Inmunoterapia y terapia dirigida en cáncer de pulmón (versión larga)

Inmunoterapia y terapia dirigida en cáncer de pulmón
Mauricio Lema Medina MD
Clínica de Oncología Astorga / Clínica SOMA - Medellín, Colombia
Medellín, 03/11/2018

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)

Atezolizumab
Docetaxel
55%
40%
41%
27%
18-mo OS
12-mo OS Minimum follow-up: 19 mos
HR: 0.73
(95% CI: 0.62-0.87;
P = .0003)
Rittmeyer A, et al. Lancet. 2017;389:255-265.
Atezolizumab vs Docetaxel in Previously Treated
Advanced NSCLC (OAK): OS (ITT; N = 850)
Pts at Risk, n
OS(%)
Mos
10
0
20
30
40
50
60
70
80
90
100
0 3 6 9 12 15 18 21 24 27
Atezolizumab
Docetaxel
1425
425
407
390
382
365
363
336
342
311
326
286
305
263
279
236
260
219
248
195
234
179
223
168
218
151
205
140
198
132
188
123
175
116
163
104
157
98
141
90
116
70
74
51
54
37
41
28
28
16
15
6
4
3

Immunotherapy in
1st-Line
Stage IV

49
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%

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

Cinética del inicio y resolución de los eventos adversos cutáneos
y gastrointestinales relacionados con terapia anti-PD-1/PD-L1
Weber JS, et al. J Clin Oncol. 2016;[Epub ahead of print].
*Cualquier grado.
Cutáneos*
GI*
Tiempo mediano (Semanas)
35
30
25
20
15
10
5
0
0 10 20 30 40
Proporciónaproximadade
pacientes(%)

Weber JS, et al. J Clin Oncol. 2016;[Epub ahead of print].
*Cualquier grado.
Tiempo mediano (Semanas)
Proporciónaproximadade
pacientes(%)
8
7
6
5
4
3
2
0
0 10 20 30 40
Endocrino*
Hepatico*
Pulmonar*
Renal*
1
Cinética del inicio y resolución de los eventos
adversos menos communes relacionados con
terapia anti-PD-1/PD-L1

IMpower150: Phase III Chemo + Atezolizumab,
Bevacizumab, or Both in Advanced NSCLC
Patients with stage
IV/recurrent
nonsquamous NSCLC,
no prior chemo*, any
PD-L1 status
(N = 1202)
Atezolizumab 1200 mg Q3W
Carboplatin/Paclitaxel
Bevacizumab 15 mg/kg Q3W
Atezolizumab 1200 mg Q3W
Bevacizumab 15 mg/kg Q3W
Continue atezolizumab until
loss of clinical benefit
Stratified by sex, PD-L1 IHC status, liver mets 4 or 6 cycles
Atezolizumab
Bevacizumab
Atezolizumab
Bevacizumab
*Patients with EGFR or ALK aberrations must have progressed on approved therapies
 Goal: Determine benefit of addition of atezolizumab to carboplatin/paclitaxel/bevacizumab
 Primary endpoints: PFS (investigator) and OS
 Secondary endpoints: PFS (IRF), responses, OS at 1 and 2 years, safety, symptoms, PK
Reck M, et al. ESMO I-O 2017. Abstract LBA1_PR.
ClinicalTrials.gov. NCT02366143.
Maintenance
(no crossover)
Continue atezolizumab until
loss of clinical benefit and
bevacizumab until PD,
toxicity, or death
Continue bevacizumab until
PD, unacceptable toxicity, or
death

IMpower150: PFS
Median PFS, Mos (95% CI)
Atez/bev/CP 8.3 (7.7-9.8)
Bev/CP 6.8 (6.0-7.1)
Reck M, et al. ESMO I-O 2017.
Abstract LBA1_PR.
Median OS (Prelim), Mos (95% CI)
Atez/bev/CP 19.2 (16.8-26.1)
Bev/CP 14.4 (12.8-17.1)
HR: 0.62 (95% CI: 0.52-0.74; P < .0001)
Minimum follow-up: 9.5 mos
Median follow-up: ~ 15 mos
PFS
OS
PFS(%)
100
80
60
40
20
0
0 6 12 18 24 30
OS(%)
100
80
60
40
20
0
0 6 12 18 24 30
HR: 0.78 (95% CI: 0.62-0.97; P = .0262)
67%
56% 37%
18%
April 2018 press release reports positive OS results in interim
analysis; data to be presented at upcoming oncology congress.

IMpower150: PFS by Patient Subgroups
 Similar results by PD-L1 expression level tested with either SP142 or SP263
antibodies
Patient Group
Median PFS, mos
HRAtezolizumab +
Bevacizumab + CP
Bevacizumab + CP
T-effector gene signature high (n = 284) 11.3 6.8 0.51
T-effector gene signature low (n = 374) 7.3 7.0 0.76
PD-L1 high (n = 101) 12.6 6.8 0.39
PD-L1 low (n = 167) 8.3 6.6 0.56
PD-L1 negative (n = 235) 7.1 6.9 0.77
EGFR/ALK positive* (n = 108) 9.7 6.1 0.59
Liver metastases (n = 110) 8.2 5.4 0.40
Kowanetz M, et al. AACR 2018. Abstract CT076. Slide credit: clinicaloptions.com
*Eligible with progression/intolerance to ≥ 1 approved targeted therapy.

IMpower 150: PFS in Patients With Actionable EGFR
Mutations (Exon 19 Deletion or L858R Mutation)
Kowanetz M, et al. AACR 2018. Abstract CT076.
Arm B: Atez/Bev/CP
Arm C: Bev/CP
HR = 0.41
(95% CI: 0.22, 0.78)
EGFR Exon 19 Deletion or L858R Mutation
Median, 6.1 mos
(95% CI: 5.1, 8.5)
Median, 10.2 mos
(95% CI: 8.3, NE)0
20
40
60
80
100
0 2 6 8 10 14 16 18
Mos
PFS(%)
27
32
25
30
24
27
20
17
18
14
9
6
5
5
4
4
Atez/Bev/CP
Bev/CP
4 12 20 22
No. at Risk
2
2
1
1
0
1
0
1

Phase III IMpower132: Addition of Atezolizumab to
First-line Carboplatin/Cisplatin + Pemetrexed in
Stage IV Nonsquamous NSCLC
Supported by educational grants from AbbVie, AstraZeneca, Genentech, and Takeda Oncology.
Building a Bridge Between Science and Practice:
CCO Independent Conference Highlights*
from the 19th World Conference on Lung Cancer;
September 23-26, 2018; Toronto, Canada
*CCO is an independent medical education company that provides state-of-the-art medical information to
healthcare professionals through conference coverage and other educational programs.

First-line Atezo + Carboplatin/Cisplatin + Pemetrexed in
Stage IV NSCLC (IMpower132): Background
 Atezolizumab is a PD-L1 inhibitor used for treating patients with NSCLC who
progress on or following platinum chemotherapy
‒ Phase III OAK: second-line atezolizumab vs docetaxel in advanced NSCLC with
progression on platinum agents[1]
‒ Median OS significantly longer with atezolizumab (HR: 0.79)
‒ Median PFS slightly longer with atezolizumab (HR: 0.95)
‒ Exploratory OS analysis: high PD-L1 expression associated with longer survival (HR:
0.64 vs 0.82 at lower PD-L1 level)
 Current analysis of IMpower132 evaluated PFS, safety of first-line
atezolizumab plus carboplatin/cisplatin and pemetrexed in patients with
stage IV nonsquamous NSCLC[2]
Slide credit: clinicaloptions.com1. Rittmeyer A, et al. Lancet. 2017;389:255-265. 2. Papadimitrakopoulou VA, et al. WCLC 2018. Abstract OA05.07.

IMpower132 Phase III Study Design: First-line Atezo +
Carboplatin/ Cisplatin + Pemetrexed in Stage IV NSCLC
 Coprimary endpoints: Investigator-assessed PFS and OS
 Secondary endpoints: Investigator-assessed ORR and DoR, patient-reported outcomes, safety
 Exploratory analyses: clinical and biomarker subgroups
Patients with stage IV
nonsquamous NSCLC
without EGFR or ALK
alterations and no prior
chemotherapy
(N = 578)
Maintenance
until PD or loss of
clinical benefit
Atezolizumab 1200 mg +
Carboplatin AUC 6 or
Cisplatin 75 mg/m2 +
Pemetrexed 500 mg/m2
Q3W x 4 or 6 cycles
(n = 292)
Carboplatin AUC 6 or
Cisplatin 75 mg/m2 +
Pemetrexed 500 mg/m2
Q3W x 4 or 6 cycles
(n = 286)
Stratified by sex, smoking status,
ECOG PS (0 vs 1), chemotherapy regimen
Atezolizumab +
Pemetrexed
4 or 6 cycles
Pemetrexed
4 or 6 cycles
Induction Maintenance
Papadimitrakopoulou VA, et al. WCLC 2018. Abstract OA05.07.

IMpower132: Baseline Characteristics
Characteristic
Atezolizumab, Platinum, Pemetrexed
(n = 292)
Platinum, Pemetrexed
(n = 286)
Median age, yrs (range) 64.0 (31-85) 63.3 (33-83)
 < 65 yrs, n (%) 153 (52.4) 167 (58.4)
Male, n (%) 192 (65.8) 192 (67.1)
White/Asian, n (%) 193 (66.1)/71 (24.3) 203 (71.0)/65 (22.7)
ECOG PS 0, n (%) 126 (43.2) 114 (40.1)
Previous carboplatin, n (%) 177 (60.6) 175 (61.1)
Completed intended 4 cycles of induction, n (%) 197 (67.5) 190 (66.4)
Current or former smoker/never smoker, n (%) 255 (87.3)/37 (12.7) 256 (89.5)/30 (10.5)
Liver metastases, n (%) 37 (12.7) 36 (12.6)
PD-L1 expression, n (%) (n = 176) (n = 168)
 Negative 88 (50.0) 75 (44.6)
 Positive 88 (50.0) 93 (55.4)
• PD-L1 low 63 (35.8) 73 (43.5)
• PD-L1 high 25 (14.2) 20 (11.9)
Slide credit: clinicaloptions.comPapadimitrakopoulou VA, et al. WCLC 2018. Abstract OA05.07.

