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2016-02 Inmunoterapia pulmón
1.
2.
3.
4. ¿Por qué el cáncer de pulmón?
Figure: Somatic mutation frequencies observed in exomes from 3,083 tumor-normal pairs
Lawrence et al; Nature 499, 214–218 (11 July 2013)
Lung tumors along with other malignancies such as bladder and melanoma display
a high number of somatic mutations rendering these tumors more immunogenic
5. Tumor infiltrating FOXP3+ regulatory T-cells are associated
with recurrence in pathologic stage I NSCLC patients
Petersen RP. Cancer 2006;107(12):2866–72.
Foxp3+/CD3+ combination risk according
to IHC score
IHC scores
CD3,Foxp3
Low risk 3,0; 2,0
Intermediate risk 1,0; 2,1; 3,1; 3,2
High risk 0,0; 1,1; 2,2; 3,3
N=64
1996-2001
6. Brambilla E, J Clin Oncol. 2016 Feb 1.
Efecto pronóstico de la infiltración tumoral linfocítica en el
cáncer de pulmón no-microcítico resecable
16. 1. Mellman, et al. Nature 2011 2. Chen & Mellman. Immunity 2013
Anti-CTLA-4
CTLA-4 is a major negative regulator of T cell activation
and inhibition of CTLA-4 can enhance T cell stimulation,
resulting in more potent anti-tumour responses1
Ipilimumab
Tremelimumab
Anti-PDL1/PD1
PD-L1 expression on tumour cells and tumour-infiltrating
immune cells can inhibit T cell activity via its receptor PD-
1, dampening the anti-tumour immune response.
Inhibition of
PD-L1 or its receptor PD-1 may restore T cell effector
function2
Atezolizumab (anti-PDL1)
Durvalumab (anti-PDL1)
Nivolumab (anti-PD1)
Pembrolizumab (anti-PD1)
Avelumab (anti-PDL1)
BMS-936559 (anti-PDL1)
CTLA-4 pathway
PD-1 pathway
17. Ellis LM. J Clin Oncol; 2014 Apr 20;32(12):1277–80.
Summary of recommended targets for meaningful clinical trials goals:
Lung Cancer
Primary End Point Secondary End Point
Current
baseline
median
OS(m)
Improvement over
current OS that
would be clinically
meaningful (months)
Targets
HR
Improvement
in 1-year
survival rate
(%)
Improvement
in PFS
(months)
Lung cancer
Non-squamous
13 3.25-4 0.76-0.8 53 61 4
Lung cancer
Squamous
10 2.5-3 0.77-0.8 44 63 3
18. Agent Immunoth.
approach
Study design Population Results
SRL172
O’Brien
Ann Oncol 2014
Nonspecific
vaccine
(killed Mycob)
Open label: CT +
SLR172 (phase
III)
Stage III/IV
unresectable
NSCLC
Primary OS
endpoint not
met
Tecemotide
Butts
Lancet Oncol
2014
Tumor-specific
MUC1 vaccine
START:
Tecemotide vs
placebo
(phase III)
Stage III after
CT-RDT
Primary OS
endpoint not
met
MAGE-3
Vanteenkiste
ESMO 2014
Tumor specific
MAGE-3 vaccine
MAGRIT: MAGE-
vs placebo
Stage IB-IIIA
resected MAGE-
3 positive
Primary DFS
endpoint not
met
GVAX
Nemunaitis
Cancer Gen Ther
2006
Autologous
tumor cell
vaccine
GVAX alone
(phase I/II)
