Immunoterapia y terapia dirigida en cáncer de pulmón

Inmunoterapia y terapia dirigida en cáncer de pulmón
Mauricio Lema Medina MD
Clínica de Oncología Astorga / Clínica SOMA - Medellín, Colombia
Ibagué, 09/11/2018

Conflicts of interest for this lecture
Mauricio Lema
Lecture fees by: Boehringer-Ingelheim, BMS, MSD

8th Edition of the TNM Classification
for Lung Cancer
N0 N1 N2 N3 M1a M1b M1c
T1a IA1 IIB IIIA IIIB IVA IVA IVB
T1b IA2 IIB IIIA IIIB IVA IVA IVB
T1c IA3 IIB IIIA IIIB IVA IVA IVB
T2a IB IIB IIIA IIIB IVA IVA IVB
T2b IIA IIB IIIA IIIB IVA IVA IVB
T3 IIB IIIA IIIB IIIC IVA IVA IVB
T4 IIIA IIIA IIIB IIIC IVA IVA IVB
International Association for the Study of Lung Cancer, 2015
Systemic therapy

Oxford overview
HR: 0.73 in favor of Cisplatin-based Chemo
Equivalent to 1.5-2.5 increase in OS

Lung cancer toolkit
What’s needed to treat
Tissue diagnosis
Histology.
Morphology
Squamous
Adeno
NSCLC NOS
SCLC.
IHC
Squamous: p63-p40
Adeno: TTF+, Napsin
PD-L1 expression (mNSCLC)
SCLC: High Ki67, Chromogranin,
synaptophysin
Genotyping
Non-Squamous, advanced NSCLC
EGFR
ALK/EML4
ROS1, and others.

How to handle small tissue samples in lung cancer
p63 and TTF1
H&E
SCC Non-SCC (Adeno)
Genomics
SCLC
EGFR
ALK/EML4
ROS1
BRAF
Her2
p63+ TTF1+
PD-L1 by IHC
(in advanced NSCLC)
PD-L1 by IHC
(in advanced NSCLC)
Chromogranin
Synaptophysin

Lung Cancer Subtypes
▪ The WHO classification for primary lung cancer recognizes 4 major histology types[1]
Small-cell
carcinoma
13.0%
Large-cell
carcinoma
5.0%
Adenocarcinoma
38.3%
19.7%
Squamous cell
carcinoma
Other*
24.0%
Percent distribution by histology among histologically
confirmed lung cancer cases, 2001-2004[2]
1. Brambilla E, et al. Eur Respir J. 2001;18:1059-1068.2. SEER Database. Lung and Bronchus Cancer
(Invasive), 1975-2004.
*Including adenosquamous
carcinoma; carcinomas with
pleomorphic, sarcomatoid or
sarcomatous elements;
carcinoid tumor; carcinomas of
salivary gland type; and
unclassified carcinoma

Genomic Evolution of Lung Cancer (Non-
Squamous NSCLC)
KRAS, 30%
EGFR, 15%
EML4-ALK, 5%
HER 2, 2%
BRAF, 2%
FGFR4, 2%
PIK3CA, 1%
MEK, 1%
ROS1, 1%
RET, 1%
Unkn, 40%
KRAS EGFR EML4-ALK HER 2 BRAF FGFR4 PIK3CA MEK ROS1 RET Unkn

Lung cancer: “relevant” subgroups
NSCLC SCLC
NSCLC with a “Driver”
NSCLC without a
“Driver”
10%
15% 75%
PD-L1
expression
1-50%
25%
PD-L1
expression
≥50%
25%
90%
EGFR: 10%
ALK/EML4: 4%
ROS1: 1%
Mostly, adenocarcinoma
Adenocarcinoma
Squamous
Large-cell
PD-L1
expression
≤1%
25%

Tumor Cell
Cytotoxic T8
Lymphocyte
PD-L1
PD-1
- - -
Tumor Cell
Cytotoxic T8
Lymphocyte
+ + +
Active T-Cell anti-tumor
cytotoxicity
Inactive T-Cell anti-tumor
cytotoxicity
PD-1: Programmed cell death protein 1
(CD279)
Involved in regulating the immune
system’s response to cytotoxic T-cells

