2015 11 Inmunoterapia en nsclc

Coley, Am J Med Sci 1893;105:487-510

ILC, innate lymphoid cell; NK, natural killer.
Abbas AK et al. Cellular and Molecular Immunology. 8th ed. Philadelphia, PA: Elsevier Saunders; 2015.
Tipos de respuesta inmune:
innata y adquirida

AIS: Lymph, APCs and Effector cells
Antigen Recognition Effector Functions
B lymphocyte
Helper T
lymphocyte
Cytotoxic T
lymphocyte
(CTL)
Regulatory
T lymphocyte
Microbe
Neutralization of
microbe,
phagocytosis,
complement
activation
Activation of
macrophages
Inflammation
T and B lymphocyte
proliferation/
differentiation
Killing of
infected cells
Suppression of
other lymphocytes
Antibody
Cytokines
Microbial antigen
presented
by antigen-
presented cell
Infected cell expressing
microbial antigen

Clinical observations and animal experiments have established that
although tumour cells are derived from host cells, they elicit immune
responses [because they have tumor Ags]
Immuno-Oncology: The Rationale
Tumor
Microenvironment

Estudio años 50

• The immune system can identify and
eliminate tumor cells based on their
expression of tumor-specific antigens1-
3
• An ideal cancer antigen:1
– Specifically and stably expressed
by the tumour
– Absent from normal tissues
– Crucial for survival of cancer cell
Tumour Antigens
1. Simpson AJ et al. Nat Rev Cancer. 2005;5(8):618-625.
2. 2. Cabellero OL, Chen Y-T. Cancer Sci. 2009; 100(11):2014-2021.
Tumor cell
Tumor
antigen
Microbial proteins/
mutated proteins/
fusion proteins

Tipo de antígeno Ejemplos
Productos de oncogenes mutados y de
genes supresores tumorales
Productos de oncogenes: mutaciones
Ras (10% de los carcinomas), p210
(producto de reordenamiento bcr/abl)
Productos de genes supresores: p53
mutado (en el 50% de los tumores)
Productos de oncogenes no mutados
pero sobreexpresados
HER2neu (mama, otros)
Formas mutadas de genes celulares no
involucradas en tumorogénesis
Varias proteínas mutadas en
melanoma reconocidas por
liinfocíticos T citotóxicos
Productos de genes que son silentes
en tejidos normales
Antígenos de cáncer /testículo
expresados en melanoma y muchos
carcinomas; normalmente expresados
en testículos y placenta
Antígenos tumorales

Tipo de antígeno Ejemplos
Proteínas no-oncogénicas normales
sobreexpresadas en células tumorales
Tirosinasa, gp100, MART en
melanomas (normalmente expresados
en melanocitos)
Productos de virus oncogénicos Proteínas del papilomavirus E6 y E7
(carcinoma cervical)
Proteína EBNA-1 del EBV (linfomas,
carcinoma nasofaríngeo)
Antígenos oncofetales CEA; AFP
Glicolípidos y glicoproteínas GM2; GD2 en melanomas
Antígenos de diferenciación
normalmente presentes en tejido de
origen
PSA en carcinoma de próstata
CD20 en linfomas B
Antígenos tumorales

Tumour Immunity: Immune Surveillance
Chen DS, Mellman I. Immunity 2013; 39:1-10.

Inmunoedición
Dorff TB. Ther Adv Med Oncol. 2009 Nov;1(3):183–205.

Los tumores pueden evadir el sistema inmune
Mechanisms of Tumor Immune Escape
Specialized tumour mechanisms for evading
host immune responses
Poor immunogenicity of tumour
Rapid growth and spread may overwhelm the
capacity of the immune system to effectively
control the tumour
Razones potenciales por las que la respuesta antitumoral es incapaz de
erradicar las células transformadas
Tumor
Microenvironment

Los tumores usan mecanismos complejos
para evadir y suprimir el sistema inmune
1. Drake CG et al. Adv Immunol. 2006;90:51-81.
2. 2. Vesely MD et al. Annu Rev Immunol. 2011;29:235-271.
Inhibition of tumour antigen
presentation
eg, down-regulation of MHC I
1APC

presentation
1APC
Secretion of
immunosuppressive factors
eg, TGF-β
2
Tumour
cell

presentation
1APC
Secretion of
eg, TGF-β
2
Tumour
cell
Inhibition of attack by
immune cells
eg, disruption of T-cell
checkpoint pathways
3
Inactive
T cell

presentation
1APC
Secretion of
eg, TGF-β
2
Tumour
cell
Inhibition of attack by
immune cells
eg, disruption of T-cell
checkpoint pathways
3
Inactive
T cell
Recruitment of
immunosuppressive cell types
eg, Treg
4