Advanced NSCLC No responses
Failed Immunotherapies tested in NSCLC
19. Agent Immunoth.
approach
Study design Population Results
Belagenpumatucel-L
Giaconne
ECCO 2014
TGF-b-
blocking
allogenic
tumor cell
vaccine
STOP:
maintenance vs
placebo (phase
III)
Stage III/IV
NSCLC; no
disease
progressión
after frontline
therapy
Primary OS
endpoint not
met; predefined
subgroups
benefit
Talactoferrin
Nemunaitis
Ann Oncol 2013
Dendritic cell
activation
FORTIS-M:
talactoferrine vs
placebo (phase
III)
Stage III/IV
NSCLC refractory
to 2 or more
therapies
Primary OS
endpoint not
met
CPG 7909
Manegold
Ann Oncol 2012
Dendritic cell
activation
Chemotherapy +
CPG 7909 (phase
III)
Stage III/IV
NSCLC naïve to
chemotherapy
Primary OS
endpoint not
met
Failed Immunotherapies tested in NSCLC
24. Fase II aleatorizado
N=87
Tremelimumab 15 mg/kg iv cada 90 d
No diferencias en SLP
Toxicidad grado ¾: 20.5%
RP en mantenimiento: 4.8%
SLP a los 3 meses: 21 vs 15%
Zatloukal, ASCO 2009; #8071
Randomized phase II clinical trial comparing tremelimumab with BSC
following first-line platinum-based therapy in pts with advanced NSCLC
26. Gettinger SN. J Clin Oncol; 2015 Jun 20;33(18):2004–12.
NIVOLUMAB: phase I dose-escalation cohort expansion trial
N=129
RR:17%
27. CheckMate 017: Nivolumab vs Docetaxel in
Previously Treated Squamous NSCLC
Open-label, randomized phase III trial
Primary endpoint: OS
Secondary endpoints: ORR, PFS, efficacy by PD-L1 expression,
safety, QoL
Pts with stage IIIB/IV
squamous NSCLC and ECOG
PS 0-1 with failure of 1
previous platinum doublet
chemotherapy
(N = 272)
Nivolumab 3 mg/kg IV q2w
(n = 135)
Docetaxel 75 mg/m2 IV q3w
(n = 137)
Until disease
progression or
unacceptable toxicity
Stratified by previous paclitaxel
therapy (yes vs no) and region
Spigel DR, et al. ASCO 2015. Abstract 8009. Brahmer J, et al. N Engl J Med. 2015;[Epub ahead of print].
28. CheckMate 017: Baseline Characteristics
Characteristic
Nivolumab
(n = 135)
Docetaxel
(n = 137)
Median age, yrs (range) 62 (39-85) 64 (42-84)
Male, % 82 71
Current/former smoker, % 90 94
ECOG PS 1, % 79 73
Stage IV disease,* % 78 82
CNS metastasis, % 7 6
Prior paclitaxel, % 34 34
PD-L1 expression,† %
≥ 1%
≥ 5%
≥ 10%
Not quantifiable
47
31
27
13
41
29
24
21
*Stage not reported in 1 pt in the nivolumab and 1 pt in the docetaxel groups.
†83% of pts had quantifiable PD-L1 expression. PD-L1 expression measured in pre-treatment tumor
biopsies with validated, automated immunohistochemical assay using PD-L1 antibody clone 28–8.
Spigel DR, et al. ASCO 2015. Abstract 8009. Brahmer J, et al. N Engl J Med. 2015;[Epub ahead of print].
29. Overall survival, PFS, and response: CheckMate 017
PFSOS
Reckamp K, et al. Presented at WCLC 2015, Abstract 736.
