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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.
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.
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.
• In 45 additional patients treated at 2 mg/kg Q3W, ORRa is 20% (95% CI, 10%-35%) per irRC by
investigator review
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.
• In 45 additional patients treated at 2 mg/kg Q3W, ORRa is 20% (95% CI, 10%-35%) per irRC by
investigator review
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.
• In 45 additional patients treated at 2 mg/kg Q3W, ORRa is 20% (95% CI, 10%-35%) per irRC by
investigator review
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.
• In 45 additional patients treated at 2 mg/kg Q3W, ORRa is 20% (95% CI, 10%-35%) per irRC by
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
Provides information on
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.
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;
Ki672
MCM72
p533,4
Prognostic
Provides information on
outcome, independent of the
administered therapy1
Predictive
Provides information on
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.
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;
Ki672
MCM72
p533,4
HER25
RET5
ROS15
Prognostic
Provides information on
outcome, independent of the
administered therapy1
Predictive
Provides information on
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.
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;
Ki672
MCM72
p533,4
HER25
RET5
ROS15
ALK5
ERCC15
BRAF5,6
EGFR5,7
KRAS5,7
MET5,8
PD-L1?9,10
Prognostic
Provides information on
outcome, independent of the
administered therapy1
Predictive
Provides information on
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.
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%
Heterogeneidad de PD-1 y sus ligandos en CPNM KRAS mutado
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
Heterogeneidad de PD-1 y sus ligandos en CPNM KRAS mutado
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?