23
IMpower132: PFS, ORR, DoR
Median follow-up: 14.8 mos
Outcome Atezolizumab,
Platinum,
Pemetrexed
(n = 292)
Platinum,
Pemetrexed
(n = 286)
PFS, %
 6 mos 59.1 40.9
 12 mos 33.7 17.0
ORR, % 47 32
 CR 2 1
 PR 45 32
Median DoR, mos 10.1 7.2
Ongoing response, % 42 30
Atezo + chemo
Chemo
7.6
5.2
0.60
(95% CI: 0.49-0.72)
< .0001
Median
PFS, Mos HR (95% CI) P Value
APP
PP
100
90
80
70
60
50
40
30
20
10
0
PFS(%)
Mos
0 1 2 3 4 5 6 7 8 9 10111213141516171819202122
Patients at Risk, n
APP
PP
292
286
2280
273
260
236
231
195
224
178
19
142
169
115
149
98
140
87
120
72
110
59
109
53
88
44
48
15
43
11
31
6
26
6
11
3
10
3
274
39

Subgroup n (%) HR (95% CI) Median PFS, Mos
APP PP
Female 194 (34) 0.51 (0.36-0.71) 8.3 5.3
Male 384 (66) 0.64 (0.51-0.79) 7.5 4.9
< 65 yrs 320 (55) 0.63 (0.49-0.80) 6.9 4.4
≥ 65 yrs 258 (45) 0.55 (0.42-0.73) 8.4 5.6
White 396 (69) 0.67 (0.54-0.84) 6.9 4.9
Asian 136 (24) 0.42 (0.28-0.63) 10.2 5.3
ECOG PS 0 240 (42) 0.56 (0.42-0.76) 8.6 5.8
ECOG PS 1 336 (58) 0.63 (0.49-0.79) 6.8 4.4
Received carboplatin 352 (61) 0.54 (0.43-0.69) 8.1 5.5
Received cisplatin 226 (39) 0.65 (0.48-0.88) 7.1 4.4
Intended 4 cycles 387 (67) 0.54 (0.43-0.67) 7.8 4.5
Intended 6 cycles 191 (33) 0.71 (0.51-0.98) 7.6 5.6
Current or former smoker 511 (88) 0.61 (0.50-0.74) 7.5 5.1
Never smoker 67 (12) 0.49 (0.28-0.87) 8.6 5.5
Liver metastases 73 (13) 0.77 (0.47-1.25) 4.4 4.0
No liver metastases 505 (87) 0.56 (0.46-0.69) 8.4 5.5
ITT population 578 (100) 0. 60 (0.49-0.72) 7.6 5.2
IMpower132: PFS by Patient Subgroup
HR
Favors PPFavors APP
0.2

IMpower132: OS (Interim)
Atezo + chemo
Chemo
18.1 (13.0-NE)
13.6 (11.4-15.5)
0.81
(95% CI: 0.64-1.03)
< .0797
Median OS,
Mos (95% CI) HR (95% CI) P Value
59.6
55.4
12-Mo OS, %
OS(%)
100
90
80
70
60
50
40
30
20
10
0
Mos
230 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
Patients at Risk
APP
PP
292
286
284
278
273
265
258
246
252
233
239
219
228
210
212
193
202
179
194
166
187
163
179
151
168
147
140
126
107
92
79
58
62
43
48
30
32
22
23
15
10
8
7
4
1
2 1

IMpower132: PFS by PD-L1 Status in Biomarker-Evaluable
Patients
PD-L1 Low
TC1/2 or IC1/2
PD-L1 Negative
TC0 and IC0
PD-L1 High
TC3 or IC3
Platinum,
Pemetrexed
Platinum,
Pemetrexed
ORR, % 72 55
 CR/PR 0/72 5/50
Median DoR, mos NE 7.2
12-mo PFS, % 46 25
Median PFS, mos 10.8 6.5
PFS HR (95% CI) 0.46 (0.22-0.96)
Platinum,
Pemetrexed
Platinum,
Pemetrexed
ORR, % 38 38
 CR/PR 2/37 0/38
12-mo PFS, % 27 20
PFS HR (95% CI) 0.80 (0.56-1.16)
Platinum,
Pemetrexed
Platinum,
Pemetrexed
ORR, % 44 27
 CR/PR 2/42 0/27
12-mo PFS, % 35 8
PFS HR (95% CI) 0.45 (0.31-0.64)
APP (n = 25)
PP (n = 20)
APP (n = 63)
PP (n = 73)
APP (n = 88)
PP (n = 75)
Mos
PFS(%)
100
90
80
70
60
50
40
30
20
10
0
230 1 2 3 4 5 6 7 8 9 10111213141516171819202122
Mos
PFS(%)
100
90
80
70
60
50
40
30
20
10
0
230 1 2 3 4 5 6 7 8 9 10111213141516171819202122
Mos
PFS(%)
100
90
80
70
60
50
40
30
20
10
0
230 1 2 3 4 5 6 7 8 9 10111213141516171819202122

IMpower132: Subsequent Cancer Therapies
Treatment Parameter, n (%) Atezolizumab, Platinum, Pemetrexed
(n = 292)
Platinum, Pemetrexed
(n = 286)
≥ 1 treatment 94 (32.2) 148 (51.7)
No. of patients with ≥ 1 immunotherapy treatment 8 (2.7) 106 (37.1)
No. of treatments by immunotherapy agent, n 10 117
 Nivolumab 4 (1.4) 64 (22.4)
 Pembrolizumab 0 27 (9.4)
 Atezolizumab 2 (0.7) 10 (3.5)
 Durvalumab 0 3 (1.0)
 Daratumumab 0 2 (0.7)
 Other immunotherapy agents 4 (1.4) 7 (2.6)
Patients with ≥ 1 chemotherapy 86 (29.5) 71 (24.8)
No. of patients with ≥ 1 targeted therapy 36 (12.3) 36 (12.6)
 No. of treatments with antiangiogenic agents 33 (11.3) 29 (10.1)

IMpower132: Safety
AE, n (%) Atezolizumab,
Platinum,
Pemetrexed
(n = 291)
Platinum,
Pemetrexed
(n = 274)
All-cause AEs 286 (98) 266 (97)
 Grade 3/4 181 (62) 147 (54)
 Grade 5 21 (7) 14 (5)
TRAEs 267 (92) 239 (87)
 Grade 3/4 156 (54) 107 (39)
 Grade 5 11 (4) 7 (3)
SAEs 134 (46) 84 (31)
Tx-related SAEs 96 (33) 43 (16)
AEs leading to withdrawal
 Of any treatment 69 (24) 48 (18)
 Of atezolizumab 44 (15) 0
AESI 141 (49) 104 (38)
AEs of Special Interest, % Atezolizumab,
Platinum,
Pemetrexed
(n = 291)
Platinum,
Pemetrexed
(n = 274)
All Grade/≥ 3 All Grade/≥ 3
Rash 24/3 21/2
Hypothyroidism 8/< 1 2/0
Pneumonitis 6/2* 2/1*
Hepatitis (diagnosis) 5/2* 1/0
Infusion-related reactions 3/< 1 1/< 1
Hyperthyroidism 2/< 1 1/0
Severe cutaneous
adverse reaction
1/1 1/0
Pancreatitis 1/< 1 1/1
Colitis 2/1 0/0
*Grade 5 event observed.

IMpower132: Conclusions
 Coprimary endpoint of investigator-assessed PFS met
‒ Atezolizumab added to first-line carboplatin/cisplatin and pemetrexed
significantly improved median PFS (ITT) in patients with stage IV
nonsquamous NSCLC
‒ 7.6 vs 5.2 mos without atezolizumab (HR: 0.60; P < .0001)
‒ Benefit seen across key clinical subgroups
 The atezolizumab-containing regimen showed a manageable safety
profile consistent with known toxicity profiles of the individual agents
‒ No new safety signals observed
 Numerical improvement in OS observed at interim analysis; next OS
analysis in 2019

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

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

CheckMate 227: Nivolumab ± Ipilimumab vs CT
as First-line Therapy in Stage IV NSCLC
 Randomized, open-label, multipart phase III trial
Patients with stage
IV/recurrent NSCLC and no
prior systemic tx, no actionable
EGFR/ALK mutations, no
autoimmune disease, no
untreated CNS mets
(N = 1739)
Nivo 3 mg/kg Q2W + Ipi 1 mg/kg Q6W
SoC Chemo* Q3W X 4 cycles
Nivolumab 240 mg Q2W
Nivo 3 mg/kg Q2W + Ipi 1 mg/kg Q6W
SoC Chemo* Q3W X 4 cycles
Nivo 360 mg Q3W + SoC Chemo* Q3W X 4 cycles
PD-L1 ≥ 1%
(n = 1189)
PD-L1 < 1%
(n = 550)
*Nonsquamous: cisplatin or carboplatin + pemetrexed with
optional maintenance pemetrexed ± nivolumab;
squamous: cisplatin or carboplatin + gemcitabine.
1:1:1
1:1:1
Stratified by histology
(sq vs nonsq)
Hellmann MD, et al. N Engl J Med. 2018;[Epub ahead of print]. Slide credit: clinicaloptions.com
 Primary endpoints: PFS by TMB
(≥ 10 mutations/Mb), OS by PD-L1
expression level

3 21
CheckMate 227: Efficacy in Patients With High
Tumor Mutation Burden
HR = 0.58 (97.5% CI: 0.41-0.81)
P < .001
Patient Subgroup Unstratified HR for
PFS (95% CI)
Age, yrs
< 65 (n = 156)
≥ 65 (n = 143)
≥ 75 (n = 27)
0.51 (0.34-0.77)
0.62 (0.40-0.97)
0.42 (0.14-1.30)
ECOG PS
0 (n = 105)
1 (n = 192)
0.62 (0.38-1.02)
0.55 (0.38-0.80)
Tumor histology
Squamous (n = 100)
Nonsquamous (n = 199)
0.63 (0.39-1.04)
0.55 (0.38-0.80)
PD-L1 expression level, %
< 1 (n = 86)
≥ 1% (n = 213)
0.48 (0.27-0.85)
0.62 (0.44-0.88)
 ORR: 45.3% vs 26.9% for nivolumab/ipilimumab vs chemotherapy,
respectively
0
20
40
60
80
100
0 6 9 12 15 18
PFS(%)
Nivolumab +
ipilimumab
Chemotherapy
24
Mos
43%
13%

CheckMate 227: Treatment-Related Adverse
Events
Event, n (%) Nivolumab + Ipilimumab
(n = 576)
Nivolumab
(n = 391)
Chemotherapy
(n = 570)
Any Grade Grade 3/4 Any Grade Grade 3/4 Any Grade Grade 3/4
Any 433 (75.2) 180 (31.2) 251 (64.2) 74 (18.9) 460 (80.7) 206 (36.1)
Any serious 138 (24.0) 102 (17.7) 42 (10.7) 30 (7.7) 79 (13.9) 61 (10.7)
Leading to
discontinuation
100 (17.4) 69 (12.0) 45 (11.5) 27 (6.9) 51 (8.9) 28 (4.9)
 Most common all-grade TRAEs (≥ 10% incidence)
– Nivolumab + ipilimumab: rash, diarrhea, pruritus, fatigue, decreased appetite, hypothyroidism;
grade 3/4 events were rare
– Chemotherapy: nausea, fatigue, anemia, neutropenia, constipation, vomiting, asthenia, decreased
appetite; only grade 3/4 anemia and neutropenia occurred in ≥ 5% of pts
 Treatment-related deaths: nivolumab + ipilimumab, n = 7; nivolumab, n = 2; chemotherapy,
n = 6

Targeted therapy
in mNSCLC
(mEGFR,
ALK/EML4+, etc)
Stage IV

Heather Wakelee, MD
Professor of Medicine, Oncology
Department of Medicine/Oncology
Stanford University/Stanford Cancer Institute
Stanford, California
The Evolving Landscape of Frontline EGFR TKIs
This activity is supported by an educational grant from Pfizer Inc.