Unselected non-
squamous
mNSCLC
Stage IV

•Untreated stage IV
NSCLC
•Non-squamous
•ECOG PS 0-1
•No significant
hemoptysis
1:1
Carboplatin + Paclitaxel
+ Bevacizumab
Carboplatin + Paclitaxel
+ Bevacizumab
ECOG 4599
Primary endpoint: OS
Sandler, A., Gray, R., Perry, M. C., Brahmer, J., Schiller, J. H., Dowlati, A., … Johnson, D. H. (2006). Paclitaxel–Carboplatin Alone or with Bevacizumab
for Non–Small-Cell Lung Cancer. New England Journal of Medicine, 355(24), 2542–2550. https://doi.org/10.1056/NEJMoa061884
Carbo/Pacli + Bevacizumab
(PCB): 1 year OS

•Untreated stage IV
NSCLC
•Non-squamous
•ECOG PS 0-1
•No significant
hemoptysis
1:1
Cisplatin + Pemetrexed
+ Maintenance Pemetrexed
Cisplatin + Pemetrexed
PARAMOUNT
Primary endpoint: OS
Sandler, A., Gray, R., Perry, M. C., Brahmer, J., Schiller, J. H., Dowlati, A., … Johnson, D. H. (2006). Paclitaxel–Carboplatin Alone or with Bevacizumab
for Non–Small-Cell Lung Cancer. New England Journal of Medicine, 355(24), 2542–2550. https://doi.org/10.1056/NEJMoa061884
Maintenance Pemetrexed
achieves > 1 yr OS

Survival
Time
Modified from Ribas A, et al. Clin Cancer Res. 2012;18:336-341.
Survival Pattern with Chemotherapy

Inmunología tumoral
Célula tumoral
PD-1
PD-L1
PD-L2
Receptor de células T
MHC-1
CD28
Shp-2
B7.1
Célula
Dendrítica
Antígeno tumoral
Linfocito T
CD8+/Citotóxico

Célula tumoral
PD-1
PD-L1
PD-L2
MHC-1
CD28
Shp-2
B7.1
Célula
Dendrítica
Antígeno tumoral
Linfocito T
CD8+/Citotóxico
Receptor de célula T (TCR) MHC II y antígeno
MHC II: Major histocompatibility complex

Cebado
(priming) y
activación de las
células T
Célula tumoral
PD-1
PD-L1
PD-L2
MHC-1
CD28
Shp-2
B7.1
Célula
DendríticaLinfocito T
CD8+/Citotóxico
Co-estimuladora CD28 Co-estimuladora B7.1
Sinapsis 1

Célula tumoral
PD-1
PD-L1
PD-L2
MHC-1
CD28
Shp-2
B7.1Antígeno + MHC-1

Activación de la
respuesta
inmunológica
CD8 efectora
Célula tumoral
PD-1
PD-L1
PD-L2
MHC-1
CD28
Shp-2
B7.1
Linfocito T
CD8+/Citotóxico
Antígeno + MHC-1
Receptor de células T (TCR)
+++
Respuesta inmune antitumoral
Presente
Sinapsis 2

Cómo se detiene la
respuesta
inmunológica?
Frenos

En la sinapsis 1
Células T – Células presentadoras de antígeno (ie, dendríticas)

Interacción de Células Presentadoras
de antígeno – Células T
Célula dendrítica
Célula T
MHC TCR
B7
CD28
CTLA-4
Célula T
Células Dendríticas
Anti-
CTLA-4
Bloqueo del CTLA-4
Los anticuerpos anti CTLA-4 restablecen
la respuesta antitumoral de linfocitos T
(ejemplo: Ipilimumab)

En la sinapsis 2
Células T – Células tumorales

Las células
tumorales
expresan PD-
L1 (PD-L2)
cuando hay
estimulación
continuada del
IFN-Gamma,
"apagando" al
linfocito T
Célula tumoral
PD-1
PD-L1
PD-L2
MHC-1
CD28
Shp-2
B7.1
Linfocito T
CD8+/Citotóxico
IFN-γ
IFN-γR
PD-L1
PD-1
- - -
Frenada

