clinical development of lung cancer...
TRANSCRIPT
Clinical development of lung cancer
immunotherapy
Luis Paz-Ares
Hospital Universitario Doce de Octubre,
Madrid, Spain
Michel-Ange 1500
Different views of Cancer
TRADITIONAL
ONCOLOGY
VIEW
A CANCER
THAT
GROW
IMMUNO-
ONCOLOGY
VIEW
A BODY THAT
LET A CANCER
GROW
CD8 T cells B cells CD4 T cells
Confirmed by Djenidi et al., J Immunol 2015 and Donnem et al., Clin Cancer Res 2015
Positive prognostic value of tumor infiltrating lymphocytes in NSCLC patients
Schalper et al., J Natl Cancer Inst 2015
Immune checkpoint inhibitors
1. Sharma P, et al. Science. 2015;348:56–66. 2. Wolchock J, et al. J Clin Oncol. 2013;31(15 suppl):abstract 9012.
T cell Tumor cell
MHC TCR
PD-L1 PD-1 T cell Dendritic
cell
MHC TCR
CD28
B7 CTLA-4 - - -
Activation (cytokines, lysis, proliferation,
migration to tumor)
B7 + + +
+ + +
CTLA-4 pathway PD-1 pathway
Anti-CTLA-4
Anti-PD-1/PD-L1
Periphery Tumor microenvironment
+ + +
PD-L2 PD-1
Anti-PD-1
- - -
- - -
• Pre-treated patients
• First line and earlier stages
• Further patient selection
• The future
Agenda
• Pre-treated patients
• First line and earlier stages
• Further patient selection
• The future
Agenda
PD-1/PD-L1 Inhibitors in pretreated NSCLC
Hirsch et al. Lancet 2015
PD-1/PD-L1 Inhibitors in pretreated NSCLC
Hirsch et al. Lancet 2015
Most responses occurred early and were
durable 50% of responders (11/22) demonstrated
response at the first tumor assessment
(8 weeks)
Responses were ongoing in 41% of
patients (9/22) at the time of analysis
Time to response is short
Nivo & Avelumab monotherapy in ≥2nd-line
Gettinger SN, et al. J Clin Oncol. 2015;33:2004–2012.
Versraegen et al., ESMO 2016
96 weeks
0 6 12 18 24 30 36 42
Time Since Treatment Initiation (months)
No
ns
qu
am
ou
s
Sq
ua
mo
us
Time to and
duration of
response
until
discontinuati
on
of therapy
Time to
response
Ongoing
response
Duration of
response
after
discontinuati
on
of therapy
Garon NEJM 2015
<1% 1-49% ≥50%
PD-L1 Expression Matters
Pembrolizumab - OS by PD-L1 expression
Summary of phase III studies of
immunotherapy in previously treated patients
*850 in primary population
NR = not reached 1. Borghaei, et al. ASCO 2016
2. Herbst, et al. Lancet 2015; 3. Barlesi, et al. ESMO 2016
CheckMate 0171
Nivolumab
vs docetaxel
CheckMate 0571
Nivolumab
vs docetaxel
KEYNOTE-0102
Pembrolizumab (2mg/kg or
10mg/kg) vs docetaxel
OAK3
Atezolizumab
vs docetaxel
Phase of study III III II/III III
PD-L1 selected No No Yes (TPS* ≥1%) No
Study size, n 272
(135 vs 137)
582
(292 vs 290)
1,033
(344 vs 346 vs 343)
1,225
(425 vs 425)*
Histology Squamous Non-squamous All-comers All-comers
Line of therapy, %
2L
3L
>3L
Other/unknown
100
0
0
0
88
11
<1
0
69
20
9
<1
75
25
0
0
Subsequent CIT
(immunotherapy arm vs
chemo arm), %
<1 vs 2 1 vs 2 0.6 vs 1.7 vs 13.1 4.5 vs 17.2
Crossover from chemo arm
to study immunotherapy, % 4 6 Not permitted Not permitted
Median OS, months
HR vs docetaxel (p value)
9.2 vs 6.0
0.62 (p=0.0004)
12.2 vs 9.5
0.75 (p<0.001)
10.4 vs 12.7 vs 8.5
2mg/kg: 0.71 (p=0.0008)
10mg/kg: 0.61 (p<0.0001)
13.8 vs 9.6
0.73 (p=0.0003)
OS by PD-L1 expression: CheckMate 057
Nivolumab
12
• PD-L1 expression was predictive of benefit with nivolumab
Nivo
Doc
100
90
80
70
60
50
40
30
10
0
20
Time (months)
24 21 18 15 12 9 6 3 0 27
Median OS(mo)
Nivo 10.4
Doc 10.1
Median OS (mo)
Nivo 17.2
Doc 9.0
≥1% PD-L1 expression level
HR (95% CI)=0.59 (0.43, 0.82)
<1% PD-L1 expression level
OS
(%
)
HR (95% CI)=0.90 (0.66, 1.24)
OS
(%
)
24 21 18 15 12 9 6 3 0 27
100
90
80
70
60
50
40
30
10
0
20
Nivo
Doc
aPD-L1 expression was measured in pretreatment tumor biopsies (DAKO automated IHC assay).2
CI=confidence interval; Doc=docetaxel; IHC=immunohistochemistry; Nivo=nivolumab;