T-Cell Activation: Priming
Two signals in a T-cell response govern whether the cell will be activated
or inhibited1
– The primary signal takes place when antigens are presented through the major
histocompatibility complex to the T-cell receptor2
– The secondary signal may be a co-stimulatory or a co-inhibitory signal, which
will lead to T-cell activation or T-cell inhibition, respectively1,2
1. Pardoll DM. Nat Rev Cancer. 2012;12(4):252-264. 2. Weber J. Semin Oncol. 2010;37(5):430-439.
T cell
APC
Primary Signal
MHC
TCR
T cell
APC
Secondary Signal
MHC
TCR
1 1 2

T-Cell Regulation: Checkpoint Pathways
Activation of T cells depends on the balance of the co-stimulatory and co-
inhibitory signals, which are also known as checkpoint pathways1,2
Activates T cell
T cell
APC
Co-stimulatory signal
MHC
TCR
Co-
stimulatory
1 2
Inhibits T cell
T cell
APC
Co-inhibitory signal
MHC
TCR
Co-
inhibitory
1 2
1. Pardoll DM. Nat Rev Cancer. 2012;12(4):252-264. 2. Weber J. Semin Oncol. 2010;37(5):430-439.

Checkpoint Pathways
Pardoll DM. Nat Rev Cancer. 2012;12(4):252-264.
APC/
Tumor
T cell
B7-DC(PD-L2)
CD40 CD40L
CD137
OX40
CD137L
OX40L
MHC
CD28B7-2 (CD86)
TCR
Activation
Inhibition
Inhibition
Inhibition
Activation
Activation
Activation
Inhibition
The number of
molecules regulating T-
cell activation is high and
the system is very
complex
The expression of certain
molecules and their
interaction with receptors
in the T cell cause either
activation or inhibition of
the T cell
Adapted from Pardoll, 2012.
“Brakes”
to
the
immune
reaction
PD-1
B7-1 (CD80)
B7-H1(PD-L1)
LAG-3
B7-1 (CD80) CTLA-4

Chen DS, Mellman I. Immunity 2013; 39:1-10.

De la teoría a la práctica
Tumor MicroenvironmentLymph Node
CTLA-4, cytotoxic T-lymphocyte antigen-4; PD-1, programmed death-1.
Pardoll DM. Nat Rev Cancer. 2012;12(4):252-264.
CTLA-4 pathway PD-1 pathway
CTLA-4B7-1 (CD80
PD-1
PD-L1 (B7-H1)MHC
TCR
MHC
TCR

Over the last several years, multiple compounds targeting CTLA-4 or PD-1/PD-L1
have been developed:
PD-1:
• Nivolumab [BMS]
• Pembrolizumab [MSD]
• Pidilizumab [Medivation]
• AMP-514 [MedImmune/Amplimmune]
• AMP-224 [MedImmune/Amplimmune]
• PDR001 [Novartis]
PD-L1:
• Atezolizumab/MPDL3280A [Roche/Genentech]
• BMS-936559 [BMS]
• Durvalumab/MEDI4736 [MedImmune/AZ]
• Avelumab/MSB0010718C [EMD Serono/Merck KGaA/Pfizer]
Targeting the CTLA-4 and PD-1
Checkpoint Pathways
CTLA-4:
• Ipilimumab [BMS]
• Tremelimumab [MedImmune/AZ]

¿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

Mayor M, European Journal of Cardio-Thoracic Surgery. 2015 Oct 29;:ezv371–10.

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

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

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

CTLA-4 = cytotoxic T-lymphocyte-associated protein 4
PD-1 = programmed death 1; PD-L1 = programmed death ligand 1
Please note that atezolizumab has not received regulatory approval in any country yet
1. Mellman, et al. Nature 2011
2. Chen & Mellman. Immunity 2013
7
Killing of cancer cells
(immune and cancer cells)
Anti-CTLA-4
CTLA-4 is a major negative regulator of T cell activationand
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)
CD28
OX40
GITR
CD137
CD27
HVEM
CTLA-4
PD-1
TIM-3
BTLA
VISTA
LAG-3
T cell targets for modulating activity
Activating
Receptors
Inhibitory
Receptors
T cell
stimulation
Agonistic
Antibodies
Blocking
Antibodies
T cell

Pennell NA. Understanding the Rationale for Immunotherapy in Non-Small Cell Lung Cancer.
Seminars in Oncology. 2015 Oct;42 Suppl 2:S3–S10.