Célula T
Célula
tumoral
MHCTCR
PD-1
PD-L1
Cancer
cell
T-cell
Anti-PD-L1
Anti-PD-1
Bloqueo PD-1
Se restablece
Los anticuerpos anti-PD-1 (anti-PD-L1,
anti-PD-L2) restablecen la respuesta
antitumoral de linfocitos T
Interacción Célula T-Célula
Tumoral
Interaction

Droga Mecanismo de acción
Pembrolizumab Anti-PD1
Nivolumab Anti-PD1
Avelumab Anti-PD-L1
Durvalumab Anti-PD-L1
Atezolizumab Anti-PD-L1
Célula T
Célula
tumoral
MHCTCR
PD-1
PD-L1
Cancer
cell
T-cell

James Allison Tasuko Honjo
2018 Nobel Prize in Medicine – Cancer Immunotherapy

Blueprint PD-L1 IHC Assay Comparison Project: Phase 1
▪ Analytical comparison of % tumor
cell staining (tumor proportion
score), by case (n = 39), for each
assay
▪ Data points represent the mean
score from 3 pathologists for each
assay on each case
▪ No clinical diagnostic cutoff applied
▪ Conclusion: 3 of 4 assays are
analytically similar for tumor cell
staining
22C3 (pembrolizumab), 28-8 (nivolumab), and
SP263 (durvalumab)
SP142 (atezolizumab)
Hirsch FR et al. J Thorac Oncol. 2017;12:208-222. Slide credit: clinicaloptions.com
100
80
60
40
20
0
1 3 5 7 9 11 13 15 17 19
%TumorCellStaining
23 25 27 29 31 33 35 3721 39
22C3
28-8
SP142
SP263

Tumor Cell
Cytotoxic T8
Lymphocyte
PD-L1
PD-1
- - -
Tumor Cell
Cytotoxic T8
Lymphocyte
- - -
Tumor Cell
Cytotoxic T8
Lymphocyte
+ + +
Pembrolizumab
Nivolumab
And many others…

Immunotherapy in
2nd-Line
Stage IV

Efficacy of Nivolumab Monotherapy in Pts With
Previously Treated Advanced NSCLC
Gettinger SN, et al. J Clin Oncol. 2015;33:2004-2012.
NonsquamousSquamous
0 6 12 18 24 30 36 42
Mos Since Treatment Initiation
Time to and duration of response until
discontinuation of therapy
Ongoing response
Time to response
Duration of response after discontinuation
of therapy
1 yr: 42%
2 yrs: 24%
3 yrs: 18%
48 54 60 6624 30 36 420 6 12 18
100
80
60
40
20
0
OS(%)
Died/Treated
99/129
Median, Mos
9.9
95% CI
7.8-12.4
1 yr: 56%
2 yrs: 42%
3 yrs: 27%
48 54 60 6624 30 36 420 6 12 18
100
80
60
40
20
0
OS(%)
Died/
Treated
26/33
23/37
50/59
Median,
Mos
9.2
14.9
9.2
95% CI
5.3-11.1
7.3-30.3
5.2-12.4
Squamous
Nonsquamous
120 140 16080 1000 20 40 60
Wks Since Treatment Initiation
120
80
40
0
-40
-100
ChangeinTargetLesion
FromBaseline(%)
mg/kg
1
3
10
100
60
20
-20
-80
-60
Slide credit: clinicaloptions.com

Survival
Time
Survival Pattern with Chemotherapy and Immune checkpoint
blockade
Immune checkpoint
Chemotherapy

Immune Checkpoint Inhibitors in Pretreated Adv
NSCLC: Randomized Late-StageTrials
CheckMate 017 CheckMate 057
KEYNOTE 010 OAK
Nonsquamous
SIIIB/IV
(N = 582)
Nivolumab
Docetaxel
Squamous
SIIIB/IV
(N = 272)
Nivolumab
Docetaxel
Adv NSCLC with
≥ 1% PD-L1+
tumor cells
(N = 1034)
Pembrolizumab
(2 mg/kg)
Docetaxel
Pembrolizumab
(10 mg/kg)
Adv NSCLC
(2L/3L)
(N = 1225)
Atezolizumab
Docetaxel