1. Paz-Ares L, et al. Presented at ASCO 2015, Abstract LBA109. 2. Rizvi NA, et al. Lancet Oncol 2015;16:257–265.
PD-L1 expression level
Median OS (mo) HR
Nivolumab Docetaxel
≥5%
<5%
18.2
9.7
8.1
10.1
HR (95% CI) = 0.43 (0.30, 0.63)
HR (95% CI) = 1.01 (0.77, 1.34)
≥10%
<10%
19.4
9.9
8.0
10.3
HR (95% CI) = 0.40 (0.26, 0.59)
HR (95% CI) = 1.00 (0.76, 1.31)
Keynote 010: OS by PD-L1 Expression
Pembrolizumab
PD-L1
> 50%
HR: 0.53
PD-L1
> 1%
HR: 0.76
R Herbst et al. Lancet 2016
Keynote 010: OS by by Subgroups
Pembrolizumab
R Herbst et al., Lancet 2016
OAK Trial: OS by PD-L1 Expression Atezoluzumab
• Barlesi, et al. ESMO 2016
Comparability among five assays on tumor cell staining
MS Tsao et al, WLCC 2017
The immune system has memory
Long term benefit from IO?
Hirsch et al. Lancet 2016
Goldberg SB et al., WLCC 2015
Brain Metastases - Pembro Phase II Trial
CheckMate 153: Continuous vs 1-Year Nivolumab
Patient Flow and Analysis Populations
Stop nivolumab
Continuous nivolumab
1,245 patients treateda
220 patients on
treatment at
1 year
76 had response or SD
at randomizationc
87 had response or SD
at randomizationd
Rb
Efficacy analyses
13% 18%
Spigel DR et al, ESMO 2017
CheckMate 153: Continuous vs 1-Year Nivolumab
PFS From Randomizationa
Median, months (95% CI)
PFS rate, %
6-month 1-year
Continuous tx NR (NR) 80 65
1-year txb 10.3 (6.4, 15.2) 69 40
HR: 0.42 (95% CI: 0.25, 0.71)
No. at risk
1-year tx
Continuous tx
87 50 43 33 21 16 5 1 0
76 60 53 49 35 22 10 3 0
No. at risk
1-year tx
Continuous tx
87 50 43 33 21 16 5 1 0
76 60 53 49 35 22 10 3 0
Time post-randomization (months)
PF
S (
%)
0
20
40
60
80
100
0 3 6 9 12 15 18 21 24
Spigel DR et al, ESMO 2017
CheckMate 153:
OS From Randomization
Median, months (95% CI)
OS rate, %
6-month 1-year
Continuous tx NR (NR) 97 88
1-year txb 23.2 (23.2, NA) 95 81
HR: 0.63 (95% CI: 0.33, 1.20)
74 72 67 62 41 29 7 2 0
79 74 70 61 38 23 4 0 0
No. at risk
1-year tx
Continuous tx
87
76
Time post-randomization (months)
0
20
40
60
80
100
OS
(%
)
0 3 6 9 12 15 18 21 24 27
Spigel DR et al, ESMO 2017
Tumor burden change
in target lesions
following retreatment
● Start of retreatment
% change truncated
to 100%
Ch
an
ge
in
targ
et
lesio
n s
ize
fro
m r
an
do
miz
ati
on
(%
)
Days since randomization
−100
−80
−60
−40
−20
0
20
40
60
80
100
0 100 200 300 400 500
PD-1/PD-L1
Inhibitor
First/SecondLine
Disease
Progression
Cohort 1
Pembrolizumab
Second line
N=24/55
Cohort 2
Platinum
Chemotherapy
Second line
Cohort 2
Pembrolizumab
Third line
N=24/55
Tumor and
blood
collection
Rechallenge study - SLCG
PI: L Paz-Ares
• Pre-treated patients
• First line and earlier stages
• Further patient selection
• The future
Agenda
KEYNOTE-024 and CheckMate 026: PFS
1.0
0.8
0.6
0.4
0.2
0
0
Time (months)
PF
S e
sti
ma
te
6 3 9 18 15 12
Pembrolizumab
Chemotherapy
HR=0.50 (95% Cl 0.37–0.68)
p<0.001