Nivolumab
(n=135)
Docetaxel
(n=137)
HR
Median OS, months 9.2 6.0 HR = 0.62 (0.48, 0.81); P =
0.0004
Median PFS, months 3.5 2.8 HR = 0.63 (0.48, 0.83); P =
0.0008
ORR, % 20 9 P = 0.008
Median DOR, months NR 8.4
Nivolumab
Docetaxel
12-mo OS rate = 42%
12-mo OS rate = 24%
OS(%)
Time (months)
30
100
90
80
70
60
50
40
30
10
0
20
33211815129630 2724
18-mo OS rate = 28%
18-mo OS rate = 13%
Nivolumab
Docetaxel
12-mo PFS rate = 21%
12-mo PFS rate = 6.4%
PFS(%)
Time (months)
30
100
90
80
70
60
50
40
30
10
0
20
211815129630 2724
18-mo PFS rate = 17%
18-mo PFS rate = 2.7%
30. OS and PFS by PD-L1 expression: CheckMate 017
83% de los pacientes: expresión de PD-L1 cuantificable
Beneficio independiente del nivel de expresión de PD-L1
PD-L1
expressiona
Patients, n Unstratified
HR (95% Cl)
Interaction
P-valueNivolumab Docetaxel
OS
≥1% 63 56 0.69 (0.45, 1.05)
0.56
<1% 54 52 0.58 (0.37, 0.92)
≥5% 42 39 0.53 (0.31, 0.89)
0.47
<5% 75 69 0.70 (0.47, 1.02)
≥10% 36 33 0.50 (0.28, 0.89)
0.41
<10% 81 75 0.70 (0.48, 1.01)
NQ 18 29 0.39 (0.19, 0.82)
PFS
≥1% 63 56 0.67 (0.44, 1.01)
0.70
<1% 54 52 0.66 (0.43, 1.00)
≥5% 42 39 0.54 (0.32, 0.90)
0.16
<5% 75 69 0.75 (0.52, 1.08)
≥10% 36 33 0.58 (0.33, 1.02)
0.35
<10% 81 75 0.70 (0.49, 0.99)
NQ 18 29 0.45 (0.23, 0.89)
PD-L1-negative expression
PD-L1-positive expression
NQ
0.25 1.0 2.0
Nivolumab Docetaxel
0.50.125
aPD-L1 expression was measured in pretreatment tumor biopsies (DAKO)
1. Brahmer J, et al. New Engl J Med. 2015;373:123–135. 2. Rizvi NA, et al. Lancet Oncol. 2015;16:257–265.
HR ± 95% CI
31. CheckMate 057: Nivolumab vs Docetaxel in
Previously Treated Non-Squamous NSCLC
Open-label, randomized phase III trial
Primary endpoint: OS
Secondary endpoints: ORR, PFS, efficacy by PD-L1 expression,
safety, QoL
Pts with stage IIIB/IV
squamous NSCLC and ECOG
PS 0-1 with failure of 1
previous platinum doublet
chemotherapy
(N = 582)
Nivolumab 3 mg/kg IV q2w
(n = 292)
Docetaxel 75 mg/m2 IV q3w
(n = 290)
Until disease
progression or
unacceptable toxicity
Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus
Docetaxel in Advanced Nonsquamous Non–Small-Cell Lung Cancer. New England Journal of
Medicine. 2015 Sep 27;:150927150118000–13.
33. Overall survival and PFS: CheckMate 057
Paz-Ares L, et al. Presented at ASCO 2015, Abstract LBA109.
PFSOS
Nivolumab
Docetaxel
1-yr OS rate = 51%
1-yr OS rate = 39%
OS(%)
Time (months)
100
90
80
70
60
50
40
30
10
0
20
27211815129630 24
Nivolumab
Docetaxel
1-yr PFS rate = 19%
1-yr PFS rate = 8%
PFS(%)
Time (months)
100
90
80
70
60
50
40
30
10
0
20
27211815129630 24
Nivolumab
(n=292)
Docetaxel
(n=290)
HR
Median OS,
months 12.2 9.4 HR = 0.73 (96% CI: 0.59, 0.89); P = 0.0015
Median PFS,
months 2.3 4.2 HR = 0.92 (95% CI: 0.77, 1.11); P = 0.3932
ORR, % 19 12 P = 0.0246
Median DOR,
months 17.2 5.6
34. OS by PD-L1 expression: CheckMate 057
PD-L1 expression was predictive of benefit with nivolumab
Nivo
Doc
100
90
80
70
60
50
40
30
10
0
20
Time (months)
242118151
2
9630 27
Median
OS(mo)
Nivo 10.4
Doc 10.1
Median OS
(mo)
Nivo 17.2
Doc 9.0
≥1% PD-L1 expression
level
HR (95% CI)=0.59 (0.43, 0.82)
<1% PD-L1 expression
level
OS(%)
HR (95% CI)=0.90 (0.66, 1.24)
OS(%)
242118151
2
9630 27
100
90
80
70
60
50
40
30
10
0
20
Nivo
Doc
1. Paz-Ares L, et al. Presented at ASCO 2015, Abstract LBA109.
2. 2. Rizvi NA, et al. Lancet Oncol 2015;16:257–265.