Nivolumab vs Docetaxel in Previously Treated
Squamous NSCLC (CheckMate 017): PFS
Pts at Risk, n
Nivolumab
Docetaxel
135 68 48 33 21 15 6 2 0
137 62 26 9 6 2 1 0 0
0 3 6 9 12 15 18 21 24
100
80
60
40
20
0
PFS(%ofPts)
Mos
Brahmer J, et al. N Engl J Med. 2015;373:123-135.
*Per investigator.
1-yr PFS rate: 21%
1-yr PFS rate: 6%
Nivolumab
(n = 135)
Docetaxel
(n = 137)
Median PFS,*
mos (95% CI)
3.5 (2.1-4.9) 2.8 (2.1-3.5)
HR (95% CI) 0.62 (0.47-0.81; P < .001)

Nonsquamous NSCLC (CheckMate 057)
 Primary endpoint: OS
 Secondary endpoints: ORR, PFS, efficacy by PD-L1 expression, safety, QoL
 Pretreatment (archival or recent) tumor samples required for measurement of PD-L1
expression
– Fully validated with analytical performance having met all
predetermined acceptance criteria
for sensitivity, specificity, precision, and robustness
Pts with stage IIIB/IV
nonsquamous NSCLC and
ECOG PS 0/1 who failed
1 prior platinum doublet
chemotherapy ± TKI therapy
(N = 582)
Nivolumab 3 mg/kg IV Q2W
(n = 292)
Docetaxel 75 mg/m2 IV Q3W
(n = 290)
Borghaei H, et al. N Engl J Med. 2015;373:1627-1639.
Until disease
progression or
unacceptable
toxicity
Stratified by previous maintenance
therapy (yes vs no) and line of
therapy (second vs third line)

100
90
80
70
60
50
40
30
10
0
20
Nivolumab
(n = 292)
Docetaxel
(n = 290)
mPFS, mos 2.3 4.2
HR (95% CI) 0.92 (0.77-1.11; P = .39)
27211815129630 24
PFS(%)
Mos
292 128 82 58 46 35 17 7 02
290 156 87 38 18 6 2 1 01
Nivolumab
Docetaxel
Pts at Risk, n
Nivolumab
Docetaxel
1-yr PFS rate: 19%
1-yr PFS rate: 8%
Nonsquamous NSCLC (CheckMate 057): PFS

12-Mo OS 18-Mo OS
Nivo
(n = 292)
Doc
(n = 290)
Nivo
(n = 292)
Doc
(n = 290)
mOS, mos 12.2 9.4 12.2 9.4
1-yr OS rate,
%
51 39 51 39
18-mo OS
rate, %
– – 39 23
Events/pts,
n/N
190/292 223/290 206/292 236/290
HR: 0.73 (96% CI:
0.59-0.89; P = .0015)
HR: 0.72 (95% CI:
0.60-0.88; post hoc
P = .0009)
Minimum follow-up for 12-mo OS rate, 13.2 mos; for 18-mo OS rate, 17.1 mos
CheckMate 057: OS in the ITT Population
Nivolumab
Docetaxel
100
90
80
70
60
50
40
30
10
0
20
27181596 211230 24 30
18-mo OS rate: 23%
18-mo OS rate: 39%
1-yr OS rate: 39%
1-yr OS rate: 51%
Mos
OS(%)

Pembrolizumab in NSCLC (KEYNOTE-001
Cohort): OS by PD-L1 Expression
Pts at Risk, n
119 92 56 22 5 4 3 0
161 119 58 15 6 4 0 0
76 55 33 8 0 0 0 0
100
80
60
40
20
0
0 4 8 12 16 20 24 28
OS(%)
Mos
PS 1-49%
PS < 1%
PS ≥ 50%
PS
Median OS,
Mos (95% CI)
≥ 50% NR (13.7-NR)
1-49% 8.8 (6.8-12.4)
< 1% 8.8 (5.5-12.0)
Garon EB, et al. N Engl J Med. 2015;372:2018-2028. Garon EB, et al. AACR 2015. Abstract CT04. Slide credit: clinicaloptions.com