Chemoterapy-
naïve stage
IIIB/IV NSCLC
(n=204)
R
A
N
D
O
M
I
Z
E
Concurrent ipilimumab +
P/C (n=70)
Phased ipilimumab + P/C
(n=68)
Placebo+ P/C
(n=66)
Ipilimumab q 12
weeks
Ipilimumab q 12
weeks
Placebo q 12 weeks
1:1:1
- P/C: 175 mg/m2 paclitaxel + AUC=6 carboplatin q 3 weeks x 6 doses
- Concurrent ipilimumab: 10 mg/kg q 3 weeks x 4 doses
- Phased ipilimumab: placebo q 3 weeks x 2 doses followed by IPI q 3 weeks x 4 doses
- Primary endpoint: inmune-related PFS (irPFS)
Lynch. Journal of Clinical Oncology. 2012 Jun 8;30(17):2046–54.

Lynch. Journal of Clinical Oncology. 2012 Jun 8;30(17):2046–54.
Phased ipilimumab regimen improved WHOPFS in patients with
squamous histology: HR: 0.40 (95% CI, 0.18-0.87)

Zielinski; Ann Oncol 2013,24(5):1170-1179

Gettinger SN. J Clin Oncol; 2015 Jun 20;33(18):2004–12.
NIVOLUMAB: phase I dose-escalation cohort expansion trial
N=129
RR:17%

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].

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.

CheckMate 017: OS in the ITT Population
0 3 6 9 12 15 18 21 24
100
80
60
40
20
0
OverallSurvival
(%ofPatients)
MosAt Risk, n
Nivolumab
Docetaxel
135
137
113
103
86
68
69
45
52
30
31
14
15
7
7
2
0
0
HR for death, 0.59 (0.44-0.79)
P < .001
Nivolumab
Docetaxel
Median OS
Months (95%CI)
1-yr OS
% of patients
(95%CI)
Nivolumab (n=135) 9.2 (7.3-13.3) 42 (34-50)
Docetaxel (n=137) 6.0 (5.1-7.3) 24 (17-31)

Brahmer, J. NEJM 2015;373:123-35
Variable Nivolumab
(n=135)
Docetaxel
(n=137)
Objective response (%) 20 9
Odds ratio (95% CI) 2.6 (1.3-5.5)
p value 0.008

Brahmer, J. NEJM 2015;373:123-35
Duración de la respuesta: NR nivolumab, 8.4 m docetaxel
Mediana número de ciclos: 8 nivolumab, 3 docetaxel

Brahmer, J. NEJM 2015;373:123-35

CheckMate 017: Tx-Related Aes
Treatment-Related AEs
≥ 10%, %
Nivolumab (n = 131) Docetaxel (n = 129)
Any Grade Grade 3/4 Any Grade Grade 3/4
All events 58 7 86 55
Leading to discontinuation 3 2 10 7
Fatigue 16 1 33 8
Decreased appetite 11 1 19 1
Asthenia 10 0 14 4
Nausea 9 0 23 2
Diarrhea 8 0 20 2
Vomiting 3 0 11 1
Myalgia 2 0 10 0
Anemia 2 0 22 3
Peripheral neuropathy 1 0 12 2
Neutropenia 1 0 33 30
Febrile neutropenia 0 0 11 10
Alopecia 0 0 22 1
Spigel DR, et al. ASCO 2015. Abstract 8009. Brahmer J, et al. N Engl J Med. 2015; [Epub ahead of print].

CheckMate 017: Select Tx-Related irAEs
Treatment-Related irAEs, %
Endocrine
 Hypothyroidism
4
4
0
0
0
0
0
0
Gastrointestinal
 Diarrhea
 Colitis
8
8
1
1
0
1
20
20
0
2
2
0
Hepatic
 ALT increase
 AST increase
2
2
2
0
0
0
2
1
1
1
1
1
Pulmonary
 Pneumonitis
 Lung infiltration
 Interstitial lung disease
5
5
1
0
1
1
0
0
1
0
0
1
0
0
0
0
Renal
 Blood creatinine increase
 Tubulointestinal nephritis
3
3
1
1
0
1
2
2
0
0
0
0
Skin 9 0 9 2
Hypersensitivity/infusion reaction 1 0 2 1
Spigel DR, et al. ASCO 2015. Abstract 8009. Brahmer J, et al. N Engl J Med. 2015; [Epub ahead of print].

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.