PD-L1
expression level
Median OS (mo)
HR
Nivolumab Docetaxel
≥5%
<5%
18.2
9.7
8.1
10.1
HR (95% CI) = 0.43 (0.30, 0.63)
HR (95% CI) = 1.01 (0.77, 1.34)
≥10%
<10%
19.4
9.9
8.0
10.3
HR (95% CI) = 0.40 (0.26, 0.59)
HR (95% CI) = 1.00 (0.76, 1.31)
35. Overall survival by PD-L1 expression levels
Median OS
(months)
Nivo 17.7
Doc 9.0
Median OS
(months)
Nivo 19.4
Doc 8.1
Median OS
(months)
Nivo 19.9
Doc 8.0
Median OS
(months)
Nivo 10.5
Doc 10.1
Median OS
(months)
Nivo 9.8
Doc 10.1
Median OS
(months)
Nivo 9.9
Doc 10.3
≥1% PD-L1 expression level
Time (mos)
100
90
80
70
60
50
40
30
10
0
20
3024211815129630 27
OS(%)
HR (95% CI) = 0.58 (0.43, 0.79)
≥5% PD-L1 expression level100
90
80
70
60
50
40
30
10
0
20
3024211815129630 27
Time (mos)
HR (95% CI) = 0.43 (0.30, 0.62)
≥10% PD-L1 expression level100
90
80
70
60
50
40
30
10
0
20
3024211815129630 27
Time (mos)
HR (95% CI) = 0.40 (0.27, 0.58)
<1% PD-L1 expression level
100
90
80
70
60
50
40
30
10
0
20
3024211815129630 27
Time (mos)
OS(%)
Nivo
Doc
<10% PD-L1 expression level100
90
80
70
60
50
40
30
10
0
20
3024211815129630 27
Time (mos)
<5% PD-L1 expression level
100
90
80
70
60
50
40
30
10
0
20
3024211815129630 27
Time (mos)
HR (95% CI) = 0.87 (0.63, 1.19) HR (95% CI) = 0.96 (0.73, 1.27) HR (95% CI) = 0.96 (0.74, 1.25)
Based on a July 2, 2015 database lock.
Borghaei H, et al. N Engl J Med. 2015;373:1627-1639.
Nivo
Doc
36. Phase 2, single-arm study, stage IIIB/IV squamous NSCLC
65% of patients ≥3 prior systemic therapies; CheckMate 063
All patients
IRC assessed
(per RECIST
v1.1)
(N=117)
ORR, %a 15
Median DOR, mosa NR
Ongoing responders, %a 76
PFS rate at 1 year, %a 20
Grade 3–4 treatment-related AEs,
%
Fatigue
Diarrhea
Rash
17
4
3
1
IRC = independent review committee; NR = not reached
Horn L, et al. Presented at WCLC 2015, Abstract 828.
