IV REUNIÓN GIDO-GGCP
Inmunoterapia en
Cáncer de Pulmón
Dr. José Muñoz Langa
Servicio Oncología Médica
Hospital Universitario y Politécnico La Fe
Baiona, 25 Abril 2015)
Despite advances, only small incremental
OS benefits in overall patient population
Docetaxel
2002
1st-line combination
with chemotherapy
Maintenance treatment after
1st-line chemotherapy
Bevacizumab‡
2006
Paclitaxel
1998
Pemetrexed‡
2008
Gemcitabine
1996
Pemetrexed‡
2009
Vinorelbine
1994
Cisplatin*
1978
Pemetrexed‡
2004
Erlotinib
2004
Docetaxel
1999
After failure of 1 prior
chemotherapy
1st-line or unspecified setting
single agent
Gefitinib†
2003
Erlotinib
2010
Carboplatin*
1989
Crizotinib§
13+
2011 (US)/2012 (EU)
Nab-Paclitaxel
2012
12+
~8–10
~6
~2–4
1970
Erlotinib**
2013
Median OS, months
1980
1990
2000
2010
Afatinib**,#
2013
*Not approved in NSCLC, but commonly used; †Restricted to patients participating in a clinical trial or continuing to benefit from treatment already initiated;
‡Non-squamous
#Afatinib
NSCLC only; §ALK-positive NSCLC only; **EGFR exon 19 deletions or exon 21 (L858R) substitution mutations only;
is approved for the treatment of patients with activating EGFR mutations but only PFS data have been published (May 2014).
U.S. Food and Drug Administration. Available at www.fda.gov. Accessed September 2014; European Medicines Agency. Available at
http://www.ema.europa.eu. Accessed September 2014; NCCN Guidelines. Non-small cell lung cancer. v3.2014.
Immuno-Oncology (I-O): can it address unmet
needs in lung cancer?
“Immunotherapy
represents a new
hope for NSCLC
patients”, Cancer
patient
“In any trial you get
the odd patient who
does very well, but this
is an order of
magnitude above
that.”, Mick Peake,
Glenfield Hospital
“The PD-1 antibodies stop lung cancer cells
from blocking the body's natural immune
response to cancer. A drug that can inhibit
PD-1 may be able to treat a variety of
cancers, which is very exciting”, Myron
Bednar, Hunterdon Regional Cancer Center
“The high level of excitement around
this space is that immune checkpoint
inhibitors may apply to a very broad
range of cancer types, as both
monotherapies and combination
therapies. The data we are seeing so far,
including recently released at ASCO,
also indicates the mechanism works in
patients who have failed previous cancer
therapies.”, Stephen Dunn, LifeTech
Capital
“We look forward to the potential for the
combination of checkpoint inhibitors, like
nivolumab, with small molecule inhibitors in
patients with EGFR mutated lung cancer”,
Naiyer Rizvi, Memorial Sloan Kettering Cancer
Center
“The field of
immunotherapy has
exploded in the last
decade, and more and
more patients are
benefiting”, Steven
O'Day, USC
Objetivos de la Charla:
 Revisar los fundamentos científicos de la inmuno-oncología en el
cáncer de pulmón y en qué se diferencia de otras modalidades de
tratamiento.
 Discutir los últimos avances en inmunoterapia para el tratamiento
del cáncer de pulmón.
 Analizar el problema de la identificación de biomarcadores para las
terapias inumono-oncológicas y su potencial valor predictivo.
 Valorar el potencial de la inmunoterapia sola o en combinación con
otras modalidades de tratamiento en la práctica clínica.
Inmuno-edición del Cáncer: Las Tres “E”.
Dunn GP et al. Immunity. 2008; 21:137-148.
The Cancer-Immunity Cycle
Chen DS and Mellman I. Immunity. 2013;39.
Stimulatory and Inhibitory Factors in the Cancer-Immunity
Cycle
Chen DS and Mellman I. Immunity. 2013;39.
Mecanismos Tumorales para Escapar del Sistema
Inmune
Goldman et al, Nature Biotechnology, 2009
Mecanismos Tumorales para Escapar del Sistema
Inmune
Mecanismos Tumorales para Escapar del Sistema
Inmune
Duray et al, J of Immunol Research, 2010
Inmunidad Adaptativa: Activación del Linfocito T
Proliferación
CD28
Célula T
Moléculas
coestimulatorias
B7
APC
Supervivencia
Activación
Célula T
TCR
MHC
Abbas AK et al. Cellular and Molecular Immunology. 6th ed. Philadelphia, PA: Elsevier Saunders, 2010
Producción
Citoquinas
Blocking CTLA-4 and PD-1 pathways
F. Presentacion Ag
F. Efectora o citotóxica
T cell
T cell
Cel Dendritica
G.Linfatico
Señales Activacion
B7
CD28
Señales Inhibitorias
B7
CTLA-4
Anti cpo
Tejidos perifericos
TCR
MHC
Cancer cell
TCR
MHC
Cancer cell
T cell
Regulación Negativa
PD-L1
PD-1
Anti cpo
Anti cpo
Sinapsis Inmunológica: Regulación función Linfocitos T
Sinapsis Inmunológica: Regulación función Linfocitos T
Nirschl CJ
Clin Cancer Res 2013
Sinapsis Inmunológica: Regulación función Linfocitos T
Glennie M. BJCP 2013
Regulating the T cell immune response
Activating
receptors
Inhibitory
receptors
CTLA-4
CD28
PD-1
OX40
TIM-3
CD137
LAG-3
Agonistic
antibodies
Antagonistic
(blocking)
antibodies
• T cell responses are regulated
through a complex balance of
inhibitory (‘checkpoint’) and
activating signals
• Tumours can dysregulate
checkpoint and activating
pathways, and consequently
the immune response
• Targeting checkpoint and
activating pathways is an
evolving approach to cancer
therapy, designed to promote
an immune response
T cell stimulation
aThe
image shows only a selection of the receptors/pathways involved.