Extracellular
Domain
Transmembrane
Domain
Intracellular
Domain
EGF Pathway
• EGFR: transmembrane protein
Tyrosine Kinase
Domain
Adapted from:
Ciardiello F, et al. N Engl J Med. 2008;358:1160-1174. www.clinicaloptions.com

HER/erbB family
Salomon DS, et al. Crit Rev Oncol Hematol 1995;19:183–232
Woodburn JR. Pharmacol Ther 1999;82:241–50
HER1
EGFR
erbB1
HER2
erbB2
neu
EGF
TGF-α
Amphiregulin
Betacellulin
HB-EGF
Epiregulin
Heregulins
NRG2
NRG3
Heregulins
Betacellulin
Cysteine-
rich
domains
Tyrosine-
kinase
domains
HER3
erbB3
HER4
erbB4
Ligands:

EGF
ActiveInactive
EGFR dimerization
Signaling
C-Lobe
JM
CR1
L2
CR2
L1
C-Lobe
JM
CR1
L2
CR2
L1
EGF
C-Lobe
JM
L1
L2
CR2
CR1
EGF

ProliferationApoptosis Resistance Transcription
TGFα Interleukin-8
bFGF VEGF
MetastasisAngiogenesis
Shc
PI3K
RafMEKK-1
MEKMKK-7
JNK ERK
Ras
mTOR
Grb2
AKT
Sos-1
EGF Pathway
www.clinicaloptions.com

p27
E2F 1-3
KSR
Growth Factor signaling modules
CR1GF
L1
L2
CR2
CR1
Y845
Kinase
Y1173
Y1086
Y891
Y992
Y1148
Y1045
Y920
Y1068
L1
L2
CR2
Y845
Kinase
Y1173
Y1086
Y891
Y992
Y1148
Y1045
Y920
Y1068
GFCR1
PI3K
PDK
aPKC
AP-1 AP-1
STAT 3
P
STAT 3
P
PP
Grb2
SOS
Ras
SHC
Src STAT 3
P
STAT 3
P
STAT 3
P
p70S6K
P
P
SRFElk Ets
P
TCFCRE NFkBCRE
PP
NFkB
P P
MEK1/2
ERK1/2S217 S221
T202
Raf1
S338
Y341
14-3-3
GSK-3
-Catenin
S9
Glycogen
syntahse
CRMP-2
WNK-1
P
P
P
P
APC
P
MAP1B
P
PKB
T308 S473
Bad
P
Cas 9
P
XIAP
P
P
PFK-2
ATP-citrate
lyase
PKC
P
PKC
P
PKC
P
PLC1
p90Rsk
MEKK2
JNK1/2
MKK7
MKK4
PP
Grb2
SOS
Rac/Rho
PP
DAG
IP3
PKC
RKIP
S153 I-1
P
PP1
MARCKS
Ca
Ca
Ca Ca
Ca
Ca
Ca
Ca
Ca
CaM
CamKIICaM MLCKCaM
P
DAPKCaM
P
P
Fascin
P
P
S129
Bcl-2
G1
S
G2
M
mTOR
P
Raptor
GL FKBP12
4EBP1
P
S6
p70S6K
P
P
AAAAA
60S
40S
PTEN
P
P
Cot
P
FOXO1
Foxa2
P
P
P
C-Myc
E2F 1-3
ATM
Cyclin D1
CDK4/6
pRb
HDM2
P
p53
P
GRK5CaM
FOXO1
P
P
P
P

Kinase domain N-lobe
EGFR mutations in human cancer
CR2
476-621
L1
1-163
N-lobe
686-769L2
310-475
CRD
961-1211
CR1
164-309
TM
622-644
JM
645-685
C-lobe
773-960
L858R
lung
R108K
neuronal
L861Q
lung
Frequency of mutation:
≥40%
<5%
5-40%
Ligand bs Ligand bs
A1048V
stomach
R677H
neuronal
C624F
neuronal
P598V
glioblastoma,
neuronal
P596L
glioblastoma,
neuronal
R324L
neuronal
D1012H
lung
686 960
Kinase domain C-lobe
E709K
lung,
prostate
E709A
lung
E709G
lung
G719S
lung,
intestine
G719C
lung
G719A
lung
L833V
lung
T790M
lung,
neuronal,
oesophagus
L858R
lung
L858Q
lung
L858M
lung
H835P
breast
H835L
breast,
lung
T710I
breast
E872K
breast
E872X
oesophagus
L861Q
lung, neuronal
L861R
lung
L861V
lung
E866K
breast, lung
delL747-A751insP
lung
delL747-A751insS
lung
delL747-T751
lung
delL747-S752
lung
delE747-A750insP
lung
delL747-P753
lung
delL747-P753insQ
lung
delL747-P753insS
lung
delE746-T751insA
lung
delE746-T751insI
lung
delE746-A751
lung
delE746-T750insRP
lung
delK745-E749
lung
delE746-A750
lung
delE746-S752insA
lung
delE746-S752insV
lung
delE746-S752insVA
lung
EGFRvIII:
delV30-R297insG
glioblastoma,
lung, breast
Catalytic site
R108K
neuronal
T263P
glioblastoma,
neuronal
A289V
glioblastoma,
neuronal
A289D
glioblastoma,
neuronal
A289T
glioblastoma,
neuronal
delD770-N771insSVD
lung
delD770-N771insG
lung
delH773_V774insNPH
lung
delV774_C775insHV
lung
delV769-D770insASV
lung
S768I
lung, neuronal,
oesophagus
S768ins
lung
H774M
lung
H773R
lung

EGFR in NSCLC: two distinct pathways
Nucleus
Adaptor
Survival
PIP2
PI3K
PIP3
PTEN
AKT
Apoptosis
regulators
Proliferation
Adaptor
Transcription
factors
MAPK
MEK
RAFGTP-RASGDP-RAS
Sordella, et al. Science 2004
ATP ATP
 Greater signalling through the
MAPK pathway producing
excessive cell proliferation
 Higher affinity for ATP than
mutant receptor, so greater
competition with EGFR TKIs for
binding sites; higher
concentrations needed to inhibit
 Successful inhibition of wild-type
EGFR reduces proliferation and
halts tumour growth
 Higher incidence of stable disease
EGFR
wild-type

EGFR in NSCLC: two distinct pathways
ATP
Nucleus
Adaptor
Survival
PIP2
PI3K
PIP3
PTEN
AKT
Apoptosis
regulators
Proliferation
Adaptor
Transcription
factors
MAPK
MEK
RAFGTP-RASGDP-RAS
Sordella, et al. Science 2004
ATP
 Preferential signalling through the PI3K-
mediated anti-apoptotic pathway –
‘oncogene addiction’
 Reduced affinity for ATP means EGFR TKIs
have less competition for binding sites;
lower concentrations sufficient to inhibit
 Successful inhibition of mutated EGFR
produces ‘apoptotic shock’
 Higher incidence of complete or partial
response
EGFR
mutation
+ve

Carboplatin
+ Paclitaxel
Gefitinib
Primary Endpoint
 PFS (noninferiority)
Secondary Endpoints
 Objective response rate
 OS
 Quality of life
 Disease-related symptoms
 Safety and tolerability
Exploratory
 Biomarkers
– EGFR mutation
– EGFR gene copy number
– EGFR protein expression
Patients
 Chemo naive
 18 yrs of age or
older
 Adenocarcinoma
histology
 Never or ex-light
smokers*
 Life expectancy
≥ 12 wks
 WHO PS 0-2
 Measurable stage
IIIB/IV disease
Conducted in China, Japan, Thailand, Taiwan, Indonesia, Malaysia,
Philippines, Hong Kong, and Singapore
94% never-smokers; ~ 80% female
Mok TS, et al. N Engl J Med. 2009;361:947-957.
IPASS: Importance of EGFR Mutation on
Patient Outcome—Gefitinib vs Chemo

EGFR Mutation Positive EGFR Mutation Negative
Treatment by subgroup interaction test, P < .0001
HR: 0.48 (95% CI: 0.36-0.64;
P < .0001)
Gefitinib events , n (%) 97 (73.5)
C/P events, n (%) 111 (86.0)
Gefitinib (n = 132)
Carboplatin/paclitaxel (n = 129)
HR: 2.85 (95% CI: 2.05-3.98;
P < .0001)
Gefitinib events, n (%) 88 (96.7)
C/P events, n (%) 70 (82.4)
0 4 8 12 16 20 24
0
0.2
0.4
0.6
0.8
1.0
ProbabilityofPFS
0 4 8 12 16 20 24
0
0.2
0.4
0.6
0.8
1.0
ProbabilityofPFS
Gefitinib (n = 91)
Carboplatin/paclitaxel (n = 85)
Mos Mos
 Clinical characteristics are insufficient for selection of first-line EGFR TKI therapy
 Front-line EGFR TKI should be restricted to EGFR mutation–positive patients
IPASS: PFS in EGFR Mutation–Positive and –Negative
Patients

PHASE III EURTAC STUDY DESIGN
Primary endpoint
• Progression-free survival (PFS)
Erlotinib
Platinum-based
doublet chemotherapy
• Chemonaїve
• Stage IIIB/IV NSCLC
• EGFR exon 19 deletion
or exon 21 L858R
mutation
• ECOG PS 0-2
(n = 174)
PD
PD
R
Rosell R et al. Lancet Oncol 2012;13(3):239-46.
Crossover

EURTAC: PFS in ITT Population
Erlotinib (n = 86)
Chemotherapy (n = 87)
HR: 0.37 (95% CI: 0.25-
0.54; log-rank P < .0001)
PFSProbability
1.0
0.8
0.6
0.4
0.2
0
0 3 6 9 12 15 18 21 24 27 30 33
Mos
5.2 9.7
Patients at Risk, n
Erlotinib
Chemo
86
87
63
49
54
20
32
8
21
5
17
4
9
3
7
1
4
0
2
0
2
0
0
0
Rosell R, et al. ASCO 2011. Abstract 7503.

EURTAC: RESPONSE, PFS AND OS
Erlotinib
(n = 86)
Chemotherapy
(n = 87)
Overall response (CR + PR) 58% 15%
Median progression-free
survival
9.7 mos 5.2 mos
Median overall survival 19.3 mos 19.5 mos
Rosell R et al. Lancet Oncol 2012;13(3):239-46.
Crossover effect?