Nivolumab
Median OS = 8.1 mos
117 93 68 51 28 5 0 0 00
117 93 69 54 45 38 30 24 06
July 2014 DBL
June 2015 DBL
Number of Patients at Risk
Nivolumab 3 mg/kg
18-mos OS = 27%
OS(%)
Time (months)
100
90
80
70
60
50
40
30
10
0
20
27211815129630 24
37. Vansteenkiste et al. Ann Oncol 2015; 26 (suppl 6): abstr 14LBA
Atezolizumab monotherapy vs docetaxel in 2L/3L non-small cell lung cancer:
Primary analyses for efficacy, safety and predictive biomarkers from a randomized
phase II study (POPLAR)
38. Atezolizumab was associated with significant improvements in OS in the ITT population
Median OS for atezolizumab was 12.6 months compared with 9.7 months for
docetaxel (HR 0.73 [95%CI 0.53, 0.99], p=0.040)
POPLAR: all patient efficacy
ITT OS (n=287)
Vansteenkiste et al. Ann Oncol 2015; 26 (suppl 6): abstr 14LBA
39. Subgroup (% of enrolled patients)
0.2 21
0.80
0.69
0.73
Hazard Ratio
In favor of atezolizumab In favor of docetaxel
ITT (N=287)
Squamous (34%)
Non-Squamous (66%)
Median OS (95% CI), mo
Atezolizumab Docetaxel
10.1 (6.7, 14.5) 8.6 (5.4, 11.6)
15.5 (9.8, NE) 10.9 (8.8, 13.6)
12.6 (9.7, 16.4) 9.7 (8.6, 12.0)
Vansteenkiste et al. Ann Oncol 2015; 26 (suppl 6): abstr 14LBA
POPLAR: OS by histology
40. • Patients with higher PD-L1 expression demonstrated improved OS with atezolizumab
• Tumour cells and tumour-infiltrating immune cells were both independent predictors of
survival improvement with atezolizumab
TC3 or IC3 (high) TC2/3 or IC2/3
TC1/2/3 or IC1/2/3 TC0 or IC0
41. Besse et al. Ann Oncol 2015; 26 (suppl 6): abstr 16LBA
Phase II, single-arm trial (BIRCH) of atezolizumab as first-line or subsequent
therapy for locally advanced or metastatic PD-L1-selected non-small cell
lung cancer (NSCLC)
42. ORR by line of therapy
TC3 or IC3 and TC2/3 or IC2/3 subgroups
Besse et al. Ann Oncol 2015; 26 (suppl 6): abstr 16LBA
43. Besse et al. Ann Oncol 2015; 26 (suppl 6): abstr 16LBA
BIRCH: Overall Survival by Line of Therapy
TC2/3 or IC2/3
Subgroup Median OS, mo
(95% CI)
6-mo OS,
%
1L (Cohort 1) 14.0 (14.0, NE) 82%
2L (Cohort 2) NE (11.2, NE) 76%
3L+ (Cohort 3) NE (8.4, NE) 71%
44. Besse et al. Ann Oncol 2015; 26 (suppl 6): abstr 16LBA
Subgroup Median OS, mo
(95% CI)
6-mo OS,
%
1L (Cohort 1) NE (10.4, NE) 79%
2L (Cohort 2) NE (10.6, NE) 80%
3L+ (Cohort 3) NE (NE, NE) 75%
BIRCH: Overall Survival by Line of Therapy
TC3 or IC3
45. KEYNOTE-001: Subanalysis of Phase I
Pembrolizumab Trial in NSCLC
Administered tumor assessment: imaging every 9 wks
• Primary: RECIST v.1.1 (independent central
review)
• Secondary: immune-related response criteria
(irRC; investigator assessed)
• Tumor biopsy
• Tumor biopsy within 60 days prior to
first dose of pembrolizumab required
• Tumor PD-L1 expression determined
by prototype assay to inform
enrollment; Samples were
independently reanalyzed using
clinical trial IHC assay
Treatment-naive
or previously
treated
advanced
NSCLC
(N = 495)
Pembrolizumab IV
2 mg/kg q3w (n = 6)
Mandatory tumor biopsy
Pembrolizumab IV
10 mg/kg q3w (n = 287)
Pembrolizumab IV
10 mg/kg q2w (n = 202)
CR, PR, SD
PD, unacceptable
AE, or investigator
decision
Continue dosing
and assessments
every 9 wks
Off study
Garon EB. N Engl J Med. 2015 May 21;372(21):2018–28.
