

Anti-PD-L1 responses by histology and EGFR/KRAS

mutation status: MPDL3280A as an example

.

Horn L, et al. Oral presentation at WCLC 2013 (Abstract 2347).

NS

S

NS

NS

NS

S

NS

S

NS

NS

NS

NS

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84

Time, weeks

On study, on treatment

Treatment discontinued

Ongoing response

First response

On study, post treatment

First PD

OR

R†,

%

EGFR

mutation

EGFR

wildtype

23%

(9/40) 17%

(1/6)

KRAS

mutation KRAS

wildtype

30%

(8/27) 10%

(1/10)

O

RR

*, %

EGFR mutation status (NSCLC; n =

53)

KRAS mutation status

(NSCLC; n = 53)

Phase 1a study, ≥1 prior lines of therapy,

metastatic NSCLC cohort

Duration of treatment and response

Response to anti-PD-1 by EGFR or KRAS mutation status: nivolumab as an example

Brahmer J, et al. Poster presented at ASCO 2014 (Abstract 8112).

Subgroup ORR, % (n/N) [95% CI]

EGFR status

Mutant 17 (2/12) [2.1, 48.4]

Wild-type 20 (11/56) [10.2, 32.4]

Unknown 15 (9/61) [7.0, 26.2]

KRAS status

Mutant 14 (3/21) [3.0, 36.3]

Wild-type 25 (9/36) [12.1, 42.2]

Unknown 14 (10/72) [6.9, 24.1]

Ch

an

ge in

tu

mo

ur

siz

e, %

-100

-80

-60

-40

120

-20

0

20

40

60

80

100

Patients

EGFR mutation status

Mutant Unknown Wild-type

-100

-80

-60

-40

120

-20

0

20

40

60

80

100

Patients

Ch

an

ge in

tu

mo

ur

siz

e, %

KRAS mutation status

Mutant Unknown Wild-type

CA209-003: phase 1 follow-up study, up to 5

prior lines of therapy, NSCLC cohort

Anti PD1/PD-L1 Inhibitors Response Rate by Smoking Status

Anti PD1 Anti PD-L 1

MK-3475 Nivolumab MEDI4736

MPDL3280A

All, N 236 129 58 53

RR 21% 17% 16% 23%

Smokers

165

27%

75

20%

? 43

26%

Never/minimal

Smokers

65

9%

13

0%

? 10

10%

Garon E, ESMO 2014; Hellman M ESMO 2014; Soria JC, ESMO 2013, Paz Ares

ESMO 2014

Esmo 2014:Pembrolizumab Antitumor Activity

N ORRa

% (95% CI)

Total 236 21 (16-27)

Previous treatment 236

Treatment naive 42 26 (14-42)

Previously treated 194 20 (15-26)

Histology 230

Nonsquamous 191 23 (17-29)

Squamous 39 18 (8-34)

Smoking history 230

Current/Former 165 27 (20-34)

Never 65 9 (4-19)

N ORRa

% (95% CI)

Dose/schedule 236

2 Q3W 6 33 (4-78)

10 Q3W 126 21 (14-29)

10 Q2W 104 21 (14-30)

PD-L1 expressionb 236

Positive 201 23 (18-30)

Negative 35 9 (2-23)

EGRFR mutation 36 14 (5-30)

KRAS mutation 39 28 (15-45)

ALK rearrangement 6 17 (0-64)

aIncludes confirmed and unconfirmed responses .ESMO 2014 bAs assessed using a prototype assay. Positive was defined as staining in ≥1% of tumor cells.

Analysis cutoff date: March 3, 2014.