Borghaei H, New England Journal of Medicine. 2015 Sep 27;:150927150118000–13.
HR= 0.73 (96% CI, 0.59-0.89)
P=.0002
Median OS
Months (95%CI)
1-yr OS
% of patients
(95%CI)
Nivolumab (n=135) 12.2 (9.7-15) 51 (45-56)
Docetaxel (n=137) 9.4 (8.1-10.7) 39 (33-45)

Variable Nivolumab
(n=135)
Docetaxel
(n=137)
Objective response (%) 19 12
Duración de la respuesta: 17.2 nivolumab, 5.6 m docetaxel
Mediana número de ciclos: 6 nivolumab, 4 docetaxel

Predictive relationship of PD-L1 expression
level for efficacy of nivolumab

OS by PD-L1 expression

CheckMate 057: Safety Profile
Treatment-Related
Adverse Events, %
All events 69 10 88 54
Fatigue 16 1 29 5
Nausea 12 1 26 1
Decreased appetite 11 0 16 1
Asthenia 10 < 1 18 2
Diarrhea 8 1 23 1
Peripheral edema 3 0 10 < 1
Myalgia 2 < 1 11 0
Anemia 2 < 1 20 3
Alopecia < 1 0 25 0
Neutropenia < 1 0 31 27
Febrile neutropenia 0 0 10 10
Leukopenia 0 0 10 8
Paz-Ares L, et al. ASCO 2015. Abstract LBA109.

CheckMate 057: Select Tx-Related irAEs
Treatment-Related irAEs, %
Endocrine
Hypothyroidism 7 0 0 0
Gastrointestinal
Diarrhea 8 1 23 1
Hepatic
Increased ALT
Increased AST
3
3
0
< 1
1
1
< 1
0
Pulmonary
Pneumonitis 3 1 < 1 < 1
Skin
Rash
Pruritus
Erythema
9
8
1
< 1
0
0
3
1
4
0
0
0
Hypersensitivity/infusion reaction 3 0 3 < 1
Paz-Ares L, et al. ASCO 2015. Abstract LBA109.

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)

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)

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)
POPLAR: OS by histology

• 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

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)

ORR by line of therapy
TC3 or IC3 and TC2/3 or IC2/3 subgroups

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%

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

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.

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%)

100
80
60
40
20
0
Keynote-001: Pembrolizumab Efficacy in Overall
Population
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
ORR by RECIST, % (95% CI) N All Cohorts
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)
All patients
Previously treated
Treatment-naïve
All patients
Previously treated
Treatment-naïve

Keynote-001: Pembrolizumab Efficacy by PD-L1
Expression
PFS OS
Proportion score for 356 pts in training, validation groups with slides sectioned ≤ 6 months of staining
100
80
60
40
20
0
PFS,%
100
80
60
40
20
0
OS,%
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Months
0 4 8 12 16 20 24
Months
28
PS ≥ 50% (n = 119)
PS < 1% (n = 76)
PS 1 - 49% (n = 161)
PS ≥ 50% (n = 119)
PS < 1% (n = 76)
PS 1 - 49% (n = 161)
ORR by RECIST, % (95% CI) N All Cohorts
Percent PD-L1 staining
 ≥ 50% 73 45.2 (33.5-57.3)
 1% - 49% 103 16.5 (9.9-25.1)
 < 1% 28 10.7 (2.3-28.2)

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

Survival: Patients Treated at 10 mg/kg
Data cutoff date: January 23, 2015.
OS PFS
Median, mo
(95% CI)
6-mo
Rate, %
Median, mo
(95% CI)
6-mo
Rate, %
TPS ≥50% (n = 99) 15.5 (10.0-NR) 71.6 5.8 (2.1-10.3) 49.9
TPS 1%-49% (n = 127) 7.8 (5.8-12.4) 57.3 2.3 (2.1-3.4) 25.3
TPS <1% (n = 68) 8.6 (5.5-12.0) 57.1 2.1 (2.0-4.0) 23.2
Total (N = 394) 11.3 (8.8-14.0) 63.0 3.0 (2.2-4.0) 34.0
99 75 45 8 3 0
127 90 44 5 1 0
68 49 21 0 0 0
394 287 154 19 7 0
65
59
34
216
17
12
9
51
4
3
0
11
0 4 8 12 16 20 24 28 32
0
10
20
30
40
50
60
70
80
90
100
Time, months
OS,%