46. PD-L1 NSCLC Sample IHC Staining
Negative Weak positive
(1% to 49%)
PD-L1 = 0% positive PD-L1 = 2% positive PD-L1 = 100% positive
Strong positive
(50% to 100%)
Garon EB. N Engl J Med. 2015 May 21;372(21):2018–28.
47. 100
80
60
40
20
0
Keynote-001: Pembrolizumab Efficacy in Overall Population
All cohorts N ORR by RECIST, % (95% CI)
Total 495 19.4 (16.0-23.2)
Treatment naive 101 24.8 (16.7-34.4)
Previously treated 394 18.0 (14.4-22.2)
Nonsquamous 401 18.7 (15.0-22.9)
Squamous 85 23.5 (15.0-34.0)
PFS OS100
80
60
40
20
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Mos
PFS,%
OS,%
0 4 8 12 16 20 24
Mos
28
All patients
Previously treated
Treatment-naïve
All patients
Previously treated
Treatment-naïve
Garon EB. N Engl J Med. 2015 May 21;372(21):2018–28.
52. Checkpoint inhibitors in 2/3L NSCLC
POPLAR
PhII allcomer 2/3L
atezo vs. doc
(n=287)
CheckMate 017
PhIII 2L Sq nivo vs. doc
(n=272)
CheckMate 057
PhIII 2L NSq nivo vs. doc
(n=582)
KEYNOTE-001
PhIb (inc. NSCLC)
pembro
(n=394 for
previously treated)
ORR,
%
Atezo 15% vs doc 15% Nivo 20% vs doc 9% Nivo 19% vs doc 12% Pembro 18%
Notes G3–4 treatment-related
AEs: 12 vs 39%
G3–4 treatment-related
AEs: 7 vs 55%
Reduction from baseline in lung
cancer symptoms with
nivolumab
G3–4 treatment-related
AEs: 10 vs 54%
Low incidence of
immune-related AEs
Refs. Spira, et al. ASCO 2015 Spigel, et al. ASCO 2015
Reckamp, et al. WCLC 2015
Gralla, et al. WCLC 2015
Paz-Ares, et al. ASCO 2015 Garon, et al. AACR 2015
Nivo
OS
Doc
OS
Pem
OS
Pem
PFS
Atezo
OS
Nivo
PFS
Doc
PFS
Nivo
OS
Doc
OS
Nivo
PFS
Doc
PFS
Doc
OS
Atezo
PFS
Doc
PFS
HR 0.59
p=0.00025
HR 0.62
p=0.0004
HR 0.73
p=0.0015
HR 0.92
p=0.3932
HR 0.77
p=0.1071
HR 0.98
p=0.8606
53. Durvalumab plus tremelimumab in NSCLC: phase 1b study
Antonia, S. Lancet Oncol 2016. Published Online February 5, 2016;
http://dx.doi.org/10.1016/S1470-2045(15)00544-6
Durvalumab: 3 mg/kg, 10 mg/kg, 15 mg/kg, or 20 mg/kg every 4 w, or 10 mg/kg every 2 w
Tremelimumab: 1, 3, or 10 mg/kg every 4 w for six doses then every 12 w for three doses
Durvalumab 10-20 mg/kg every 2 weeks or 4 weeks
plus tremelimumab 1 mg/kg (n=56)
Grado 1/2
%
Grado 3
%
Grado 4
%
Grado 5
%
Diarrea 17 7 0 0
Colitis 2 2 0 0
Enteritis 0 2 0 0
Prurito 20 0 0 0
Rash 11 0 0 0
Hipotiroidismo 7 2 0 0
Incremento amilasa 14 0 2 0
Incremento GPT/GOT 7/2 2/4 2/2 0
54. Durvalumab 10-20 mg/kg every 2 weeks or 4 weeks plus
tremelimumab 1 mg/kg
Todos los pacientes evaluables; %; n=52
Tasa de respuestas 23
Control de enfermedad 35
PD-L1-positivo (>25%); %; n=18
Tasa de respuestas 22
Control de enfermedad 33
PD-L1 negativo (<25%); %; n=28
Tasa de respuestas 29
Control de enfermedad 43
PD-L1 negativo (0%); %; n=20
Tasa de respuestas 40
Control de enfermedad 50
63. Grado
CTCAE
Tipo de