CD = cluster of differentiation; CTLA-4 = cytotoxic T-lymphocyte antigen-4; LAG-3 = lymphocyte-activation gene 3;
PD-1 = programmed cell death TIM-3 = T-cell immunoglobulin domain and mucin domain 3.
Adapted from Mellman I, et al. Nature. 2011:480;481–489; Pardoll DM. Nat Rev Cancer. 2012;12:252–264.
Objetivos de la Charla:
 Revisar los fundamentos científicos de la inmuno-oncología en el
cáncer de pulmón y en qué se diferencia de otras modalidades de
tratamiento.
 Discutir los últimos avances en inmunoterapia para el tratamiento
del cáncer de pulmón.
 Analizar el problema de la identificación de biomarcadores para las
terapias inumono-oncológicas y su potencial valor predictivo.
 Valorar el potencial de la inmunoterapia sola o en combinación con
otras modalidades de tratamiento en la práctica clínica.
Immuno-Oncology: an emerging
immunotherapy strategy for NSCLC
Immunotherapy
Passive (adoptive)
Active
Designed to act on the immune system itself
Antigen
dependent
Antigen
independent
Enhancing
immune
cell function
Therapeutic
vaccines
Modulate T cell
function
Cytokines
GSK1572932A
TG4010
Belagenpumatucel-L
Tergenpumatucel-L
Racotumomab
L-BLP25
CIMAvax
Designed to act at tumour;
immune-based mechanism
Anti-tumour
mAbs
Adoptive
Bavituximab
EGFR inhibition
Adoptive
cell transfer
Immuno-Oncology
CTLA-4 inhibition
PD-1 inhibition
PD-L1 inhibition
.
EGFR = epidermal growth factor receptor.
www.clinicaltrials.gov. Accessed September 2014; NCCN Guidelines. Non-small cell lung cancer. v3.2014; Peters S, et al. Ann Oncol. 2012;23:vii56–vii64.
Blocking CTL4 and PD-1/PD-L1 Patway
Un agente único es capaz de proporcionar
beneficio clínico en múltiples líneas de
tratamiento y con largos supervivientes.
Anti-PD-1 demonstrates encouraging survival in
pre-treated patients: Nivolumab as an example
CA209-003: phase 1 follow-up study, up to 5 prior lines of therapy,
stage IIIB/IV squamous and non-squamous NSCLC cohort
Dose
(mg/kg)
Died/
Treated
ORR,
%
(n/N)
Median OS
(95% CI)
1.0
Overall survival
1-year OS
2-year OS
1
26/33
3.0
(1/33)
9.2
(5.3, 11.1)
32 (16, 49)
[8]
12 (3, 27) [2]
3
20/37
24.3
(9/37)
14.9
(7.3, —)
56 (38, 71)
[17]
45 (27, 61) [9]
10
48/59
20.3
(12/59)
9.2
(5.2, 12.4)
40 (27, 52)
[23]
19 (10, 31) [9]
0.8
0.6
OS rate, % (95% CI) [patients at
risk]
0.4
0.2
0.0
0
Patients at risk
1 mg/kg
3 mg/kg
10 mg/kg
3
6
9
12
15
18
21
24
27
30
33
36
39
42
45
48
51
54
57
0
1
2
0
1
1
0
1
0
0
1
0
0
1
0
0
0
0
0
0
0
Months since treatment initiation
33
37
59
26
34
51
21
26
35
16
21
29
8
17
23
6
13
16
5
12
14
5
11
12
2
9
9
1
4
4
0
1
3
0
1
2
0
1
2
70% of patients had 3–5 prior lines of therapy; 46% of these patients had received 12 prior lines of therapy and 54% had received 35 prior lines
of therapy.
Gettinger NS et al. J Clin Oncol. 2015; 33
Anti-PD-1 clinical activity in pre-treated patients:
Pembrolizumab as an example
KEYNOTE 001: phase 1 study of pre-treated patients,
stage IV NSCLC
RECIST v1.1
Immune-related response criteria
PD-L1 positive
PD-L1 negative
PD-L1 positive
PD-L1 negative
n = 159
n= 35
n = 177
n = 40
ORR, % (95% CI)
23 (16, 30)
9 (2, 23)
19 (14, 26)
12 (4, 27)
Disease control rate, % (95% CI)
42 (34, 50)
31 (17, 49)
51 (44, 59)
53 (36, 69)
9 (6, 31)
14 (9, 18)
9 (6, 22)
13 (9, 18)
31 (0+ to 37+)
NR (9+ to 22+)
NR (0+ to 37+)
NR (0+ to 30+)
n = 177
n= 40
n = 177
n = 40
11 ( 9, 16)
10 (9, 16)
16 (10, 18)
16 (9, 28)
Best overall response*
Time to response, weeks, median
(range)
Response duration, weeks, median
(range)
PFS
Median, weeks (95% CI)
•
Most common treatment-related AE: fatigue 20%
•
10% experienced ≥1 grade 35 treatment-related AEs
–
Incidence of fatigue, arthralgia and nausea, <1% each
•
Grade 3–4 pneumonitis occurred in 2 patients in each dosing arm
•
Grade 3–4 immune-related AEs occurred in 2 patients in each dosing arm and included:
–
Fatigue, arthralgia and neck pain
*Includes confirmed and unconfirmed responses as assessed in patients with measurable disease at baseline.