Pembrolizumab 2 mg/kg IV Q3W
(n = 345)
Docetaxel 75 mg/m2 IV Q3W
(n = 343)
Herbst RS, et al. Lancet. 2015;387:1540-1550.
Treatment
continued for
24 mos or until PD
or unacceptable
toxicity
Stratified by ECOG PS (0 vs 1), region (east
Asia vs not east Asia), and PD-L1 expression
(≥ 50% vs 1% to 49%)
Pts with advanced NSCLC who
progressed after platinum-based
chemotherapy (and TKI if EGFR+
or ALK+); ≥ 1% PD-L1+ tumor
cells; ECOG PS 0/1, no active
brain mets
(N = 1034)
Pembrolizumab 10 mg/kg IV Q3W
(n = 346)
Pembrolizumab vs Docetaxel in Adv NSCLC After
Progression on Platinum CT (KEYNOTE-010)
 Endpoints (in the TPS ≥ 50% stratum and TPS ≥ 1% population)
– Primary: PFS, OS
– Secondary: ORR, DoR, safety Slide credit: clinicaloptions.com

Herbst RS, et al. Lancet. 2015;387:1540-1550.
KEYNOTE-010: PD-L1 Expression Correlates With
Improved OS in Advanced NSCLC
100
80
60
40
20
0
50 10 15 20 25
OS(%)
Mos
Pembrolizumab 2 mg/kg: 43%
Docetaxel: 35%
PD-L1 TPS ≥ 1%
12 mos
100
80
60
40
20
0
50 10 15 20 25
OS(%)
Mos
Docetaxel: 38%
12 mos
PD-L1 TPS ≥ 50%
HR: 0.71 (95% CI: 0.58-0.88)
HR: 0.61 (95% CI: 0.49-0.75)
HR: 0.54 (95% CI: 0.38-0.77)
HR: 0.50 (95% CI: 0.36-0.70)

Immunotherapy in
1st-Line
Stage IV

48
KEYNOTE 001
W H Y P E M B R O L I Z U M A B I N N S C L C
L O N G - T E R M O S F O R P A T I E N T S W I T H A D V A N C E D N S C L C E N R O L L E D I N T H E K E Y N O T E - 0 0 1 S T U D Y O F
P E M B R O L I Z U M A B .
Leighl– ASCO 2017
A L I V E AT 3 Y E A R S
26%

KEYNOTE-024: Pembrolizumab vs CT as First-
line Therapy for Adv NSCLC
 Primary endpoint: PFS
 Secondary endpoints: ORR, OS, and safety
Pts with stage IV NSCLC
and ECOG PS 0/1, no
previous systemic
therapy, no actionable
EGFR/ALK mutations,
and PD-L1 TPS ≥ 50%*
(N = 305)
Pembrolizumab 200 mg IV Q3W
for up to 35 cycles
(n = 154)
Chemotherapy (histology
based) for up to 6 cycles
(n = 151)
Until PD or
unacceptable
toxicity
Stratified by ECOG PS (0 vs 1),
histology (squamous vs nonsquamous),
and enrollment region
Reck M, et al. N Engl J Med. 2016;375:1823-1833.
Until PD
(crossover to
pembrolizumab
allowed)
*≥ 50% tumor cell staining using 22C3 companion diagnostic IHC assay.

KEYNOTE-024: First-line Pembrolizumab vs
Chemotherapy—PFS and OS
Reck M, et al. N Engl J Med. 2016;375:1823-1833.
PFS OS
Mos
PFS(%)
100
80
60
40
20
0
180 3 6 9 12 15
HR for PFS: 0.50 (95% CI: 0.37-0.68; P < .001)
Mos
OS(%)
100
80
60
40
20
0
210 3 6 9 12 15
Pembrolizumab
Chemotherapy
HR for OS: 0.60 (95% CI: 0.41-0.89; P = .005)
18
6.0
10.3
 ORR
– Pembro: 44.8%
– Chemo: 27.8%
 FDA approval
10/2016 for pts
with ≥ 50% PD-
L1 expression
 Now SOC to test
for PD-L1 at
initial diagnosis
(22C3 assay)