cuidado Corticoides
Otros
fármacos
inmunosupresores
Inmunoterapia:
actitud
posterior
1 Ambulatorio No recomendado No Continuar
2 Ambulatorio Cortic tópicos
Cort sistémicos:
0.5-1 mg/kg/d
No Suspender
temporalmente
(excepto
cutánea/endoc
rina)
3 Hospitalización Cort sistémicos
1-2 mg/kg/d x 3 d;
pauta descendente
Considerar si no se
resuelve tras 3-5 d
con corticoides
Suspender y
discutir
riesgo/benefici
o
4 Hospitalización;
Considerar UCI
Cortic iv: 6-MP
1-2 mg/kg/d x 3 d;
reducir
Considerar si no se
resuelve tras 3-5 d
con corticoides
Discontinuar
Infliximab si no mejoría en 3 días
66. McLaughlin J, Han G, Schalper KA, Carvajal-Hausdorf D, Pelakanou V, Rehman J, et al.
Quantitative Assessment of the Heterogeneity of PD-L1 Expression in Non–Small-Cell Lung
Cancer. JAMA Oncol. 2015 Nov 12;:1–9.
67. N=160
PD-L1: TC and IC
Overall discordance
rate:
48%
Ilie M, Ann Oncol. 2015 Oct 19;:mdv489–7.
Comparative study of the PD-L1 status between surgically resected
specimens and matched biopsies of NSCLC patients reveal major
discordances: a potential issue for anti-PD-L1 therapeutic strategies
68. En todos los casos
discordantes la
biopsia infravaloró
el resultado del
especimen
quirúrgico,
fundamentalmente
en células inmunes
Ilie M, Ann Oncol. 2015 Oct 19;:mdv489–7.
69. Eficacia y seguridad
Grado de innovación del fármaco
Necesidad no cubierta
Severidad de la enfermedad
Biomarcador eficiente y seguro
Coste
70.
71. Para concluir…
Inmunoterapia en cáncer de pulmón:
funciona
Cambio de estándar en segunda línea
Futuro: combinaciones
Múltiples checkpoints
Radioterapia
Quimioterapia
Necesitamos biomarcadores
Anti-PD1 vs Anti-PDL1??
Mecanismos de resistencia
74. Adaptación darwiniana del Oncólogo Médico
1960
Internista
1ª mutación +
1979
Quimioterapeuta
Vía muerta
75. Adaptación darwiniana del Oncólogo Médico
1960
Internista
1ª mutación +
2ª mutación +
1979
Quimioterapeuta
Vía muerta
1984
O. Médico
Oncólogo
insuficiente
76. Adaptación darwiniana del Oncólogo Médico
1960
Internista
1ª mutación +
2ª mutación +
3ª mutación +
1979
Quimioterapeuta
Vía muerta
1984
O. Médico
Oncólogo
insuficiente
2000
O. Médico
Molecular
Oncólogo
moderno
77. Adaptación darwiniana del Oncólogo Médico
1960
Internista
1ª mutación +
2ª mutación +
3ª mutación +
4ª mutación +
1979
Quimioterapeuta
Vía muerta
1984
O. Médico
Oncólogo
insuficiente
2000
O. Médico
Molecular
Oncólogo
moderno
2010
O. Médico
Molecular
Inmunólogo
Oncólogo
del futuro
78. No hay una clara asociación entre la expresión de PD-
L1 y la histología del CP
100
80
60
40
20
0
Non-squamous
14/30 (47%)
Squamous
11/29 (38%)
PD-L1 IHC
5% cut-off
NSCLC histology
PD–L1tumor
membranestaining(%)
PD-L1–positive
PD-L1–negative
Harbison CT, et al. Poster presented at ELCC 2014 (Abstract 102P).