Garon E, et al. Oral presentation at ASCO 2014 (Abstract 8020).
Anti-PD-L1 clinical activity and safety in
pre-treated patients: MEDI-4736 as an example
Phase 1 dose expansion study, ≥1 prior lines of therapy,
stage IIIB/IV squamous and non-squamous NSCLC cohort
ORR RECIST v1.1, n/N (%)
MEDI-4736
10 mg/kg Q2W*
MEDI-4736
all evaluated doses
6/47 (13)
9/58 (16)
PD-L1 positive
5/13 (39)
5/20 (25)
PD-L1 negative
1/19 (5)
1/29 (3)
Total evaluable
•
•
•
No DLTs in Q2W or Q3W dose phases during dose escalation
No drug-related AEs leading to discontinuation
Low rates of treatment-related grade 34 AEs
–
•
•
10 mg/kg Q2W, 4%; all doses: 3%
The most common related grade ≥3 AE was arthralgia (1%)
No drug-related colitis; no grade 34 pneumonitis or dyspnoea
*MEDI-4736 10 mg/kg Q2W for up to 1 year for study expansion.
Approximately 45% of patients had ≥3 prior lines of therapy.
Brahmer J, et al. Poster presented at ASCO 2014 (Abstract 8021).
Anti-PD-L1 clinical activity and safety in
pre-treated patients: MPDL3280A as an example
Phase 1a expansion study ongoing, ≥1 prior lines of therapy,
stage IIIB/IV NSCLC cohort
RECIST 1.1
ORR*, %
SD ≥ 24 weeks, %
24-week
PFS rate, %
21
19
42
23
17
45
Non-squamous (n = 42)
21
17
44
Squamous (n = 11)
27
18
46
Overall (N = 175)
NSCLC (n = 53)
•
•
•
•
•
The majority of AEs were grade 12 and did not require intervention
There was no maximum tolerated dose or dose-limiting toxicities
No grade 35 pneumonitis observed
Treatment-related death (cardio-respiratory arrest) in one patient with sinus thrombosis and large tumour
mass invading the heart at baseline
Immune-related grade 34 AE observed in one patient with large cell neuroendocrine NSCLC (diabetes
mellitus, 1%)
*ORR includes investigator-assessed unconfirmed and confirmed PR.
55% of patients had ≥3 prior lines of therapy.
Soria J, et al. Oral presentation at ECC 2013 (Abstract 3408).
Phase 3 study of Nivolumab compared with docetaxel in
second- line advanced/metastatic squamous cell NSCLC
(CA209-017/NCT01642004)
Phase 3 study of Nivolumab compared with docetaxel in
second- line advanced/metastatic squamous cell NSCLC
(CA209-017/NCT01642004)
Anti-PD-1 clinical activity and safety as 1st-line
treatment: nivolumab as an example
CA209-012: phase 1 study interim results, chemotherapy-naïve,
stage IIIB/IV squamous or non-squamous NSCLC cohort
Nivolumab 3 mg/kg IV Q2W
Squamous
(n = 9)
Non-squamous
(n = 11)
Total
(N = 20)
2 (22) [2.8, 60.0]
4 (36) [10.9, 69.2]
6 (30) [11.9, 54.3]
Complete response*
1 (11)
1 (9)
2 (10)
Partial response*
1 (11)
3 (27)†
4 (20)
Stable disease
3 (33)
4 (36)
7 (35)
Progressive disease
4 (44)
2 (18)
6 (30)
Unable to determine
0
1 (9)
1 (5)
44 (14, 72)
73 (37, 90)
60 (36, 78)
Median PFS, weeks (range)
15.1 (5.9, 63.3+)
47.3 (9.6, 80.7+)
36.1 (5.9, 80.7+)
1-year OS rate, % (95% CI)
67 (28, 88)
82 (45, 95)
75 (50, 89)
Median OS, weeks (range)
68.0 (13.3, 73.1)
NR (16.6, 89.1+)
NR (13.3, 89.1+)
ORR, n (%) [95% CI]
Best overall response, n (%)
PFS rate at 24 weeks, % (95% CI)
•
•
•
Treatment-related AEs (all grades), n = 17 (85%), most frequently fatigue n = 8 (40%)
No pneumonitis (any grade) was observed
Five treatment-related grade 34 AEs were reported in 4 patients (20%)
–
–
Increased AST or ALT, hyperglycaemia, rash and cardiac failure, n = 1 each
All resolved with treatment discontinuation and/or management per guidelines
*Confirmed responses by a subsequent tumour assessment per RECIST 1.1; †One patient with confirmed partial response had unconfirmed CR by the time of this analysis. NR
= not reached; + = response ongoing.
Gettinger S, et al. Poster presented at ASCO 2014 (Abstract 8024).
Anti-PD-1 clinical activity as 1st-line treatment:
pembrolizumab as an example
KEYNOTE 001: phase 1 study of patients with treatment-naïve,
PD-L1 positive ≥1%, stage IV NSCLC
RECIST v1.1
•
n
ORR
n (%) [95% CI]
n
ORR
n (%) [95% CI]
2 mg/kg Q3W
6
2 (33) [4, 78%]
6
4 (67) [22, 96]
10 mg/kg Q3W
20
4 (20) [6, 44]
22
10 (46) [24, 68]
10 mg/kg Q2W
16
5 (31) [11, 59]
17
7 (41) [18, 67]
Total
42
11 (26) [14, 42]
45
21 (47) [32, 62]
Interim median PFS:
–
RECIST v1.1 central review: 27.0 weeks (95% CI: 13.6, 45.0)
–
irRC investigator review: 37.0 weeks (95% CI: 27.0, NR)
•
Most common treatment-related AE: fatigue 10/45 patients (22%)
•
Grade 34 treatment-related AEs, all n = 1:
–
•
irRC
Blood creatine phosphokinase increase (grade 4), pericardial effusion (grade 3),
pneumonitis (grade 3)
Discontinuation due to AEs: acute kidney injury (grade 2), pneumonitis (grade 3)
NR = not reached.