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

EGFR TKIs: Targeted Therapies for EGFR Mutations
Afatinib [package insert]. 2018. Erlotinib [package insert]. 2016. Gefitinib [package insert]. 2015. Osimertinib [package
insert]. 2015. Lin YT, et al. Clin Lung Cancer. 2017;18:324-332. Morgillo F, et al. ESMO Open. 2016;1:e000060.
FDA-Approved EGFR TKI
Location of EGFR Mutation
Exon 18 Exon 19 Exon 20 Exon 21
Erlotinib
Gefitinib
Afatinib
-- Deletion -- L858R
Osimertinib -- Deletion T790M L858R
Justified use (on/off label) of
erlotinib, gefitinib, afatinib
G719X* Insertion
A763_Y764insFQEA
S768I*
L861Q*
Mutations causing EGFR TKI
insensitivity
-- --
Insertion
C797S
T790M
--
*Afatinib approved with these mutations alone or in combination.

Parameter Erlotinib Gefitinib Afatinib Osimertinib Dacomitinib
Receptor
binding
EGFR/HER1,*
SRC, ABL?
EGFR/HER1,*
IGF, PDGF
EGFR/HER1,*
HER2, HER4
EGFR/HER1,*
HER2, HER3,
HER4, BLK,
ACK1
EGFR/HER1,*
HER2, HER4
EGFR binding Reversible Reversible Irreversible Irreversible Irreversible
Half life, hrs 36 48 37 48 59-85
Food effect
(take on empty
stomach)
Increase F from
~ 60% to ~ 100%
No change Decrease
AUC by 39%
No change No change
CNS
penetration,
AUC ratio
0.03X
CSF/Plasma
0.01X
CSF/Serum
0.02X
CSF/Plasma
2X
Brain/Plasma
Data not
available
EGFR TKIs: Properties
*All inhibit exon 19 deletion and L858R.
References in slidenotes. Slide credit: clinicaloptions.com

First-line EGFR TKIs vs Chemotherapy in
EGFR Mutation–Positive NSCLC: A Clear Pattern
Study N Treatment ORR, % Median PFS, Mos Median OS, Mos
NEJ002[1] 230
Gefitinib vs
carboplatin/paclitaxel
74 vs 31
10.8 vs 5.4
(P < .001)
30.5 vs 23.6
(HR: 0.89)
WJTOG 3405[2,3] 172
Gefitinib vs
cisplatin/docetaxel
62 vs 32
9.6 vs 6.6
(P < .001)
34.8 vs 37.3
(HR: 1.25)
OPTIMAL[4,5] 165
Erlotinib vs
carboplatin/gemcitabine
83 vs 36
13.1 vs 4.6
(P < .0001)
22.8 vs 27.2
(HR: 1.19)
EURTAC[6,7] 174
Erlotinib vs platinum-based
chemotherapy
58 vs 15
9.7 vs 5.2
(P < .0001)
22.9 vs 19.5
(HR: 0.93)
LUX-Lung 3[8,9] 345
Afatanib vs
cisplatin/pemetrexed
56 vs 23
11.1 vs 6.9
(P = .001)
28.2 vs 28.2
(HR: 0.88)
LUX-Lung 6[9,10] 364
Afatinib vs
cisplatin/gemcitabine
67 vs 23
11.0 vs 5.6
(P < .0001)
23.1 vs 23.5
(HR: 0.93)
References in slidenotes. Slide credit: clinicaloptions.com

Phase IIb LUX-Lung 7: Afatinib vs Gefitinib in EGFR-Mutated Advanced
NSCLC
 Coprimary endpoints: PFS, TTF, OS
 Secondary endpoints: ORR, time to response, DoR, DCR, duration of
disease control, tumor shrinkage, QoL
Park K, et al. Lancet Oncol. 2016;17:577-589. Slide credit: clinicaloptions.com
Afatinib*† 40 mg PO QD
(n = 160)
Gefitinib†‡ 250 mg PO QD
(n = 159)
Treatment continued
until PD or
unacceptable toxicity
Stratified by EGFR mutation (exon 19 deletion vs
L858R) and brain metastases at baseline (yes vs no)
Treatment-naive patients with
stage IIIB or IV lung adenocarcinoma,
exon 19 deletion or L858R
EGFR mutations, ECOG PS 0/1,
adequate organ function
(N = 319)
*Dose escalation to 50 mg allowed in absence of TEAEs.
†Treatment interruptions ≤ 14 days allowed. ‡Dose modifications allowed.

LUX-Lung 7: Survival
 Median follow-up: 42.6 mos
 Median treatment duration: afatinib, 13.7 mos; gefitinib, 11.5 mos
Paz-Ares L, et al. Ann Oncol. 2017;28:270-277. Slide credit: clinicaloptions.com
Afatinib
Gefitinib
Median PFS, Mos
11.0
10.9 HR: 0.86 (95% CI: 0.66-
1.12)
P = .2580
Afatinib
Gefitinib
Median OS, Mos
27.9
24.5
PFS
HR: 0.74 (95% CI: 0.57-0.95)
P = .0178
OS
0
Mos
PFS(%)
246 12 18 30 36 42
100
80
60
40
20
0Patients at
Risk, n
Afatinib
Gefitinib
3 9 2715 21 33 39 45 48 51
16
0
15
9
14
2
13
2
11
3
10
5
9
4
8
2
6
7
5
1
4
7
2
1
3
4
1
5
2
6
1
0
2
0
7
1
3
5
1
0
5
8
5
4
3
3
3
0
0
0
0
0
0
0
0
0
Mos
OS(%)
246 12 18 30 36 42
100
80
60
40
20
0Patients at
Risk, n
Afatinib
Gefitinib
3 9 2715 21 33 39 45 48 51
16
0
15
9
15
6
15
3
15
3
14
8
14
8
14
2
139
133
125
119
11
1
10
5
10
4
90
9
4
8
0
8
1
7
1
7
4
6
2
6
1
5
6
5
0
4
8
3
6
4
4
3
0
2
7
1
2
7
2
0
0
0

Phase III ARCHER 1050: Dacomitinib vs Gefitinib in EGFR-Mutated
Advanced NSCLC
 Primary endpoint: PFS by blinded independent review
 Secondary endpoints: PFS by investigator assessment, ORR, DoR, TTF,
OS, safety, patient-reported outcomes
Treatment-naive patients with
stage IIIB/IV or recurrent NSCLC,
EGFR-activating mutation(s);
ECOG PS 0/1; no prior systemic
therapy for advanced NSCLC;
no CNS metastases
(N = 452)
Stratified by race (Japanese vs Chinese vs other east Asian vs non-Asian),
EGFR mutation (exon 19 deletion vs L858R)
Dacomitinib 45 mg PO QD
(n = 227)
Gefitinib 250 mg PO QD
(n = 225)
Wu YL, et al. Lancet Oncol. 2017;18:1454-1466. Mok TS, et al. J Clin Oncol. 2018;36:2244-2250.
Treatment
continued in 28-day
cycles until PD or
unacceptable
toxicity

0
ARCHER 1050: PFS by Blinded Independent Review
Dacomitinib (n = 227)
Gefitinib (n = 225)
Median PFS,
Mos (95% CI)
14.7 (11.1-16.6)
9.2 (9.1-11.0)
Events, n
136
179
Mos
PFS(%)
HR: 0.59 (95% CI: 0.47-0.74; P < .0001)
246 12 18 30 36 42
100
80
60
40
20
0
Censored
Wu YL, et al. Lancet Oncol. 2017;18:1454-1466.
Patients at Risk, n
(no. censored)
Dacomitinib
Gefitinib
227 (0)
225 (0)
154 (23)
155 (15)
106 (31)
69 (23)
73 (36)
34 (27)
20 (74)
7 (40)
6 (88)
1 (45)
0 (91)
0 (46)
0 (91)
0 (46)

ARCHER 1050: Overall Survival
Slide credit: clinicaloptions.comMok TS, et al. J Clin Oncol. 2018;36:2244-2250.
HR: 0.760 (95% CI: 0.582-0.993; P = .0438)
Dacomitinib Gefitinib
Patients, n
Deaths, n
Median OS, mos
(95% CI)
30-mo OS rate, %
227
103
34.1
(29.5-37.7)
56.2
225
117
26.8
(23.7-32.1)
46.3
Mos
OS(%)
100
80
60
40
20
0
0 6 12 18 24 30 36 42 48
Patients at Risk, n
Dacomitinib
Gefitinib
227
225
206
213
188
186
167
144
138
113
77
63
14
12
3
3
0
0
Censored++++
+++ +
+
+
+
+ ++ ++
+
+++++ ++ ++
++++ ++++++ +++++ ++++++++++++ ++++++++
+ ++ + ++
+
+
++
+++++++ ++++++ + +++++++++
++
+
+
++++++
+ + ++ ++++ ++
+
+++ +++
++
+++
+ +
++
+
+
++
++

ARCHER 1050: Safety
 Most frequent grade ≥ 3 AEs with dacomitinib: dermatitis acneiform (13.7%),
diarrhea (8.8%), paronychia (7.5%), rash (4.4%), stomatitis (3.5%)
 Most frequent grade ≥ 3 AE with gefitinib: ALT increase (8.5%), AST increase (4.0%)
Parameter Dacomitinib
(n = 227)
Gefitinib
(n = 224)
Median time to dose reduction, mos (range) 2.8 (0.3-20.3) 3.3 (1.2-25.7)
Median duration of dose reduction, mos (range) 11.3 (0.1-33.6) 5.2 (0.3-17.8)
Dacomitinib reduction to 30 mg/day,* n (%) 88 (38.8) NA
Dacomitinib reduction 15 mg/day,† n (%) 63 (27.8) NA
Patients with dose reduction, n (%) 151 (66.5) 18 (8.0)
Mok T, et al. ASCO 2018. Abstract 9004.
*First dose reduction. †Second dose reduction.

AURA3: Osimertinib vs Platinum/Pemetrexed in EGFR
T790M–Positive Advanced NSCLC
 Multicenter, randomized, open-label phase III trial
 Primary endpoint: PFS (investigator assessed)
 Secondary endpoints: ORR (investigator assessed), DoR, DCR, tumor shrinkage, OS,
patient-reported outcomes, safety
Locally advanced or metastatic NSCLC
with disease progression and EGFR
T790M mutation after first-line EGFR
TKI therapy; ≤ 1 line of therapy for
advanced NSCLC
(N = 419)
Osimertinib 80 mg QD
(n = 279)
Platinum/Pemetrexed Chemotherapy*
Q3W for up to 6 cycles
(n = 140)
Stratified by race (Asian vs non-Asian)
*Pemetrexed 500 mg/m2 plus either carboplatin AUC 5 or cisplatin 75 mg/m2.