N ORRa

% (95% CI)

Total 236 21 (16-27)




Histology 230


Squamous 39 18 (8-34)

Smoking history 230


Never 65 9 (4-19)

N ORRa

% (95% CI)

Dose/schedule 236

2 Q3W 6 33 (4-78)

10 Q3W 126 21 (14-29)

10 Q2W 104 21 (14-30)


Positive 201 23 (18-30)








N ORRa

% (95% CI)

Total 236 21 (16-27)




Histology 230


Squamous 39 18 (8-34)

Smoking history 230


Never 65 9 (4-19)

N ORRa

% (95% CI)

Dose/schedule 236

2 Q3W 6 33 (4-78)

10 Q3W 126 21 (14-29)

10 Q2W 104 21 (14-30)


Positive 201 23 (18-30)







• In 45 additional patients treated at 2 mg/kg Q3W, ORRa is 20% (95% CI, 10%-35%) per irRC by

investigator review


N ORRa

% (95% CI)

Total 236 21 (16-27)




Histology 230


Squamous 39 18 (8-34)

Smoking history 230


Never 65 9 (4-19)

N ORRa

% (95% CI)

Dose/schedule 236

2 Q3W 6 33 (4-78)

10 Q3W 126 21 (14-29)

10 Q2W 104 21 (14-30)


Positive 201 23 (18-30)








investigator review


N ORRa

% (95% CI)

Total 236 21 (16-27)




Histology 230


Squamous 39 18 (8-34)

Smoking history 230


Never 65 9 (4-19)

N ORRa

% (95% CI)

Dose/schedule 236

2 Q3W 6 33 (4-78)

10 Q3W 126 21 (14-29)

10 Q2W 104 21 (14-30)


Positive 201 23 (18-30)








investigator review


N ORRa

% (95% CI)

Total 236 21 (16-27)




Histology 230


Squamous 39 18 (8-34)

Smoking history 230


Never 65 9 (4-19)

N ORRa

% (95% CI)

Dose/schedule 236

2 Q3W 6 33 (4-78)

10 Q3W 126 21 (14-29)

10 Q2W 104 21 (14-30)


Positive 201 23 (18-30)








investigator review

Es PD-L1 el biomarcador que estamos buscando ???

Qué pacientes tratar?

Qué tumores seleccionar?

PD-L1 expression and survival in patients with NSCLC in Korea

• Background:

– PD-L1 positivity and increased TILs has been associated with better outcome in lung carcinomas (Velcheti V. Nature 2014)

• Study objective

– Prognostic impact of PD-L1 expression by IHQ among 1070 Korean patients with NSCLC (62% ADC; 28% SCC; 10% other; 75% stage I/II)

• Key results

– Higher incidence of PD-L1 positivity in males, elderly, smokers, SCC and advanced-stage (p<0.001)

– PD-L1 positivity was associated with worse OS

• 5-year OS, PD-L1+ 51% (95% CI 39, 63) vs PDL-1- 73% (69, 76) (HRa 1.57; p=0.02)

• 5-year OS in ADC, PD-L1+ 53% (95% CI 36, 69) vs PD-L1- 77% (72, 82) (HRa 1.86; p=0.02)

Sun et al. ASCO 2014, poster, abstr 8066

55%

6%

Prognostic/predictive biomarkers in NSCLC

1. Oldenhius CNAM, et al. Eur J Cancer. 2008;44:946–953; 2. Liu YZ, et al. Lung Cancer. 2012;77:176-182;

Prognostic

Provides information on

outcome, independent of the

administered therapy1

Predictive


outcome with regards to

a specific therapy1

3.Steels E, et al. Eur Respir J. 2001;18:705–719; 4. Tsao M-S, et al. J Clin Oncol. 2007;25:5240-5247;