Rizvi N, et al. Oral presentation at ASCO 2014 (Abstract 8007).
Blocking CTL4 and PD-1/PD-L1 Patway
Un agente único es capaz de proporcionar
beneficio clínico en múltiples líneas de
tratamiento y con largos supervivientes.
Toxicidad clase específica con un perfil de
seguridad manejable
Common immune-related adverse events
experienced with I-O therapies
Pneumonitis (anti-PD-1)
Rash (anti-CTLA-4)1
Reticular erythematous
rash
Perivascular lymphocyte infiltrate
extending into epidermis
Gastrointestinal adverse events (anti-CTLA-4)2
Colonoscopy
Histopathology
Bowel oedema and ulceration in
the descending colon
Focal active colitis (left) with crypt destruction, loss of goblet cells,
and neutrophilic infiltrates in the crypt epithelium (right)
1. Hodi F, et al. Proc Natl Acad Sci USA. 2003;100:4712–4717; 2. Maker A, et al. Ann Surg Oncol. 2005;12:1005–1016.
Select adverse events (≥1%) in patients with NSCLC
treated with nivolumab
•
•
Demonstrates a safety profile managed by protocol algorithms
No new safety signals emerging; all patients >1 year of follow-up
Patients, n (%) [N = 129]
Any grade
Grade 34
41 (53)
5 (6)
Skin
16 (20)
0
Gastrointestinal
12 (15)
1 (1)
Pneumonitis
8 (6)
3 (2)†
Pulmonary
7 (9)
2 (3)
Endocrinopathies
6 (8)
0
Hepatic
5 (6)
1 (1)
Infusion reaction
4 (5)
1 (1)
Renal
3 (4)
0
Any treatment-related select adverse event*
*Defined as an event with potential immunological aetiologies that require more frequent monitoring and/or unique intervention.
†2/3 cases were fatal.
Brahmer J, et al. Poster presented at ASCO 2014 (Abstract 8112).
Inhibition of CTL4 and PD-1/PD-L1 Patway
Un agente único es capaz de proporcionar
beneficio clínico en múltiples líneas de
tratamiento y con largos supervivientes.
Toxicidad clase específica con un perfil de
seguridad manejable
Respuestas rápidas y duraderas
independientes del tipo histológico y de la
presencia mutaciones.
Anti-PD-1 response by histology: nivolumab as an example
CA209-003: phase 1 follow-up study, up to 5 prior lines of therapy,
stage IIIB/IV NSCLC cohort
Time to and duration of
response while on treatment
Ongoing response
Squamous
(n = 9)
Time to response
Response duration following
latest reported dose of therapy
Non-squamous
(n = 13)
0
16
32
48
64
80
96
112
128
144
160
Time , weeks
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).
Anti-PD-1 survival rates appear independent of
histology: nivolumab as an example
1.0
Overall survival
0.9
Group
Died/TreatedMedian OS (95% CI)
Squamous
38/54
9.2 (7.3, 12.5)
Non-squamous 55/74
10.1 (5.7, 13.7)
Censored
0.8
0.7
0.6
0.5
1-year OS Rate = 43%
0.4
1-year OS Rate = 40%
2-year OS Rate = 24%
2-year OS Rate = 23%
0.3
0.2
0.1
0.0
0
Patients at Risk
Squamous
Non-squamous
3
6
9
12
15
18
21
24
27
30
33
36
39
42
45
48
51
54
2
0
1
0
1
0
1
0
0
0
Months since treatment initiation
54
74
44
66
36
45
26
39
19
28
12
22
11
19
Brahmer J, et al. Poster presented at ASCO 2014 (Abstract 8112).
10
17
9
10
4
5
3
1
2
1
2
1
2
1
Response to anti-PD-1 by EGFR or KRAS mutation
status: nivolumab as an example
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]
120
100
Mutant
Unknown
Wild-type
60
40
20
0
-20
-40
-60
-80
-100
Patients
KRAS status
120
Wild-type
25 (9/36) [12.1, 42.2]
Unknown
14 (10/72) [6.9, 24.1]
KRAS mutation status
100
14 (3/21) [3.0, 36.3]
Change in tumour size, %
Mutant
EGFR mutation status
80
Change in tumour size, %
CA209-003: phase 1 follow-up study, up to 5
prior lines of therapy, NSCLC cohort
Mutant
Unknown
Wild-type
80
60
40
20
0
-20
-40
-60
-80
Brahmer J, et al. Poster presented at ASCO 2014 (Abstract 8112).
-100
Patients
Objetivos de la Charla:
 Revisar los fundamentos científicos de la inmuno-oncología en el
cáncer de pulmón y en qué se diferencia de otras modalidades de
tratamiento.
 Discutir los últimos avances en inmunoterapia para el tratamiento
del cáncer de pulmón.
 Analizar el problema de la identificación de biomarcadores para
las terapias inumono-oncológicas y su potencial valor predictivo.
 Valorar el potencial de la inmunoterapia sola o en combinación con
otras modalidades de tratamiento en la práctica clínica.