AURA3: PFS for Osimertinib vs Pemetrexed-Platinum in EGFR T790M–
Positive NSCLC
Mok TS, et al. N Engl J Med. 2017;376:629-640. Slide credit: clinicaloptions.com
mPFS, Mos
(95% CI)
HR for disease progression or death:
0.30 (95% CI: 0.23-0.41; P < .001)
Osimertinib
Pemetrexed-
platinum
Patients, n
10.1 (8.3-12.3)
4.4 (4.2-5.6)
279
140
9
0
20
40
60
80
100
0 3 6
PFS(%)
MosPatients at Risk, n
Osimertinib
Pemetrexed-platinum
279
140
240
93
162
44
88
17
12 15 18
50
7
13
1
0
0

Phase III FLAURA: Osimertinib vs SoC in EGFR-Mutated Advanced NSCLC
 Primary endpoint: PFS
 Secondary endpoints including ORR, DoR, DCR, OS, safety
Treatment-naive patients
with advanced NSCLC
adenocarcinoma with an
EGFR exon 19 or 21
mutation, WHO PS 0/1,
stable CNS mets permitted
(N = 556)
Osimertinib 80 mg PO QD
(n = 279)
Erlotinib 150 mg or Gefitinib 250 mg PO QD
(n = 277)
Until PD or
unacceptable
toxicity
Stratified by EGFR mutation (exon 19 deletion
vs L858R) and race (Asian vs non-Asian)
Soria JC, et al. N Engl J Med. 2018;378:113-125. Slide credit: clinicaloptions.com

FLAURA: PFS
PFS(%)
MosPatients at Risk, n
Osimertinib
Erlotinib or Gefitinib
100
80
60
40
20
0
0 6 9 2112 18 24 27
279
277
262
239
233
197
210
152
139
78
71
37
26
10
0
0
153
178
107
4
2
Median PFS, Mos (95%
CI)
Osimertinib (n = 279) 18.9 (15.2-21.4)
Erlotinib or Gefitinib (n = 277) 10.2 (9.6-11.1)
HR: 0.46 (95% CI: 0.37-0.57; P < .001)

Median OS,
Mos (95%
CI)
Osimertinib (n =
279)
NC
E or G (n = 277) NC
HR: 0.63 (95% CI: 0.45-0.88; P = .007*)
ProbabilityofOS
1.0
0.8
0.6
0.4
0.2
0
Mos
0 6 9 2112 18 24 27153 30 33
Patients at Risk, n
Osimertinib
E or G
279
277
276
263
269
252
253
237
243
218
232
200
154
126
87
64
4
1
0
0
0
0
29
24
FLAURA: Overall Survival (Preliminary Analysis)
 141 deaths in 556 patients at data cutoff: 25% maturity (osimertinib: 58 [21%]; SoC: 83 [30%])
*P < .0015 was required
for statistical significance
at current maturity.

AE, n (%)
Osimertinib (n = 279) Erlotinib or Gefitinib (n = 277)
Grade 1 Grade 2 Grade 3 Grade 1 Grade 2 Grade 3
Diarrhea 120 (43) 35 (13) 6 (2) 116 (42) 35 (13) 6 (2)
Dry skin 76 (27) 11 (4) 1 (< 1) 70 (25) 17 (6) 3 (1)
Paronychia 37 (13) 43 (15) 1 (< 1) 46 (17) 32 (12) 2 (1)
Stomatitis 65 (23) 13 (5) 1 (< 1) 47 (17) 8 (3) 1 (< 1)
Dermatitis acneiform 61 (22) 10 (4) 0 71 (26) 50 (18) 13 (5)
Decreased appetite 27 (10) 22 (8) 7 (3) 24 (9) 22 (8) 5 (2)
Pruritus 40 (14) 7 (3) 1 (< 1) 30 (11) 13 (5) 0
Cough 34 (12) 12 (4) 0 25 (9) 16 (6) 1 (< 1)
Constipation 33 (12) 9 (3) 0 28 (10) 7 (3) 0
AST increased 18 (6) 6 (2) 2 (1) 38 (14) 18 (6) 12 (4)
ALT increased 11 (4) 6 (2) 1 (< 1) 31 (11) 19 (7) 21 (8)
Grade 4 AEs: osimertinib, n = 1 stomatitis; SoC, n = 4 ALT increased.
FLAURA: Adverse Events
 Mean duration of exposure, mos: 16.2 (range: 0.1-27.4) with osimertinib; 11.5 (range: 0-26.2) with SoC
Soria JC, et al. N Engl J Med. 2018;378:113-125. Ramalingam S, et al. ESMO 2017. Abstract LBA2_PR. Slide credit: clinicaloptions.com

Evidence-Based Treatment for ALK rearrangement Positive NSCLC

ALK Gene Rearrangements
▪ Most common in younger nonsmokers with adenocarcinoma,
adenosquamous carcinoma, and rarely SCC
▪ Frequency: 4% overall, 33% in EGFR-negative never-smokers
▪ Several ALK variants identified in NSCLC
▪ Testing
– Vysis break apart FISH (> 15% cells with split signal in 50 nuclei
scored); ALK IHC also approved
– ALK next generation sequencing
▪ 3 agents now approved for ALK-positive NSCLC (first line and/or
after progression)
Shaw AT, et al. J Clin Oncol. 2009;27:4247-4253.
Soda M, et al. Nature. 2007;448:561-566. Slide credit: clinicaloptions.com

Hallberg B. Ann Oncol, 2016
ALK

Crizotinib
Ceritinib Alectinib
Lorlatinib Brigatinib
ALK

ALK TKI-treated patients
ALK

Crizotinib
(n = 172)
Chemotherapy
(n = 171)
HR (95% CI) 0.45 (0.35-0.60)
P value < .001
ORR, % 74 45
P value < .001
PROFILE 1014: First-line Crizotinib vs Pemetrexed/Platinum* in
Advanced NSCLC
• Phase III trial (N = 343) ALK-positive pts with nonsquamous NSCLC and no
prior systemic treatment for advanced disease
Solomon BJ, et al. N Engl J Med. 2014;371:2167-2177.
*Carboplatin or cisplatin.
100
80
60
40
0
20
0 5 10 15 20 25 30 35
PFS(%)
172
171
120
105
65
36
38
12
19
2
7
1
1
0
0
0
Crizotinib
Chemotherapy
Mos
Pts at
Risk, n
Crizotinib
CT

1
J-ALEX: Alectinib vs Crizotinib as First-line
Therapy for ALK-Positive NSCLC
Nokihara H, et al. ASCO 2016. Abstract 9007. Slide credit: clinicaloptions.com
10.2 mos
NR
270 3 6 9 12 15 18 21 24
100
80
60
40
20
0
PFS(%)
Pts at Risk, n
Alectinib
Crizotinib
103
104
103
102
93
86
76
65
49
40
36
21
27
14
9
4
1
Alectinib
(n = 103)
Crizotinib
(n = 104)
Events, n (%)
Median, mos (95% CI)
P value
HR (99.6826% CI)
25 (24.3)
NR (20.3-NR)
58 (55.8)
10.2 (8.2-12.0)
< .0001
0.34 (0.17-0.71)
Mos

ASCEND-4: First-line Ceritinib Vs Chemotherapy for
ALK-Positive NSCLC
 Randomized, global, open-label phase III study
 Primary endpoint: PFS
 Median DoR of 23.9 mos for pts treated with ceritinib
 Median PFS of 26.3 mos for pts without brain metastases at
screening treated with ceritinib
De Castro G, et al. WCLC 2016. Abstract PL03.07. Slide credit: clinicaloptions.com
Efficacy outcome
Ceritinib
(n = 189)
Chemotherapy
(n = 187)
HR P Value
Median PFS, mos 16.6 8.1 0.55 < .001
ORR, % 72.5 26.7 -- --
OIRR, % 72.7 (n = 22) 27.3 (n = 22) -- --

Response to Ceritinib or Alectinib in Previously Treated
ALK-Positive NSCLC
 Ceritinib
(2014) and
alectinib
(2015)
approved for
pts with ALK-
positive,
metastatic
NSCLC with
disease
progression on
or who are
intolerant to
crizotinib
Kim DW, et al. Lancet Oncol. 2016;17:452-63. Shaw AT, et al. Lancet Oncol.
2016;17:234-242. Ou SH, et al. J Clin Oncol. 2016;34:661-668. Slide credit: clinicaloptions.com
Pts
Alectinib
SLD,MaximumDecrease
FromBaseline(%)
140
120
100
80
60
40
20
0
-20
-40
-60
-80
-100
Systemic best overall response
PD (n = 11)
SD (n = 18)
PR (n = 35)
Ceritinib
ChangeFromBaseline
inSLDs(%)
100
80
60
40
20
0
-20
-40
-60
-80
-100
PD
SD
PR + CR

Key Treatment-Related AEs Associated With ALK
Inhibitors
 Predominantly grade 1/2
 Visual disorders: median onset < 2 wks
 GI effects include diarrhea, nausea, and vomiting
1. Rothenstein JM, et al. Curr Oncol.2014;21:19-26. 2. Liao BC, et al.
Ther Adv Med Oncol. 2015;7:274-290. 3. Kim DW, et al. Lancet Oncol.
2016;17:452-463. 4. Ou S, et al. J Clin Oncol. 2016;34:661-668. 5. Kim
DW, et al. ASCO 2016.Abstract 9007. Slide credit: clinicaloptions.com
AE, %
(All Grades)
Crizotinib[1] Ceritinib[2,3] Alectinib[2,4] Brigatinib[2,5]
Visual disorders 50-60 NR NR NR
Liver dysfunction 35-40 15-35 10-25 15
GI effects 40-60 60-85 10-15 25-40
Edema 20-30 NR 15-25 NR
Fatigue 15-30 40-45 25-30 20-30
HTN NR NR NR 21

Second-Generation ALK Inhibitor CNS
Activity
BrainORR(%)
(n = 8) (n = 28) (n = 33) (n = 17) (n = 16) (n = 35) (n = 25) (n = 18) (n = 18)
*No previous ALK inhibitor.
Ceritinib
(750 mg/day)
Alectinib
(600 mg BID)
Brigatinib
(90 or 180 mg QD)
Lorlatinib
(Various)
63.0%*
36.0%
39.4%
58.8%*
75.0%
57.0%
36.0%
67.0%
39.0%
0
10
20
30
40
50
60
70
80
90
100
Kim DW, et al. Lancet Oncol. 2016;17:452-463. Mok T, et al. ASCO 2015. Abstract
8059. Felip E, et al. ASCO 2015. Abstract 8060. Shaw AT, et al. Lancet Oncol.
2016;17:234-242. Ou S, et al. J Clin Oncol. 2016;34:661-668. Kim DW, et al. ASCO
2016. Abstract 9007. Solomon BJ, et al. ASCO 2016. Abstract 9009. Slide credit: clinicaloptions.com