5. Peters S, et al. Ann Oncol. 2012;23(suppl 7):vii56–vii64; 6. Marchetti A, et al. J Clin Oncol. 2011;29:3574–3579;

7. Eberhard D, et al. J Clin Oncol. 2005;23:5900–5909; 8. Cappuzzo F, et al. J Clin Oncol. 2009;27:1667–1674;

9. Mu C, et al. Med Oncol. 2011;28:682–688; 10. Garon E, et al. Oral presentation at WCLC 2013. (Abstract 2416);

11. Pao W and Girard N. Lancet Oncol. 2011;12:175–180; 12. Rothschild S, et al. Curr Opin Oncol. 2011;23:150–157.



Ki672

MCM72

p533,4

Prognostic




Predictive



a specific therapy1








Ki672

MCM72

p533,4

HER25

RET5

ROS15

Prognostic




Predictive



a specific therapy1








Ki672

MCM72

p533,4

HER25

RET5

ROS15

ALK5

ERCC15

BRAF5,6

EGFR5,7

KRAS5,7

MET5,8

PD-L1?9,10

Prognostic




Predictive



a specific therapy1






Anti PD1/PD-L1 Inhibitors Response Rate by PD-L1 Status

Anti PD1 Anti PD-L 1

MK-3475 Nivolumab MEDI4736

MPDL3280A

All, N 236 129 58 53

RR 21% 17% 16% 23%

PD-L1 +

201

23%

33

15%

20

25%

26

31%

PD-L1 - 35

9%

35

14%

29

3%

20

20% Garon E, ESMO 2014; Brahmer J, ASCO 2014 (P-293); Gettinger ASCO 2014;

Soria JC, ESMO 2014/Paz Ares ESMO 2014

Agent Assay Analysis Definition of positivity PD-L1 expression

Nivolumab (anti-PD-1) 14

Dako automated IHC assay (28-8 rabbit Ab) Analytically validated

• Archival FFPE • 1% and 5% cut-off among >100 evaluable tumour cells

• 56%: 1% cut-off • 49%: 5% cut-off

Pembrolizumab (anti-PD-1)5,6

Dako automated IHC assay (22C3 mouse Ab)

• New tumour biopsy within 60 days prior to first dose of pembrolizumab

• Tumour dependent: - Melanoma > 1% - NSCLC PD-L1 (+): Strong (≥50%) and

weak staining (1–49%) PD-L1 (–): no staining

• ~25%: ≥50% staining • ~45–70%: ≥1%

staining

MPDL3280A (anti-PD-L1)7,8,9

Ventana automated clinical research IHC assay

• Archival FFPE

• PD-L1 (+): IHC 3 (≥10%),

IHC 2,3 (≥5%), IHC 1,2,3 (≥1%)

• PD-L1 (–): IHC 0 (<1%)

• 11%: IHC 3 • 25%: IHC 2 and 3 • 49%: IHC 1/2/3

MEDI-4736 (anti-PD-L1)10

First-generation or Ventana IHC Automated Assay (in development)

• Archival FFPE • Not reported • Not reported

PD-L1 analysis: differences in evaluation and interpretation

1. Antonia S, et al. Poster presented at WCLC 2013 (Abstract P2.11-035); 2. Brahmer J, et al. Poster 293 presented at ASCO 2014 (Abstract 8112); 3. Gettinger S, et al. Poster presented at ASCO 2014 (Abstract 8024); 4. Topalian S, et al. N Engl J Med. 2012;366:2443–2454; 5. Garon E, et al. Poster presented at ASCO 2014 (Abstract 8020); 6. Gandhi L, et al. Oral presentation at AACR 2014 (Abstract CT105); 7. Soria J, et al. Oral presentation at ECC 2013 (Abstract 3408); 8. Rizvi N, et al. Poster presented at ASCO 2014 (Abstract TPS 8123); 9. Soria J, et al. Poster presented at ESMO 2014 (Abstract 1322P); 10. Brahmer J, et al. Poster presented at ASCO 2014 (Abstract 8021).

Biomarcadores predictivos:PD-L1 • Se sabe q la expresion de PD-L1 varía con:

• El microambiente celular

• Es dinámica en el tiempo

• En los TIL vs el tumor

• El método diagnóstico (parafina, fresco...)

• Tumor primario vs metástasis • Diagnóstico vs progresión

• Tratamientos previos (qt, radio, terapias dirgidas, IT..)

• Es necesaria la standarización y

• Validar su valor predictivo para supervivencia

Pembrolizumab Kaplan-Meier Estimates of Survival

aEvaluable patients were those patients in the training set with evaluable tumor PD-L1 expression.

Strong PD-L1 positivity defined as staining in ≥50% of tumor cells, and weak PD-L1 positivity as staining in 1-49% of tumor cells. Negative staining is no PD-L1 staining in tumor cells. Data cut-off: March 3, 2014.