KEYNOTE-042: Pembrolizumab vs CT as First-
line Therapy for Adv PD-L1 Positive NSCLC
 Primary endpoint: OS (PD-L1 TPS ≥ 1%, ≥ 20%, and ≥ 50%)
 Secondary endpoints: PFS, ORR
 April 2018 press release reports positive OS benefit; data to be reported at
later date
Pts with locally adv or
metastatic NSCLC and
ECOG PS 0/1, no
previous systemic
therapy, no actionable
EGFR/ALK mutations,
and PD-L1 TPS ≥ 1%*
(N = 1274)
Pembrolizumab 200 mg IV Q3W
for up to 35 cycles
Carboplatin/paclitaxel or
carboplatin/pemetrexed for
up to 6 cycles
ClinicalTrials.gov. NCT02220894.
Pemetrexed
maintenance therapy
allowed for pts w/
non-squamous
NSCLC
Randomized, open-label phase III trial

KEYNOTE-021g: Pembrolizumab + Chemo vs
Chemo Alone in Stage IIIB/IV NSCLC
 Open-label, randomized phase II study
 Primary endpoint: ORR
 Secondary endpoints: PFS, duration of response
Patients with untreated
stage IIIB or IV
nonsquamous NSCLC
without activating
EGFR mutations or
ALK translocation;
ECOG PS 0-1
(N = 123)
Pembrolizumab 200 mg Q3W
for 2 yrs + CP*
(n = 60)
CP*
(n = 63)
Slide credit: clinicaloptions.comPapadimitrakopoulou V, et al. ASCO 2017. Abstract 9094.
Pembrolizumab†
200 mg Q3W for 2 yrs
Pts stratified at randomization for PD-L1 TPS < 1% vs ≥ 1%.
*CP dosing: pemetrexed 500 mg/m2 + carboplatin AUC 5 mg/mL/min Q3W for 4 cycles. Optional
maintenance therapy with pemetrexed 500 mg/m2 Q3W permitted in both arms.
†Pts in CP arm could cross over to pembrolizumab monotherapy following disease progression.
PD

KEYNOTE-021g: PFS
Slide credit: clinicaloptions.comBorghaei H, et al. ESMO 2017. Abstract LBA49.
PFS(%)
Mos
0 3 6 9 12 15 18 21 24 27
0
20
40
60
80
100
60
63
Patients at Risk, n
51
42
43
35
32
25
24
18
22
13
17
8
9
5
1
1
0
0
Median, Mos (95% CI)
19.0 (8.5-NR)
8.9 (6.2-11.8)
57%
37%
52%
29% Events,
n/N
26/60
40/63
Pembro + PC
PC alone
HR
(95% CI)
0.54
(0.33-0.88)
P = .0067

Eventos Adversos Relacionados con Autoinmunidad Observados Con los Inhibidores
del Retén Inmunológico
Minchot JM, et al. Eur J Cancer. 2016;54:139-148. Photo courtesy of Elizabeth R. Plimack, MD, MS.
Uveitis
Inflamación orbital
PneumonitisHipotiroidismo
Hepatitis
Rash y
vitiligo
Pancreatitis
Diabetes autoinmune
Insuficiencia
adrenal
Enterocolitis
Artralgia
Xerostomía
Hipofisitis

Survival
Time
?
Survival Pattern with Chemotherapy Immune checkpoint blockade
and combinations (potential)
Immune checkpoint
Combinations immune (in theory)

Conclusions
Immunotherapy for NSCLC
Improvement in
disease-related
outcomes in NSCLC
Second-Line
Nivolumab approved in squamous
and non-squamous NSCLC: improves OS
First-Line
Single-agent Pembrolizumab with or
without chemotherapy for Non-mutated
Metastatic NSCLC: improves OS
Genotyping is necessary
Non-Squamous, advanced NSCLC
- First-Line targeted therapy
- continues to be the best option

Control
Targeted therapies
Immune checkpoint blockade
Combinations/sequencing
Survival
Time
Survival
Time
?
Survival Pattern with Chemotherapy (Control), Targetet therapies,
Immune checkpoint blockade and combinations (potential)

Survival
Time
?
Survival Pattern with Chemotherapy (Control), Immune checkpoint
blockade and combinations (potential)
Immune checkpoint
Combinations immune (in theory)

Immunoterapia y terapia dirigida en cáncer de pulmón

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