Ceritinib
(N = 24)
Alectinib
(N = 17)
L1196M
G1269A
C1156Y
I1171T/N/S
G1202R G1202del
F1174C
V1180LS1206Y
E1210K
≥ 2 ALK mutations
ALK amplification
ALK WT
Gainor JF, et al. Cancer Discovery. 2016;6:1118-1133.
Brigatinib
(N = 6)
WT WT
WT
Resistance to Second-Generation ALK TKIs

Lorlatinib Inhibits All Known Crizotinib-
Resistance Mutations, Including ALK G1202R
Pt 1: ALK+ NSCLC
 Previously treated with crizotinib
and ceritinib
 Local molecular testing after
ceritinib with ALK G1202R
 Started lorlatinib at 75 mg QD
 Dose reduced to 50 mg QD
 Ongoing at > 16 mos
Pt 2: ALK+ NSCLC
 Previously treated with crizotinib
and brigatinib
 Local molecular testing after
brigatinib with ALK G1202R
 Started lorlatinib at 200 mg QD
 Dose reduced to 100 mg QD
 Ongoing at > 12 mos
Shaw AT, et al. ASCO 2015. Abstract 8018. Slide credit: clinicaloptions.com

Summary: ALK-Driven Disease
 All nonsquamous NSCLC should be tested for ALK mutations
– Pts tend to develop brain metastases
 Crizotinib improves response rate and PFS over chemotherapy in first-line and
second-line settings
 Second-generation ALK inhibitors ceritinib and alectinib are approved for secondary
refractory disease or intolerance to crizotinib
– Second-generation ALK inhibitors active in CNS disease
 Alectinib demonstrated improved response rate and PFS over crizotinib as first-line
therapy (J-ALEX)
 Many ALK-positive pts may derive benefit from multiple sequential ALK inhibitors

Evidence-Based Treatment for ROS1
rearrangement Positive NSCLC

ROS1 Fusion
 Most common in younger pts, never-smokers, adenocarcinoma, high-grade
histology[1]
 Frequency: 1.2% to 1.7% overall[2]
 Several variants identified; clinical significance unknown[3]
– FIG-, CD74-, SCL34A2-, TPM3-, SDC4-, EZR-, LRIG3, KDELR2-, and CCDC6-
 Testing: Vysis break apart FISH (> 15% cells with split signal in 50 nuclei
scored)[4-6]
– ROS1 NGS, PCR, IHC (not validated)
 Crizotinib highly active; FDA approved in March 2016 for ROS1-positive
NSCLC[7]
1. Bergethon K, et al. J Clin Oncol. 2012;30:863-870. 2. Davies KD, et al. Clin Cancer
Res. 2012;18:4570-4579. 3. Takeuchi K, et al. Nat Med. 2012;18:378-381. 4. Gu TL,
et al. PLoS One. 2011;6:e15640. 5. Birch AH, et al. PLoS One. 2011;6:e28250. 6. Lee
J, et al. Cancer. 2013;119:1627-1635. 7. Shaw AT, et al. ASCO 2012. Abstract 7508. Slide credit: clinicaloptions.com

ALK and ROS1 Encode Related Receptor
Tyrosine Kinases
Brock TG, Receptors and Tyrosine Kinases
http://www.caymanchem.com/app/template/Article.vm/article/2187
Ron
PTK7
ROS1
ALK
LTK

ROS 1 Fusion Gene
Arai, PLOS ONE; February 2013.

ROS1 Fusion
• Patients: Younger, never smokers, adenocarcinoma, high grade
histology
• Frequency: 1.2 -1.7% in all
• Biology: 9 variants have been identified in NSCLC so far
– Clinical significance is unknown. Mechanism of activation is
different.
– FIG-, CD74-, SCL34A2-, TPM3-, SDC4-, EZR-, LRIG3, KDELR2–,
and CCDC6–
• Testing: Visys break apart FISH (> 15% cells with split signal in 50
nuclei scored)
– ROS PCR, IHC
• Therapy: crizotinib
Shaw AT, JCO 2012;30:(suppl; abstr 7508)
Ou, Exp revi. of anticancer therapy 2012,;12
Gu TL, PLoS One. 2011; 6:e15640.
Birch AH, PLoS One. 2011; 6:e28250
Lee, Cancer May 2013
Davis Clin Cancer Res . Sep 2012
Bergeron, JCO, 30, 2012

Methods of ROS1 Detection
• RT-PCR
– Cons: False negatives; 9 variants have been described in a matter of
12 months. Has to be multiplexed, i.e., probes to all known variants.
Unknown variants will not be detected.
• FISH break apart
– Cons: if inversion involves a small locus it could be false negative; can
not distinguish variants; cut of is 15% of nuclei with split signal; low
throughput
• IHC
– Cons: not commercially available, several antibodies appear promising

Liu S. Future Medicinal Chemistry, 2018
ROS1
Crizotinib

Clinical Validation of ROS1 as a
Therapeutic Target
• 14 patients enrolled in phase I study
• Safety/efficacy of crizotinib 250mg bid
• ROS1 rearrangement by FISH
• Negative for ALK rearrangement
• Average 54 yo, 13/14 never smokers
• 80% received prior therapy
• 8/14 responded (57%)
Shaw et al. JCO. 2012, 30 (suppl; abstr 7508.)

Liu S. Future Medicinal Chemistry, 2018
ROS1

Activity of Crizotinib in Pts With ROS1 Fusions: Best
Overall Response
80
60
40
20
0
-20
-40
-60
-80
-100
ChangeFromBaseline(%)
PD
SD
PR
CR
Pts With NSCLC Who Tested Positive for ROS1 Fusion (N = 50)
100
72% ORR
Median PFS: 19.2 mos
(95% CI: 14.4-NR)
Shaw AT, et al. N Engl J Med. 2014;371:1963-1971.

1.0
Prolonged PFS With Crizotinib in ROS1-Positive NSCLC
0
ProbabilityofPFS
0 5 10 15 20 25
Mos
FDA approved in 2016 for ROS1-positive NSCLC
0.8
0.6
0.4
0.2
Median PFS: 19.2 mos
Shaw AT, et al. N Engl J Med. 2014;371:1963-1971. Slide credit: clinicaloptions.com

Summary: ROS1-Driven Disease
 All nonsquamous NSCLC should be tested for ROS1 mutations
 Crizotinib is highly active in patients with ROS1-positive NSCLC
– ORR of approximately 70%
– Prolonged PFS
 Crizotinib is approved by the FDA for pts with ROS1-positive NSCLC and is the
guideline recommended first-line therapy option in this setting

Entrectinib in ROS1-Positive NSCLC:
Pooled Analysis of 3 Early-Phase Studies
Supported by educational grants from AbbVie, AstraZeneca, Genentech, and Takeda Oncology.
Building a Bridge Between Science and Practice:
from the 19th World Conference on Lung Cancer;
September 23-26, 2018; Toronto, Canada

Entrectinib in ROS1+ NSCLC: Background
 Entrectinib: oral, potent, selective ROS1/NTRK/ALK TKI with CNS activity[1]
‒ More potent ROS1 inhibitor than crizotinib in preclinical studies
‒ Demonstrated pan-TRK inhibition in clinical trials across multiple tumor types
‒ Inhibition of MAPK-PI3K/AKT downstream pathways inhibits tumor growth and cell proliferation, spurs cell cycle arrest and
apoptosis, and inhibits TRK phosphorylation
‒ Can cross blood–brain barrier and remain within CNS
‒ Demonstrated activity in primary brain tumors, secondary CNS metastases
 Current analysis pools efficacy and safety data from 3 early studies of entrectinib in ROS1+ NSCLC: STARTRK-2,
STARTRK-1, and ALKA-372-001[2]
1. Rolfo C, et al. Expert Opin Investig Drugs. 2015;24:1493-1500. 2. Doebele RC, et al. WCLC 2018. Abstract OA02.01. Slide credit: clinicaloptions.com

Treatment of Brain Metastases: An Unmet Need in ROS1+ NSCLC
ROS1 fusions are oncogenic driver mutations occurring in 1% to 2% of patients with NSCLC[1,2]
Brain metastases are common in treatment-naive patients with stage IV ROS1+ NSCLC (36%)[3]
Current standard of care for ROS1+ NSCLC is crizotinib, although outcomes vary based on presence/absence of
CNS disease and baseline ECOG PS
─ PROFILE 1001 (N = 50)[4]: 72% ORR; median PFS 19.2 mos; median DoR 17.6 mos
─ CNS a common first site of progression in patients on crizotinib for ROS1+ NSCLC (52%)[3]
 Patients with ROS1+ tumors may benefit from first-line treatment with a CNS-penetrant ROS1 inhibitor
1. Bergethon K, et al. J Clin Oncol. 2012;30:863-870. 2. Dugay F, et al. Oncotarget. 2017;8:53336-53351.
3. Bowles DW, et al. WCLC 2018. Abstract P1.01-78. 4. Shaw AT, et al. N Engl J Med. 2014;371:1963-1971. Slide credit: clinicaloptions.com

Entrectinib in ROS1+ NSCLC: Integrated Analysis
Doebele RC, et al. WCLC 2018. Abstract OA02.01. ClinicalTrials.gov. NCT02568267.
Drilon A, et al. Cancer Discov. 2017;7:400-409. Slide credit: clinicaloptions.com
 Primary endpoints: ORR, DoR
 Secondary endpoints: PFS, OS, intracranial ORR and DoR, safety/tolerability
Efficacy population:
ROS1+ NSCLC with no
prior ROS1 inhibitor
(n = 53)
Safety population:
Entrectinib-treated
ROS1+, all tumor types
and gene rearrangements
(n = 355)
STARTRK-2
Multicenter, global basket phase II study; 600 mg QD, 28-day cycle
(n = 37 with NSCLC)
ALKA-372-001
Phase I dose escalation
(n = 9 with NSCLC)
STARTRK-1
Phase I dose escalation
(n = 7 with NSCLC)

Entrectinib in ROS1+ NSCLC: Baseline Characteristics
Doebele RC, et al. WCLC 2018. Abstract OA02.01. Slide credit: clinicaloptions.com
Outcome ROS1+ NSCLC (N = 53)
Median age, yrs (range) 53 (27-73)
Female, % 64.2
Asian, % 35.8
White, % 58.5
ECOG PS 0-1, % 87.79
ECOG PS 2, % 11.3
Never smoker, % 58.5
Current/former smoker, % 41.5
Adenocarcinoma histology, % 76.1
0 prior lines of systemic therapy, % 13.2
1-2 prior lines of systemic therapy, % 39.7
≥ 3 prior lines of systemic therapy, % 47.1
CNS disease at baseline, n (%) 23 (43.4)