KEYNOTE-010: Phase II/III Pembrolizumab Trial in
NSCLC
• Primary endpoint: OS
• Secondary endpoints:
– PFS
– Safety
• Evaluations: at week 12; every 6 weeks therefore
• Subgroup of strongly PD-L1 + assessed
(>50%)
Pts with stage
IIIB/IV squamous
NSCLC and
ECOG PS 0-1 with
failure of 1
previous platinum
doublet
chemotherapy or
EGFR/ALK-
targeted agents
and PD-L1 + >1%
(N = 1034)
Pembrolizumab IV
2 mg/kg q3w (n = 6)
Pembrolizumab IV
10 mg/kg q3w (n = 287)
Docetaxel IV
75 mg/kg q3w (n = 202)
CR, PR, SD
PD, unacceptable
AE, or investigator
decision
Continue dosing
and assessments
every 9 wks
Off study

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

Combination therapy: 1L NSCLC
PD-L1/PD-1 inhibitors are being combined with chemotherapy
and other immunotherapies in the 1L setting
GP28328
PhIb solid tumours (incl.
1L NSCLC) atezo + chemo
(n=58)
KEYNOTE-021
PhI/II 1L NSCLC
pembro + chemo
(n=49)
CheckMate 012
PhI 1L NSCLC
nivo (N) + chemo
(n=56)
CheckMate 012
PhI 1L NSCLC
nivo (N) + ipi (I)
(n=49)
Atezo +
carbo/
pac
Atezo +
carbo/
pem
Atezo +
carbo/
abrax
Pembro +
carbo/
pac
Pembro +
carbo/
pem
N10 +
gem/
cis
N10 +
pem/
cis
N10 +
carbo/
pac
N5 +
carbo/
pac
N1 q3w +
I1 q3w
N1 q2w +
I1 q6w
N3 q2w +
I1 q12w
N3 q2w +
I1 q6w
n 8* 17* 16* 25 24 12 15 15 15 31 40 38 39
ORR, %
Grade 3–4
treatment-
related AEs
69% 35% 45%
29% 35% 29% 28%
71% 54% 85% 32% 38% 25% 47% 73% 29%
50
77
56
28
58
33
47 47 43
13
25
39
31
Refs.
Camidge, et al.
WCLC 2015
Papadimitrakopoulos,
et al. ASCO 2015
Gettinger, et al.
ESMO 2014
Rizvi, et al.
WCLC 2015

Nuevos retos
• Nuevas toxicidades
• Pseudoprogresión
• Biomarcadores

Summary of PD-1/PD-L1 Blockade Immune-
Mediated Toxicities
Occasional (5% to 20%)
 Fatigue
 Rash: maculopapular and
pruritus
– Topical treatments
 Diarrhea/colitis
– Initiate steroids early, taper
slowly
 Hepatitis/liver enzyme
abnormalities
 Infusion reactions
 Endocrinopathies: thyroid,
adrenal, hypophysitis
Infrequent (< 5%)
 Pneumonitis
 Grade 3/4 toxicities
uncommon
Topalian SL, et al. N Engl J Med. 2012;366:2443-2454. Patnaik A, et al. ASCO 2012. Abstract 2512.
Brahmer JR, et al. N Engl J Med. 2012;366:2455-2465. Herbst RS, et al. ASCO 2013. Abstract 3000.

Immune Adverse Events
• Onset:
– Average is 6-12 wks after initiation of therapy
– Can occur within days of the first dose, after several months of
treatment, and after discontinuation of therapy
• Pt complaints are autoimmune and drug related until
proven otherwise
– Rule out infections, metabolic causes, tumor effects, etc
• Early recognition, evaluation, and treatment are critical

Kinetics of appearance of immune-related adverse event.
Jeffrey S. Weber et al. JCO 2012;30:2691-2697
©2012 by American Society of Clinical Oncology

Pseudoprogresión
8-10-2014 19-2-2015

Will These PD-1/PD-L1 Agents End Up Being
“Untargeted Use of Targeted Therapy”?

Hansen AR, Siu LL. JAMA Oncol. 2015.
25% 46% 16-68%Cumplirían
criterios

McLaughlin J. JAMA Oncol. 2015 Nov 12;:1–9.
N=49

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.

N=160
PD-L1: TC and IC
Overall discordance
rate:
48%
Ilie M, Ann Oncol. 2015 Oct 19;:mdv489–7.

En todos los casos
discordantes la
biopsia infravaloró el
resultado del
especimen quirúrgico,
fundamentalmente
en células inmunes

Eficacia y seguridad
Grado de innovación del fármaco
Necesidad no cubierta
Severidad de la enfermedad
Biomarcador eficiente y seguro
Coste

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

2015 11 Inmunoterapia en nsclc

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