Understanding of NSCLC subtyping has
evolved in parallel with treatment strategies
Lung cancer as 2 main diseases1–2
Current NSCLC landscape4–8
Tumour histology and genotype influence treatment selection (From 2011)
Chemotherapy only (1990s)
SCLC
<15%
NSCLC
>85%
Non-squamous
NSCLC –
adenocarcinoma1,2
(~40%) †,3
NSCLC: histology-based subtyping3
NRAS, 1%
PDGFR, 1%
EGFR,
15%
VEGFR, 1%
AKT1, 1%
MEK1, 1%
ROS1, 1%
ALK, 7%
BRAF, 3%
RET, 1%
Chemotherapy and targeted therapies (Early 2000s)
Large cell
7%
Other*
8%
HLA-A,
3%
ADC
36%
Squamous
49%
Squamous NSCLC4,5
(~2530%) †,3
KRAS,
25%
Unknown,
35%
FGFR2,
3%
HER2,
4%
BRAF,
4%
DDR2,
4% PDGFRA,
HER2,
2%
MET, PI3K,
3% 3%
Unknown,
18%
PIK3CA,
16%
†
EGFR,
9%
PTEN,
15%
FGFR1,
15%
9%
*Bronchioloalveolar carcinoma 6%, adenosquamous 2%; †Of all histologies.
1. Carney DN. N Engl J Med. 2002;346:126–28; 2. American Cancer Society. Lung Cancer (Small Cell). Available from http://www.cancer.org/cancer/lungcancersmallcell/detailedguide/small-cell-lung-cancer-what-is-small-cell-lung-cancer. Accessed September 2014;
3. Chansky K, et al. J Thorac Oncol. 2009;4:792-801; 4. Pao W, et al. Lancet Oncol. 2011;12:175–180;
5. Molecular profiling of lung cancer. Available at http://www.mycancergenome.org/content/disease/lung-cancer. Accessed September 2014;
6. American Cancer Society. Lung Cancer (Non-Small Cell); What is non-small cell lung cancer? Available at http://www.cancer.org/cancer/lungcancer-nonsmallcell/detailedguide/non-small-cell-lung-cancer-what-is-non-small-cell-lung-cancer. Accessed September 2014; 7. Kim HS, et al. Lung Cancer. 2013;80:249–255; 8. The Cancer
Genome Atlas Research Network. Nature. 2012;489:519–525.
Prognostic/predictive biomarkers in NSCLC
Prognostic
Predictive
Provides information on
outcome, independent of the
administered therapy1
Provides information on
outcome with regards to
a specific therapy1
Ki672
MCM72
p533,4
•
•
ALK5
ERCC15
BRAF5,6
EGFR5,7
KRAS5,7
MET5,8
PD-L1?9,10
HER25
RET5
ROS15
Routine assessment recommended for EGFR and ALK only5
A number of additional potential predictive or prognostic biomarkers are being further investigated,
e.g. AKT, BRCA1, PIK3CA, RRM1 and TS11,12
1. Oldenhius CNAM, et al. Eur J Cancer. 2008;44:946–953; 2. Liu YZ, et al. Lung Cancer. 2012;77:176-182;
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.
Lack of definitive biomarkers associated with
anti-CTLA-4 therapy
Potential predictive
biomarker
Association with anti-CTLA-4 treatment
Absolute lymphocyte
count (ALC)
• ALC ≥1000 μL after 2 ipilimumab treatments
(week 7) correlates with improved clinical benefit
and OS1–4
CD8+/CD4+ T cells
Absolute CD8+
T cell count
• Clinical activity relates to increased frequency of
absolute numbers of CD8+ cells2,4
ICOS
• Positive correlation between clinical activity and
frequency of CD8+ ICOShigh T cells4
• Correlation between CD4+ ICOShigh T cells and
increased OS4
Tregs
FOXp3
• Clinical activity relates to high protein
expression2,5
IDO
• Clinical activity relates to high protein
expression2,5
1. Ascierto P, et al. Clin Cancer Res. 2013;19:1009–1020; 2. Hamid O, et al. J Transl Med. 2011;9:204; 3. Ku G, et al. Cancer. 2010;116:1767–1775;
4. Callahan M et al. Semin Oncol. 2010;37:473–484; 5. Ascierto P, et al. J Transl Med. 2013;11:54.
ALC
Treg cells
1.0
Individual responder
0.5
Individual nonresponder
0.0
Responder mean
-0.5
Nonresponder mean
C6D1
C5D1
C4D1
C3D1
C2D1
-1.0
Baseline flow cytometry value (cells/μL)
3 mg/kg
C6D1
C1D1
ALC change from baseline (×10*3 c/μL)
Biomarkers not predictive of response
to anti-PD-1
350.00
300.00
250.00
200.00
150.00
100.00
50.00
0.00
-50.00
N=37
NSCLC
No response
N=14
NSCLC
Response
Brahmer J, et al. Poster presented at ELCC 2014 (Abstract 96PD).