KEYNOTE-024 PFS1,2 (PD-L1 >50% of cells) CheckMate-026 PFS3 (PD-L1 >5% of cells)
6.0 10.3
1. Reck, et al. N Engl J Med 2016;
2. Reck, et al. ESMO 2016; 3. Socinski, et al. ESMO 2016
Brahmer et al. WLCC 2017
EMA approval December 2016
30% of 1ºL patients
KeyNote 024 Trial – Updated OS
Overall Survival: TPS ≥1%
Presented By Gilberto Lopes at 2018 ASCO Annual Meeting
KEYNOTE-042 Trial: Pembro v QT
First Line treatment in PD-L1 > 1% NSCLC
Chemo + Pembrolizumab in Non-SCC NSCLC
KeyNote 189 Trial
Ghandi et al., NEJM 2018
Gandhi et al., NEJM 2018
Chemo + Pembrolizumab in Non-SCC NSCLC
KeyNote 189 Trial
Benefit according to PD-L1 expression
Chemo+ Beva + Atezolizumab in Non-SCC NSCLC
IMPower 150 Trial
Socinski et al, NEJM, 2018
Chemo+ Beva + Atezolizumab in Non-SCC NSCLC
IMPower 150 Trial – Overall Survival
Socinski et al, NEJM, 2018
Chemo + Atezolizumab in SCC NSCLC
IMPower 131 Trial – Overall Survival
Presented By Robert Jotte at 2018 ASCO Annual Meeting
Chemo + Atezolizumab in SCC NSCLC
IMPower 131 Trial – Overall Survival
Minimum follow-up: 9.8
mo
Median follow-up: 17.1
mo
Time (months)
12.0
%
24.
7%
12-month PFS
Presented By Robert Jotte at 2018 ASCO Annual Meeting
Chemo + Pembrolizumab in SCC NSCLC
KeyNote 407 Trial
Paz-Ares eta al., ASCO2018
Chemo + Pembrolizumab in SCC NSCLC
KeyNote 407 Trial
Paz-Ares et al., ASCO 2018
Chemo + Pembrolizumab in SCC NSCLC
KeyNote 407 Trial – Benefit by PD-L1 expression
Paz-Ares et al., ASCO 2018
PACIFIC: Study Design
• Patients with stage III, locally
advanced, unresectable NSCLC
who have not progressed following
definitive platinum-based cCRT
(≥2 cycles)
• 18 years or older
• WHO PS score 0 or 1
• Estimated life expectancy of ≥12
weeks
All-comers population
(i.e. any PD-L1 status)
Durvalumab
10 mg/kg q2w for
up to 12 months
N=476
Placebo
10 mg/kg q2w for
up to 12 months
N=237
2:1 randomization,
stratified by age, sex,
and smoking history
N=713
Secondary endpoints
• Proportion of patients alive and
progression-free at 12 and 18
months (per BICR)
• ORR (per BICR)
• DoR (per BICR)
• OS at 24 months
• Safety and tolerability
• PROs
• Pharmacokinetics
• Immunogenicity
Co-primary endpoints
• PFS by BICR using RECIST v1.1*
• OS
R
1–42 days
post-cCRT
Paz-Ares L et al, ESMO 2017 Antonia S et al., NEJM 2017
PFS by BICR (Primary Endpoint; ITT) P
FS
pro
bab
ility
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0 3 6 9 12 15 18 21 24 27
Time from randomization (months)
Placebo
Durvalumab
476 377 301 264 159 86 44 21 4 237 163 106 87 52 28 15 4 3
1 0
No. At Risk Durvalumab
Placebo
Durvalumab
(N=476) Placebo
(N=237)
Median PFS (95% CI), months 16.8 (13.0–18.1) 5.6 (4.6–7.8)
12-month PFS rate (95% CI) 55.9% (51.0–60.4) 35.3% (29.0–41.7)
18-month PFS rate (95% CI) 44.2% (37.7–50.5) 27.0% (19.9–34.5)
Stratified hazard ratio, 0.52 (95% CI, 0.42–0.65) Two-sided P<0.0001
28,4 16,0 0
5
10
15
20
25
30
35