Entrectinib in ROS1+ NSCLC: ORR (BICR Assessment)
Response
Total
(N = 53)
CNS Disease at Baseline
(n = 23)
No CNS Disease at Baseline
(n = 30)
ORR, n (%) 41 (77.4)
(95% CI: 63.8-87.7)
17 (73.9)
(95% CI: 51.6-89.8)
24 (80.0)
(95% CI: 61.4-92.3)
CR, n (%) 3 (5.7) 0 3 (10.0)
PR, n (%) 38 (71.7) 17 (73.9) 21 (70.0)
SD, n (%) 1 (1.9) 0 1 (3.3)
PD, n (%) 4 (7.5) 4 (17.4) 0
Non-CR/non-PD, n (%) 3 (5.7) 0 3 (10.0)
Missing or unevaluable, n (%) 4 (7.5) 2 (8.7) 2 (6.7)
Clinical benefit rate (CR/PR/SD for ≥ 6 mos), n (%) 41 (77.4)
(95% CI: 63.8-87.7)
Median DoR, mos 24.6
(95% CI: 11.4-34.8)
12.6
(95% CI: 6.5-NE)
24.6
(95% CI: 11.4-34.8)
 12-mo probability of EFS  Median follow-up from first response: 16.6 mos

Entrectinib in ROS1+ NSCLC: Survival Outcomes
 Median follow-up: 15.5 mos
Total
(N = 53)
CNS Disease at
Baseline
(n = 23)
No CNS Disease at
Baseline
(n = 30)
Median PFS by BICR, mos 19.0
(95% CI: 12.2-36.6)
13.6
(95% CI: 4.5-NE)
26.3
(95% CI: 15.7-36.6)
Patients with PFS event, n (%) 25 (47.2) 11 (47.8) 14 (46.7)
 PD, n
 Death, n
20
5
8
3
12
2
 12-mo probability of PFS: 65%
 12-mo probability of OS: 85%

Entrectinib in ROS1+ NSCLC: Intracranial ORR and DoR (BICR Assessment)
Response Patients With CNS Metastases at Baseline (n = 20)
Intracranial ORR, n (%) 11 (55) (95% CI: 31.53-76.94)
 CR 4 (20)
 PR 7 (35)
 SD 0
 PD 3 (15)
Non-CR/non-PD and nonevaluable 6 (30)
Median intracranial DoR, mos 12.9 (95% CI: 5.6-NE)
Patients with event, n (%) 5 (45.5)
 Disease progression, n 3
 Death, n 2
Patients at risk at 6 mos, n 7
6-mo event-free probability, % 71

Entrectinib in ROS1+ NSCLC: Safety Summary
Treatment-Related AE in ≥ 10% of
Patients, n (%)
Safety-Evaluable Population (N = 355)
All Grades Grade 3/4
Dysgeusia 147 (41.4) 1 (0.3)
Fatigue 99 (27.9) 10 (2.8)
Dizziness 90 (25.4) 2 (0.6)
Constipation 84 (23.7) 1 (0.3)
Nausea 74 (20.8) 0
Diarrhea 81 (22.8) 5 (1.4)
Weight increased 69 (19.4) 18 (5.1)
Paresthesia 67 (18.9) 0
Blood creatinine increased 54 (15.2) 2 (0.6)
Myalgia 54 (15.2) 2 (0.6)
Peripheral edema 50 (14.1) 1 (0.3)
Vomiting 48 (13.5) 0
Anemia 43 (12.1) 16 (4.5)
Arthralgia 44 (12.4) 2 (0.6)
AST increased 39 (11.0) 4 (1.1)
 N = 355 patients in 3 clinical trials
 Most AEs grade 1/2, reversible
 Treatment-related AEs
─ Leading to treatment
discontinuation: 3.9%
─ Leading to dose reduction: 27.3%
─ Leading to dose interruption: 25.4%
─ Serious AEs: 8.5%
─ No deaths due to treatment-related
AEs

Entrectinib in ROS1+ NSCLC: Conclusions
 Entrectinib demonstrated activity with durable responses in ROS1+ NSCLC with and without CNS metastases
‒ ORR: 77.4%; median DoR: 24.6 mos
‒ Median PFS: 26.3 mos (no CNS metastases) and 13.6 mos (CNS metastases)
 Durable intracranial activity reported in patients with baseline CNS disease
‒ Intracranial ORR: 55%
‒ Median intracranial DoR: 12.9 mos
 Entrectinib was tolerable with a manageable safety profile
‒ Most AEs were low grade and managed with dose interruption or reduction
‒ Few patients discontinued entrectinib due to treatment-related toxicity

IMpower150 Interim OS Analysis: Atezolizumab + CT ± Bevacizumab
vs CT + Bevacizumab in Patients With Untreated Advanced
Nonsquamous NSCLC
This activity is supported by educational grants from Amgen; Astellas; AstraZeneca;
Celgene Corporation; Eisai; Genentech; Janssen; Merck & Co., Inc.; and Seattle
Genetics.
of the 2018 ASCO Annual Meeting; June 1-5, 2018; Chicago, Illinois

Atezolizumab + CT ± Bevacizumab vs CT + Bevacizumab in Nonsquamous
NSCLC (IMpower150): Background
 Atezolizumab: anti–PD-L1 antibody; increased OS vs docetaxel in previously treated patients with NSCLC, regardless of PD-
L1 level[1]
 Bevacizumab: VEGF inhibitor approved by FDA in combination with chemotherapy for treatment of metastatic
nonsquamous NSCLC[2]
 Combination of atezolizumab and bevacizumab may provide synergistic antitumor effect with reversal of
immunosuppression[3,4]
 IMpower150: phase III trial evaluating safety, efficacy of adding atezolizumab to carboplatin/paclitaxel ± bevacizumab in
patients with untreated nonsquamous NSCLC[5-7]
‒ Met coprimary endpoint of significantly improved investigator-assessed PFS in ITT WT population with addition of atezolizumab to
CT + bevacizumab vs CT + bevacizumab alone[5]
‒ Median PFS: 8.3 vs 6.8 mos; HR: 0.617 (95% CI: 0.517-0.737; P < .0001)
 Current analysis reports updated PFS and interim OS data of IMpower150[6,7]
References in slidenotes Slide credit: clinicaloptions.com

IMpower150: Study Design
 Multicenter, open-label, randomized phase III trial (data cutoff: January 22, 2018)
 Coprimary endpoints: investigator-assessed PFS in ITT WT, Teff-high WT; OS in ITT WT
 Secondary endpoints: investigator-assessed PFS, OS in ITT; investigator-assessed PFS in PD-L1
subgroups; IRF-assessed PFS; ORR, DoR per RECIST v1.1; safety in ITT
Socinski MA, et al. ASCO 2018. Abstract 9002. Socinski MA, et al. N Engl J Med. 2018; 378:2288-2301. Slide credit: clinicaloptions.com
Patients with stage IV
or recurrent metastatic
nonsquamous NSCLC,
no prior CT,* and tumor
tissue available for
biomarker analysis
(N = 1202)
Atezolizumab 1200 mg IV Q3W +
Carboplatin/Paclitaxel†
(n = 402)
Bevacizumab + Carboplatin/Paclitaxel†§
(n = 400)
Atezolizumab 1200 mg IV Q3W +
Bevacizumab + Carboplatin/Paclitaxel†
(n = 400)
Stratified by sex,
PD-L1 expression,
liver metastases
Atezolizumab
Atezolizumab +
Bevacizumab
Bevacizumab
*If sensitizing EGFR mutation or ALK translocation present, must have PD on or intolerance to ≥ 1 approved targeted therapy. †Bevacizumab 15 mg/kg;
carboplatin AUC 6; paclitaxel 200 mg/m2; all given IV Q3W for 4 or 6 cycles. ‡No crossover permitted. §Control arm.
Atezolizumab
until PD or loss
of clinical benefit
and/or
bevacizumab
until PD
Maintenance‡

IMpower150: Baseline Patient Characteristics
Socinski MA, et al. ASCO 2018. Abstract 9002. Socinski MA, et al. N Engl J Med. 2018; 378:2288-2301. Slide credit: clinicaloptions.com
Characteristic Atezolizumab + Carbo/Pac
(n = 402)
Atezolizumab + Bev +
Carbo/Pac (n = 400)
Bev + Carbo/Pac
(n = 400)
Median age, yrs (range) 63 (32-85) 63 (31-89) 63 (31-90)
Male, n (%) 241 (60) 240 (60) 239 (60)
ECOG PS 0, n (%) 180 (45) 159 (40) 179 (45)
Tobacco use, n (%)
 Current/former smoker
 Never smoker
98 (24)/227 (57)
77 (19)
90 (23)/228 (57)
82 (21)
92 (23)/231 (58)
77 (19)
Liver metastases, n (%) 53 (13) 52 (13) 57 (14)
EGFR mutation positive, n (%) 45 (11) 34 (9) 45 (11)
EML4-ALK rearrangement positive, n (%) 9 (2) 11 (3) 20 (5)
High Teff gene signature expression,* n
(%)
177 (44) 166 (42) 148 (37)
PD-L1 expression,† n (%)
 TC3 or IC3
 TC2/3 or IC2/3
 TC1/2/3 or IC1/2/3
 TC0 or IC0
68 (17)
137 (34)
213 (53)
188 (47)
75 (19)
140 (35)
209 (52)
191 (48)
73 (18)
133 (33)
195 (49)
205 (51)*Cutoff: ≥ -1.91. †High: TC ≥ 50% or IC ≥ 10%; low: TC ≥ 1% and < 50% or IC ≥ 1% and < 10%; negative: TC and IC < 1%.