100.00
50.00
0.00
-50.00
N=37
N=14
NSCLC
No response
NSCLC
Response
Activated CD4+ T cells
Baseline flow cytometry value (cells/μL)
Baseline flow cytometry value (cells/μL)
Activated CD8+ T cells
150.00
200.00
150.00
100.00
50.00
0.00
N=37
N=14
-50.00
NSCLC
No response
NSCLC
Response
PD-L1 expression and response to
anti-PD-1/anti-PD-L1 agents in NSCLC
Nivolumab1,2
(anti-PD-1)
Pembrolizumab3,4
(anti-PD-1)
MEDI-47365
(anti-PD-L1)
MPDL3280A6,7
(anti-PD-L1)
Pre-treated
(All doses)
Pre-treated
(All doses)
Pre-treated1
(All doses)
1st-line2
(3 mg/kg
dose)
Pre-treated3
(10 mg/kg dose)
1st-line4
(All doses)
Overall
22/129 (17)
6/20 (30)
NR/194 (20)
NR
9/58 (16)
12/53 (23)
PD-L1+
5/33 (15)
5/10 (50)
NR/159 (23)
11/42 (26)
5/20 (25)
IHC 3: 5/6 (83)
IHC 2: 1/7 (14)
IHC 1: 2/13 (15)
PD-L1
5/35 (14)
0/7
NR/35 (9)
NR
1/29 (3)
IHC 0: 4/20 (20)
Overall
2.3 mos
36.1 wks
NR
NR
NR
NR
PD-L1+
3.6 mos
45.6 wks
11 wks
NR
NR
NR
PD-L1
1.8 mos
36.1 wks
10 wks
NR
NR
NR
Overall
9.9 mos
Not reached
NR
NR
NR
NR
PD-L1+
7.8 mos
Not reached
NR
NR
NR
NR
PD-L1
10.5 mos
Not reached
NR
NR
NR
NR
ORR, n/N (%)
Median PFS
Median OS
NR = not reported.
1. Brahmer J, et al. Poster presented at ASCO 2014 (Abstract 8112); 2. Gettinger S, et al. Poster presented at ASCO 2014 (Abstract 8024); 3. Garon E, et al. Poster presented at
ASCO 2014 (Abstract 8020); 4. Rizvi N, et al. Oral presentation at ASCO 2014 (Abstract 8007); 5. Brahmer J, et al. Poster presented at ASCO 2014 (Abstract 8021); 6. Soria J, et al.
Oral presentation at ECC 2013 (Abstract 3408); 7. Soria J-C, et al. Poster presented at ESMO 2014 (Abstract 1322P).
PD-L1 expression and response to
anti-PD-1/anti-PD-L1 agents in NSCLC
PD-L1 analysis:
differences in evaluation and interpretation
Agent
Assay
Analysis
Definition of positivity
Nivolumab
(anti-PD-1) 14
Dako automated
IHC assay
(28-8 rabbit Ab)
Analytically
validated
Pembrolizumab
(anti-PD-1)5,6
PD-L1 expression
• Archival FFPE
• 1% and 5% cut-off among
>100 evaluable tumour
cells
• 56%: 1% cut-off
• 49%: 5% cut-off
Dako automated • New tumour biopsy
IHC assay
within 60 days prior
(22C3 mouse Ab)
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
• Archival FFPE
automated
clinical research
IHC assay
• 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 • Archival FFPE
or Ventana IHC
Automated Assay
(in development)
• Not reported
• Not reported
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).
Limitations associated with the assessment of
tumour PD-L1 expression
Tumour
heterogeneity
Tissue
acquisition
Role of fresh vs
archived
samples
PD-L1
expression
• Numerous histological subtypes and diverse genomic
aberrations in patients with NSCLC
• Intratumour heterogeneity with markers for both poor and
good prognosis within the same tumour
• Limited sample size
• Difficult to retain tissue architecture and tumour
microenvironment
• Aging of FFPE tissue sections causes degradation of
epitopes and DNA
• Age, gender, histology and stage of disease appear
associated with PD-L1 expression in patients with NSCLC
• May change after exposure to treatment
FFPE = formalin fixed, paraffin‐embedded.
Li T, et al. J Clin Oncol. 2013;31:1039–1049; Thomas A, et al. Ann Oncol. 2013;24:577–585; Gerlinger M, et al. N Engl J Med. 2012;366:883–889; Kerr K, et al.
Ann Oncol. 2014 Apr 8. [Epub ahead of print]; Sun J-M, et al. Poster presented at ASCO 2014 (Abstract 8066).
PD-L1 expression is dynamic and may change
after exposure to treatment
Baseline
CD8 T cells
On-treatment
PD-L1
CD8 T cells
PD-L1
MPDL3280A
T cells and tumour
cells expressing
PD-L1
Powderly J, et al. Oral presentation at ASCO 2013 (Abstract 3001).
Objetivos de la Charla:
 Revisar los fundamentos científicos de la inmuno-oncología en el
cáncer de pulmón y en qué se diferencia de otras modalidades de
tratamiento.
 Discutir los últimos avances en inmunoterapia para el tratamiento
del cáncer de pulmón.
 Analizar el problema de la identificación de biomarcadores para las
terapias inumono-oncológicas y su potencial valor predictivo.
 Valorar el potencial de la inmunoterapia sola o en combinación
con otras modalidades de tratamiento en la práctica clínica.
Therapies that Might Affect the Cancer-Immunity
Cycle
Chen DS and Mellman I. Immunity. 2013;39.
Base de la combinación de inmunoterapias
Inmunoterapias combinadas
I-O agents have a unique MoA, offering the
opportunity for combination with other agents
I-O
Drake C. Ann Oncol. 2012;23(suppl 8):viii41–viii46; Hannani D, et al. Cancer J 2011;17:351–358;
Ménard C, et al. Cancer Immunol Immunother. 2008;57:1579–1587; Ribas A, et al. Curr Opin Immunol. 2013:25:291–296.