• PFS was longer in patients with PD-L1 strong-positive versus PD-L1 weak-positive/ negative tumors (HR, 0.52; 95% CI, 0.33-0.80)

• OS was longer in patients with PD-L1 strong-positive versus PD-L1 weak-positive/ negative tumors (HR, 0.59; 95% CI, 0.35-0.99)

Ove

rall

Surv

ival

, %

Strong Weak Negative

0 2 4 6 8 10 13

100 90 80 70 60 50 40 30 20 10

0

Time, months

44 53 49

43 51 42

34 34 29

27 22 14

21 18 8

18 11 6

5 5 0

12 11 9 7 5 3 1

8 7 2

9 8 4

30 26 21

32 31 26

38 48 38

38 40 34

5 5 0

14

4 4 0

OS PFS (RECIST v1.1, Central Review)

0 8 16 24 32 40 48

100 90 80 70 60 50 40 30 20 10

0 Pro

gres

sio

n-F

ree

Surv

ival

, %

Time, weeks n at risk Strong Weak Negative

44 53 49

28 43 30

18 17 15

17 12 7

9 6 1

6 0 0

3 0 0

Strong Weak Negative

MPDL3280A Activity

According to PDL-2 Expression

Soria JC, ESMO 2014

Heterogeneidad de PD-1 y sus ligandos en CPNM KRAS mutado

PD-L1- PD-L2+ PD-1+ 25%

PD-L1- PD-L2- PD-1+ 25%

PD-L1- PD-L2- PD-1- 16%

PD-L1+ PD-L2- PD-1+ 10%

PD-L1- PD-L2+ PD-1- 11%

PD-L1+ PD-L2+ PD-1+

8%

PD-L1+ PD-L2+ PD-1-

3%

PD-L1+ PD-L2- PD-1-

2%


PD-1

200μm

PD-L1 PD-L2

CD3 PD-L1- PD-L2+ PD-1+ 25%

PD-L1- PD-L2- PD-1+ 25%

PD-L1- PD-L2- PD-1- 16%

PD-L1+ PD-L2- PD-1+ 10%

PD-L1- PD-L2+ PD-1- 11%

PD-L1+ PD-L2+ PD-1+

8%

PD-L1+ PD-L2+ PD-1-

3%

PD-L1+ PD-L2- PD-1-

2%

200μm 200μm

200μm


Conclusiones: en pacientes con CNMP Kras mutado

• La expresion de PD1 y sus ligandos es heterogénea en este

análisis retrospectivo

• La expresion de PDL1 se asocia con el tabaquismo

• PDL2 podría ser otro biomarcador opcional(“PD-L2 se expresa casi en

el doble de pacientes que PD-L1, y no se asocia a la expresión de PD-L1 ni al tabaquismo”)

• Se debe analizar la presencia de biomarcadores en muestra recientes

• La expresión es cambiante en el tiempo ( de la enfermedad y de la muestra)

• Un inmunoscore ,de varios biomarcadores, podría ser mejor que uno solo

• “Reportamos el uso de 3 nuevos anticuerpos con alta sensibilidad y especificidad para PD-L1, PD-L2 y PD-1 que

pueden utilizarse en la práctica clínica”

“Tumor heterogeneity might be the Achilles heel for inmunotherapy”

Charles Swanton . Esmo 2014

graciassssssss

Preguntas • Es un dato novedoso en su serie que los

fumadores digamos empedernidos tengan mayor expresión e intensidad de PD-L1?

• Como explica la expresión diferencial de PD-L1 y PD-L2 por órgano (ie Pleural, cerebral)?

• Por qué la expresion de PDL2 , es más elevada a pesar de usar un score más alto y no está relacionada con el tabaquismo?

• Si la expresión de PD-L2 no varía con la antiguedad de la muestra no sería por todo lo dicho mejor marcador que PD-L1?

Documents

Discusion Dra Pilar Lianes - Sociedad Española de ... · •Se detecta en el 30% de fumadores y 10% de no-fumadores •Hasta ahora las terapias dirigidas no han tenido éxito en