IMpower150: Updated PFS in ITT WT Population* (Coprimary Endpoint)
Socinski MA, et al. ASCO 2018. Abstract 9002. Reproduced with permission. Slide credit: clinicaloptions.com
*ITT WT: patients without EGFR or ALK genetic alterations; 87% of randomized patients.
Atezolizumab +
Bev +
Carbo/Pac
Bev +
Carbo/Pac
Median PFS, mos
(95% CI)
8.3
(7.7-9.8)
6.8
(6.0-7.1)
6-mo PFS, % 66 56
12-mo PFS, % 38 20
18-mo PFS, % 27 8
HR: 0.59 (95% CI: 0.50-0.70; P < .0001)
Median follow-up: ~ 20 mos.
Patients at Risk, n
PFS(%)
Mos
100
90
80
70
60
50
40
30
20
10
0
340 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33
Carbo/Pac
Bev + Carbo/Pac
359
337
336
323
315
294
301
263
293
244
267
215
234
180
213
148
190
127
168
103
154
89
146
78
125
61
112
50
85
35
80
29
69
21
68
18
53
14
50
13
37
6
33
6
24
5
20
5
12
1
11
1
6 3 1 1 1
+
+
+
++ ++
+
+
+++ ++ +++++ +++++++++++
+ ++
+
+++
++++ ++ +++++ +++++
++ + ++ ++ + ++ +
+++++++ ++++ +++
+
++
++
+
+
+++
+

IMpower150: PFS by Subgroup
Socinski MA, et al. N Engl J Med. 2018; 378:2288-2301. Slide credit: clinicaloptions.com
Favors
Atezolizumab + Bev + Carbo/Pac
Favors
Bev + Carbo/Pac
0.2
5
1.0
0
1.2
5
Patients, n (%) HR (95% CI)Median PFS, MosPopulation
0.61 (0.52-
0.72)
0.59 (0.37-
0.94)
0.62 (0.52-
0.74)
0.39 (0.25-
0.60)
0.50 (0.39-
0.64)
0.56 (0.41-
0.77)
0.68 (0.56-
0.82)
0.77 (0.61-
0.99)
0.51 (0.38-
0.68)
0.76 (0.60-
0.96)
8.3
9.7
8.3
12.6
11.0
8.3
8.0
7.1
11.3
7.3
6.8
6.1
6.8
6.8
6.8
6.6
6.8
6.9
6.8
7.0
800 (100)
108 (14)
692 (87)
135 (20)
354 (51)
224 (32)
557 (80)
338 (49)
284 (43)
374 (57)
ITT population
Patients with EGFR or ALK
genetic alterations
WT population
PD-L1 subgroups (in WT population)
TC3 or IC3
TC1/2/3 or IC1/2/3
TC1/2 or IC1/2
TC0/1/2 and IC0/1/2
TC0 and IC0
Teff subgroups (in WT population)
High gene signature expression
Low gene signature expression
ABCP BCP

34
50
IMpower150: Interim OS in ITT WT Population* (Coprimary Endpoint)
 Median OS for atezolizumab + carbo/pac vs bev + carbo/pac: 19.4 vs 14.7 mos (HR: 0.88; P = .2041)
*ITT WT: patients without EGFR or ALK genetic alterations; 87% of randomized patients.
OS(%)
Atezolizumab +
Bev +
Carbo/Pac
Bev +
Carbo/Pac
Patients, n 359 337
Median OS, mos
(95% CI)
19.2
(17.0-23.8)
14.7
(13.3-16.9)
12-mo OS, % 67 61
18-mo OS, % 53 41
24-mo OS, % 43 34
HR: 0.78 (95% CI: 0.64-0.96; P = .0164)
Median follow-up: ~ 20 mos.
Mos
100
90
80
70
60
40
30
20
10
0
330 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32
++
+
++ +
+
+
+
+
++++
+++++++ ++ + ++++
+
+++
+ +++ +++ +++++++++++++++++++++ +++ ++ ++
+
++
+
+ ++ +
++++ +++++++++++++ ++++++++++++++++++++++
+ ++++ ++
+++++ ++ ++ ++++++++
++++++++++
+
+
++++++ ++ +++ +
+
+++++ +++++ +
+
+
+
+++++++++++++++++++++
+++ +
++++

IMpower150: OS by Subgroup
Favors
Favors
Bev + Carbo/Pac
*For prevalence, ITT WT (n = 696) used for PD-L1,
liver metastases groups; ITT (n = 800) for rest.
Median OS, Mos
25.2
20.3
17.1
13.2
19.8
19.8
NE
19.2
15.0
16.4
14.1
9.1
16.7
14.9
17.5
14.7
Subgroup
PD-L1 high (TC3 or IC3) WT
PD-L1 low (TC1/2 or IC1/2) WT
PD-L1 negative (TC0 and IC0) WT
Liver metastases WT
No liver metastases WT
ITT (including EGFR/ALK+)
EGFR/ALK+ only
ITT WT
n (%)*
136 (20)
226 (32)
339 (49)
94 (14)
602 (86)
800 (100)
104 (13)
696 (87)
0.2 1.0 2.0
HR
HR
0.70
0.80
0.82
0.54
0.83
0.76
0.54
0.78
ABCP BCP

IMpower150: OS by PD-L1 Expression Status
PD-L1 High (TC3 or IC3) PD-L1 Low (TC1/2 or IC1/2) PD-L1 Negative (TC0 and IC0)
Atezolizumab + Bev + Carbo/Pac Bev + Carbo/Pac
HR: 0.80
(95% CI: 0.55-1.15)
10
090
80
70
60
50
40
30
20
10
0
OS(%)
Mos
340 2 4 6 8 101214161820222426283032
HR: 0.70
(95% CI: 0.43-1.13)
Patients
at Risk, n
Atezo + Bev +
CP
Bev + CP
71
65
64
60
64
56
61
53
55
50
54
36
53
33
43
28
34
23
30
19
23
14
17
10
15
9
6
6
2
1
2
HR: 0.82
(95% CI: 0.62-1.08)
15.0 mos 25.2 mos
10
090
80
70
60
50
40
30
20
10
0
OS(%)
Mos
340 2 4 6 8 101214161820222426283032
Patients
at Risk, n
Atezo + Bev +
CP
Bev + CP
12
1
10
5
10
7
10
0
10
5
91
100
86
93
78
87
68
79
60
63
46
52
39
39
30
32
23
23
13
11
10
6
1 1
16.4 mos 20.3 mos
10
090
80
70
60
50
40
30
20
10
0
OS(%)
Mos
340 2 4 6 8 101214161820222426283032
Patients
at Risk, n
Atezo + Bev +
CP
Bev + CP
16
7
17
2
15
7
16
0
14
5
14
5
13
5
13
4
12
5
12
3
11
5
11
5
10
3
10
6
82
79
61
54
50
39
29
29
17
17
8
10
4
6 1 1
14.1 mos 17.1 mos
1

IMpower150: OS in Special Populations
 No significant difference in OS outcomes for these subgroups of patients with atezolizumab + CT and bevacizumab + CT
suggesting that it is the interplay of anti–PD-L1 and anti-VEGF therapy that leads to the OS benefit
Patients With Liver Metastases (ITT WT) Patients With EGFR or ALK Aberrations
HR: 0.54
(95% CI: 0.33-0.88)
HR: 0.54
(95% CI: 0.29-1.03)
ABCP BCP
Median
OS, mos
13.2 9.1
ABCP BCP
Median OS,
mos
NE 17.5
Mos
OS(%)
100
90
80
70
60
50
40
30
20
10
0
300 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Patients at Risk, n
Atezo + Bev + CP
Bev + CP
47
47
41
42
39
34
36
29
32
27
31
20
26
17
20
13
18
8
13
6
10
4
5
1
3
1
1
1
Mos
OS(%)
100
90
80
70
60
50
40
30
20
10
0
300 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Patients at Risk, n
Atezo + Bev + CP
Bev + CP
41
63
39
61
37
57
37
49
35
46
32
39
30
37
20
28
15
24
11
17
9
12
5
11
4
7
2
2

IMpower150: Updated ORR and DoR in ITT Population
*Per RECIST v1.1.
Atezolizumab + Carbo/Pac
Bev + Carbo/Pac
PR CR
ITT PD-L1 High
TC3 or IC3
PD-L1 Low
TC1/2 or IC1/2
PD-L1 Negative
TC0 and IC080
70
60
50
40
30
20
10
0
ORR*(%)
40
56
41
62
69
49
44
58
41
31%
51
36
Median DoR,
mos (range)
8.3
(1.9-26.0)
11.5
(2.0-29.0)
6.0
(1.5-23.1)
12.2
(1.9-26.0)
22.1
(2.8-29.0)
7.0
(1.5-22.1)
8.3
(2.8-24.5)
10.4
(2.7-24.3)
6.9
(2.8-23.1)
7.6
(1.9-24.9)
8.2
(2.0-24.6)
5.5
(2.0-16.6)

IMpower150: Safety
Socinski MA, et al. ASCO 2018. Abstract 9002. Slide credit: clinicaloptions.com
Safety Outcome Atezolizumab +
Carbo/Pac
(n = 400)
Atezolizumab +
Bev + Carbo/Pac
(n = 393)
Bev + Carbo/Pac
(n = 394)
Median doses received, n (range)
 Atezolizumab
 Bevacizumab
10 (1-43)
NA
12 (1-44)
10 (1-44)
NA
8 (1-38)
Treatment-related AE, n (%)
 Grade 3/4
 Grade 5
• Fatal hemorrhagic
377 (94)
172 (43)
4 (1)
2 (< 1)
370 (94)
223 (57)
11 (3)
6 (2)
377 (96)
191 (49)
9 (2)
3 (< 1)
Serious AE, n (%) 157 (39) 174 (44) 135 (34)
AE leading to d/c of any treatment, n (%) 53 (13) 133 (34) 98 (25)

IMpower150: Immune-Related AEs
Immune-Related AEs
Occurring in > 5% of
Patients in Any Arm, n (%)
Atezolizumab +
Carbo/Pac
(n = 400)
Carbo/Pac
(n = 393)
Bev + Carbo/Pac
(n = 394)
Any
Grade
Grade
3/4
Any
Grade
Grade
3/4
Any
Grade
Grade
3/4
Rash 119 (30) 14 (4) 117 (30) 9 (2) 53 (14) 2 (1)
Hepatitis
 Laboratory
abnormalities
42 (11)*
36 (9)
12 (3)
10 (3)
54 (14)
48 (12)
20 (5)
18 (5)
29 (7)
29 (7)
3 (1)
3 (1)
Hypothyroidism 34 (9) 1 (< 1) 56 (14) 1 (< 1) 18 (5) 0
Pneumonitis 23 (6)† 8 (2) 13 (3) 6 (2) 5 (1) 2 (1)
Hyperthyroidism 11 (3) 0 16 (4) 1 (< 1) 5 (1) 0
Colitis 3 (1) 2 (1) 11 (3) 7 (2) 2 (1) 2 (1)*Grade 5 acute hepatitis, n = 1. †Grade 5 interstitial lung disease, n = 1.

IMpower150: Conclusions
 In patients with untreated advanced nonsquamous NSCLC, addition of atezolizumab to
carboplatin/paclitaxel + bevacizumab significantly prolonged survival vs carboplatin/paclitaxel +
bevacizumab alone
‒ Median PFS: 8.3 vs 6.8 mos (HR: 0.59; 95% CI: 0.50-0.70; P < .0001)
‒ Median OS: 19.2 vs 14.7 mos (HR: 0.78; 95% CI: 0.64-0.96; P = .0164)
 Benefit associated with atezolizumab observed in patients with liver metastases or EGFR/ALK
genomic aberrations, across PD-L1 subgroups, and regardless of Teff gene signature expression
 Combination of anti–PD-L1 and anti-VEGF therapies does not appear to increase the risk of irAEs
 OS data for comparison of atezolizumab + CT vs bevacizumab + CT not yet mature
‒ Median OS for atezolizumab + carbo/pac vs bev + carbo/pac: 19.4 vs 14.7 mos (HR: 0.88; P = .2041)
 Investigators conclude that atezolizumab + carboplatin/paclitaxel + bevacizumab is a new SoC
option for first-line management of patients with advanced nonsquamous NSCLC

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)

Inmunoterapia y terapia dirigida en cáncer de pulmón (versión larga)

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