Anti-PD-1 plus TKI in EGFR TKI-resistant NSCLC:
nivolumab plus erlotinib as an example
CA209-012: phase 1 study interim results, chemotherapy-naïve,
stage IIIB/IV EGFR mutation-positive NSCLC*
Patient
1 (T790M-positive)
*
*
2
3
Time to and duration of response on
treatment
Ongoing response
Time to response
*
4 (Erlotinib-naïve)
*
*
0
6
12
18
24
30
36
42
48
54
60
66
72
78
84
90
Duration of study drug exposure at time of
data analysis (dosing beyond progression)
Response duration following latest reported
dose of therapy
Time, weeks
Nivolumab + erlotinib (N = 21)
ORR, n (%) [95% CI]
4 (19) [5.4, 41.9]
Estimated median DOR, weeks (95% CI)
NR (60.1, )
PFS rate at 24 weeks, % (95% CI)
51 (28, 70)
Median PFS, weeks (range)
29.4 (4.6, 81.7+)
1-year OS rate, % (95% CI)
71 (46, 88)
Median OS, weeks (range)
NR (10.7+, 86.9+)
*20/21 patients received prior erlotinib and represented a refractory population.
Rizvi N, et al. Poster presented at ASCO 2014 (Abstract 8022).
I-O agents have a unique MoA, offering the
opportunity for combination with other agents
I-O
Drake C. Ann Oncol. 2012;23(suppl 8):viii41–viii46; Hannani D, et al. Cancer J 2011;17:351–358;
Ménard C, et al. Cancer Immunol Immunother. 2008;57:1579–1587; Ribas A, et al. Curr Opin Immunol. 2013:25:291–296.
Anti-CTLA-4 plus chemotherapy as 1st-line treatment:
ipilimumab plus carboplatin/paclitaxel as an example
CA184-041: phase 2 study results, no prior therapy for lung cancer,
stage IIIB/IV NSCLC, ECOG PS ≤1, all histologies
Ipilimumab + concurrent chemotherapy
Ipilimumab + phased chemotherapy
1.0
irPFS, probability
irPFS, probability
1.0
0.8
0.6
0.4
0.2
0
0.8
0.6
0.4
0.2
0
0
2
4
6
8
10
12
14
16
0
2
4
Placebo
Ipilimumab 55/70
Median
irPFS,
months
4.63
5.52
95% CI
4.14, 5.52
HR P- value
4.17, 6.74 0.81
Lynch T, et al. J Clin Oncol. 2012;30:2046–2054.
8
10
12
14
16
Time, months
Time, months
Events/
patients
56/66
6
Placebo
0.13
Events/
patients
56/66
Ipilimumab 54/68
Median
irPFS,
months
4.63
5.68
95% CI HR P -value
4.14, 5.52
4.76, 7.79 0.72
0.05
Anti-PD-1 plus chemotherapy as 1st-line treatment:
nivolumab plus platinum-based regimens as an example
Change in baseline target
lesions, %
CA209-012: phase 1 study interim results, chemotherapy-naïve,
stage IIIB or IV NSCLC, ECOG PS ≤1, all histologies
40
20
0
-20
-40
-60
-80
-100
Nivolumab 10 mg/kg
+ Gem/Cis
(squamous)
Nivolumab 10 mg/kg
+ Pem/Cis
(non-squamous)
Nivolumab 10 mg/kg
+ Pac/Carb
(any histology)
Nivolumab 5 mg/kg
+ Pac/Carb
(any histology)
Nivolumab 10 mg/kg
Nivolumab 5 mg/kg
Gem/Cis (n = 12)
Pem/Cis (n = 15)
Pac/Carb (n = 15)
Pac/Carb (n = 14)
4 (33) [10, 65]
7 (47) [21, 73]
7 (47) [21, 73]
6 (43) [18, 71]
45.0 (17.7, 56.7)
25.4 (13.1, )
23.9 (12.3, )
NR (22.0, )
51 (19, 76)
71 (39, 88)
38 (14, 61)
51 (21, 75)
Median PFS, weeks (range)
24.7 (0.1+, 61.4)
29.7 (4.0+, 91.9+)
21.0 (3.1, 97.9+)
31.0 (0.1+, 82.4+)
1-year OS rate, % (95% CI)
50 (21, 74)
87 (56, 96)
60 (32, 80)
85 (51, 96)
Median OS, weeks (range)
50.5 (19.7, 99.3+)
83.4 (33.0, 105.1+)
64.9 (13.9, 105.0+)
NR (33.7+, 87.1+)
ORR, n (%) [95% CI]
Est. median DOR, weeks (95%
CI)
PFS rate at 24 weeks, % (95% CI)
Cis = cisplatin; Gem = gemcitabine; Pem = pemetrexed; Pac = paclitaxel; Carb = carboplatin.
Includes patients with baseline target lesion and ≥1 post-baseline target lesion assessment with non-missing value.
Antonia S, et al. Poster presented at ASCO 2014 (Abstract 8113); Antonia S, et al. Presented at LALCA 2014 (Abstract O.3).
I-O agents have a unique MoA, offering the
opportunity for combination with other agents
I-O
Drake C. Ann Oncol. 2012;23(suppl 8):viii41–viii46; Hannani D, et al. Cancer J 2011;17:351–358;
Ménard C, et al. Cancer Immunol Immunother. 2008;57:1579–1587; Ribas A, et al. Curr Opin Immunol. 2013:25:291–296.
Anti-PD-1 plus anti-CTLA-4 tumour response and survival
outcomes: nivolumab plus ipilimumab as an example
Change in baseline target lesions, %
200
CA209-012: phase 1 study interim results, chemotherapy-naïve,
non-squamous/squamous stage IIIB/IV NSCLC
180
160
140
120
100
80
60
40
20
0
-20
-40
-60
-80
Includes patients with baseline target lesion and ≥1 post-baseline target lesion assessment with non-missing value.