79. In a meta-analysis, PD-L1 expression by IHC was related to worse prognosis (HR=1.72; 95% CI: 1.32–2.24)
• PD-L1 positivity by QIF alone could not show any predictive value
Study or
subgroup
log [hazard
ratio] SE Weight
Hazard ratio
IV, fixed, 95%
CI Year
Hazard ratio
IV, fixed, 95% CI
8.1.1 IHC
Mu 2011
Ma 2011
Chen YB 2012
Azuma 2014
Zhang 2014
Yang 2014
Subtotal (95%CI)
0.65
0.19
1.02
0.2
0.5
0.09
0.28
0.89
0.26
0.22
0.53
0.73
15.3%
1.5%
17.7%
24.7%
4.3%
2.2%
65.7%
1.92 [1.11, 3.32]
1.21 [0.21, 6.92]
2.77 [1.67, 4.62]
1.22 [0.79, 1.88]
1.65 [0.58, 4.66]
1.09 [0.26, 4.58]
1.72 [1.32, 2.24]
2011
2011
2012
2014
2014
2014
Heterogeneity: Chi2 = 6.49, df = 5 (P = 0.26); I2 = 23%
Test for overall effect: Z = 4.01 (P < 0.0001)
8.1.2 QIF
Velcheti (US) 2014
Velcheti (Greece) 2014
Subtotal (95% CI)
–0.23
0.26
0.32
0.23
11.7%
22.6%
34.3%
0.79 [0.42, 1.49]
1.30 [0.83, 2.04]
1.10 [0.76, 1.58]
2014
2014
Heterogeneity: Chi2 = 1.55, df = 1 (P = 0.21); I2 = 35%
Test for overall effect: Z = 0.50 (P = 0.62)
Total (95% CI)
Heterogeneity: Chi2 = 11.81, df = 7 (P = 0.11); I2 = 41%
Test for overall effect: Z = 3.54 (P = 0.0004)
Test for subgroup differences: Chi2 = 3.78, df = 1 (P = 0.05); I2 = 73.5%
100.0%
1.47 (1.19,
1.83)
PD-L1 expression may be predictive of worse prognosis
QIF = quantitative immunofluorescence.
Pan ZK, et al. J Thorac Dis. 2015;7(3):462-470.
0.1 0.2 0.5 1 2 5 10
Favors (PD-L1–) Favors (PD-L1+)
80. Pembro
10 mg/kg
Q3W
Nonrandomized
(N = 38)
• PD-L1+ or PD-L1–
tumors
• ≥2 previous
therapies
Randomized
(N = 280)
• PD-L1+ tumors
• ≥1 previous
therapy
Pembro
10 mg/kg
Q3W
Pembro
10 mg/kg
Q2W
R
(3:2)
Pembro
10 mg/kg
Q2W
Nonrandomized
(N = 43)
• PD-L1– tumors
• ≥1 previous
therapies
Pembro
10 mg/kg
Q3W
Nonrandomized
(N = 33)
• PD-L1+ tumors
• ≥2 previous
therapies
Pembro
2 mg/kg
Q3W
Nonrandomized
(N = 55)
• PD-L1+ tumors
• ≥1 previous
therapies
• Patients with tumors of any histology eligible
• Treatment continued until confirmed disease progression, intolerable toxicity, or other reason
• Response assessed every 9 weeks per RECIST v1.1 per central reviewa
• PD-L1 assessment1
• Enrollment: Prototype assay using the Merck 22C3 antibody
• Relationship with efficacy: Dako PD-L1 IHC 22C3 pharmDx™ Assay
aTreatment decisions were managed per irRC by investigator review.
1. Garon EB et al. N Engl J Med. 2015;372:2018-20.
Soria et al. Ann Oncol 2015; 26 (suppl 6): abstr 33LBA
Efficacy and Safety of Pembrolizumab (MK-3475) for Patients With Previously
Treated Advanced NSCLC Enrolled in KEYNOTE-001