-100
Nivolumab 1 mg/kg +
ipilimumab 3mg/kg
(squamous)
Nivolumab 1 mg/kg
+ ipilimumab
3mg/kg
(non-squamous)
Nivolumab 3 mg/kg +
ipilimumab 1mg/kg
(squamous)
Nivolumab 1 mg/kg + ipilimumab 3 mg/kg
PFS rate at 24 weeks, % (95% CI)
Median PFS, weeks (range)
Median OS, weeks (range)
Nivolumab 3 mg/kg
+ ipilimumab 1mg/kg
(non-squamous)
Nivolumab 3 mg/kg + ipilimumab 1 mg/kg
Squamous
(n = 9)
Non-squamous
(n = 15)
Squamous
(n = 9)
Non-squamous
(n = 16)
25 (4, 56)
51 (21, 74)
44 (14, 72)
20 (5, 43)
41 (20, 61)
8.9 (0.1+, 44.7)
32.9 (0.1+, 54.1+)
16.1 (0.1+, 54.1+)
44.3 (1.4, 53.1+)
NR (4.9+, 54.1+)
NR (1.4, 54.1+)
Antonia S, et al. Poster presented at ASCO 2014 (Abstract 8023).
29 (13, 48)
20.6 (9.7, 33.3+)
9.9 (4.1+, 58.1+)
14.4 (4.1+, 58.1+)
NR (9.7, 50.1+)
NR (8.1, 58.1+)
NR (8.1, 58.1+)
I-O agents have a unique MoA, offering the
opportunity for combination with other agents
I-O
Drake C. Ann Oncol. 2012;23(suppl 8):viii41–viii46; Hannani D, et al. Cancer J 2011;17:351–358;
Ménard C, et al. Cancer Immunol Immunother. 2008;57:1579–1587; Ribas A, et al. Curr Opin Immunol. 2013:25:291–296.
Potential of anti-CTLA-4 plus radiation:
ipilimumab in one patient with melanoma as an example
•
•
The target and other lesions regressed
Regression of distant lesions may be due to an enhanced systemic response
A
B
August 2009
C
November 2010
D
January 2011
E
April 2011
October 2011
Ipilimumab
F
Recurrence of
unresectable cancer
Induction
Maintenance
Stable
December 2010
Aug.
2009
A
Sept.
2009
Radiation
Maintenance
Slow Progression
Dec.
2009
Figure adapted from Postow M, et al. N Engl J Med. 2012;366(10): 925–931.
Nov.
2010
A
Response
Dec.
2010
B
Jan.
2010
C
Stable
April
2010
D
Oct.
2010
E
Examples of ongoing combination trials with I-O
therapies
Chemotherapy
Radiotherapy
Targeted
Immunotherapy
Nivolumab
(anti-PD-1)
+ cisplatin/gemcitabine,
cisplatin/pemetrexed or
carboplatin/paclitaxel
(NCT01454102)
NR
+ bevacizumab
or erlotinib
(NCT01454102)
+ ipilimumab (NCT01454102)
+ anti-KIR (NCT01714739)
+ anti-LAG3 (NCT01968109)
Pembrolizumab
(anti-PD-1)
+ cisplatin/pemetrexed or
carboplatin/paclitaxel
(NCT01840579)
+ paclitaxel/carboplatin
± bevacizumab (NCT02039674)
NR
+ gefitinib or
erlotinib
(NCT02039674)
+ ipilimumab
(NCT02039674)
+ INCB024360
(NCT02178722)
NR
+ gefitinib
(NCT02088112)
+ AZD9291
(NCT02143466)
+ tremelimumab
(NCT02000947,
NCT02141347)
+ ipilimumab
(NCT02174172)
MEDI-4736
(anti-PD-L1)
NR
MPDL3280A
(anti-PD-L1)
NR
NR
+ erlotinib
(NCT02013219)
+ cobimetinib
(NCT01988896)
Ipilimumab
(anti-CTLA-4)
Various
(NCT00527735; NCT01165216;
NCT01285609; NCT01331525;
NCT01450761;NCT1454102)
+ stereotactic radiosurgery*
(NCT02107755,
NCT02239900)
+ ionizing radiation
(NCT02221739)
+ erlotinib or
crizotinib
(NCT01998126)
+ nivolumab (NCT01454102)
+ pembrolizumab
(NCT02039674)
Tremelimumab
(anti-CTLA-4)
NR
NR
+ gefitinib
(NCT02040064)
+ MEDI-4736 (NCT02000947)
*Trial in patients with melanoma with metastatic disease to a visceral organ (lung, liver, brain, adrenal, nodal station outside the regional lymph drainage of the
primary, vertebral bodies).
NR = no trials reported.
www.clinicaltrials.gov. Accessed September 2014.
In summary
 Los agentes bloqueantes de los estímulos inhibitorios Inmunológicos han
demostrao un potencial en respuestas duraderas a través de diferentes
histologías, diferentes líneas de tratamiento e independiente de las
mutaciones oncogénicas.
 La identificación de biomarcadores para terapias IO es compleja. Los
futuros datos de los ensayos clínicos y el uso de métodos estandarizados de
evaluación ayudarán a clarificar su papel pronóstico y predictivo en CPNM.
 Los AcMo IO ofrecen la oportunidad de tratamientos combinados con otros
agentes IO y con otras modalidades de tratamiento, para aumentar aún
más el potencial de beneficio clínico.
 La IO puede representar la base de los futuros tratamientos de los diversos
tumores malignos sólidos o hematológicos, ofreciendo una posibilidad para
la supervivencia a largo plazo.
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IV REUNIÓN GIDO-GGCP (Baiona, 25 Abril 2015)