Durvalumab(N=443)*
Placebo(N=213)*
% p
atie
nts
(95
% C
I)
Confirmed Objective Response
Paz-Ares L et al, ESMO 2017 Antonia S et al., NEJM 2017
Durvalumab
(N=475)
Placebo
(N=234)
Any-grade all-causality AEs, n (%) 460 (96.8) 222 (94.9)
Grade 3/4 142 (29.9) 61 (26.1)
Grade 5 21 (4.4) 13 (5.6)
Leading to discontinuation 73 (15.4) 23 (9.8)
Any-grade treatment-related AEs, n (%) 322 (67.8) 125 (53.4)
Any-grade all-causality AESIs, n (%) 311 (65.5) 114 (48.7)
Grade 3/4 39 (8.2) 9 (3.8)
Grade 5 4 (0.8) 4 (1.7)
Requiring concomitant treatment 200 (42.1) 40 (17.1)
Any-grade immune-mediated AEs, n (%) 115 (24.2) 19 (8.1)
Grade 3/4 16 (3.4) 6 (2.6)
Grade 5 4 (0.8) 3 (1.3)
PACIFIC: AEs Profile
Paz-Ares L et al, ESMO 2017 Antonia S et al., NEJM 2017
PEARLS Adjuvant ETOP-EORTC Trial (KeyNote 091)
Randomized Phase III Trial
Stage IB, II-IIIA NSCLC
Radically resected (R0)
Standard of care as adjuvant CT
Pembrolizumab 2mg q21d for 18 injections
Placebo q21d for 18 injections
Stratification factors
•Stage (IB versus II versus IIIA)
•Histology (non-squamous versus squamous)
•PDL-1 IHC expression (0 versus 1-49% versus > 50%)
•No chemotherapy versus adjuvant platinum-based chemotherapy
PIs: L Paz-Ares & M O´Brien
Radiographic
response (N=20)
RECIST 1.1
N (%)
Partial Response 2 (10%)
Stable Disease 18 (85%)
Progressive
Disease
1 (5%)
Tumor pathologic response after
neoadjuvant anti-PD-1 (N=20)
39% (95% CI 20-61% ) of per protocol
patients, 7 of 18, had <10% residual viable
tumor at resection
1 patient had a pathologic complete response
0 10 20 30 40 50 60 70 80 90 100
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Percent Pathologic Response
Major pathologic response
Minor or no response
Neo-Adjuvant Nivolumab – WOO trial
Forde et al., ESMO 2016; Chaft et al. ASCO 2017
<10% residual viable tumor cells
defines major pathologic response per
Pataer et al. JTO 2012
Radiographic
response (N=20)
RECIST 1.1
N (%)
Partial Response 2 (10%)
Stable Disease 18 (85%)
Progressive
Disease
1 (5%)
Tumor pathologic response after
neoadjuvant anti-PD-1 (N=20)
39% (95% CI 20-61% ) of per protocol
patients, 7 of 18, had <10% residual viable
tumor at resection
1 patient had a pathologic complete response
0 10 20 30 40 50 60 70 80 90 100
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Percent Pathologic Response
Major pathologic response
Minor or no response
Neo-Adjuvant Nivolumab – WOO trial
Forde et al., ESMO 2016; Chaft et al. ASCO 2017
<10% residual viable tumor cells
defines major pathologic response per
Pataer et al. JTO 2012
• Pre-treated patients
• First line and earlier stages
• Further patient selection
• The future
Agenda
APC, antigen-presenting cell; CTL, cytotoxic T cell; IFN-γ, interferon gamma; M2, M2 macrophage; MDSC, myeloid derived suppressor cell; MHC, major histocompatibility complex;
PD-1, programmed death protein 1; PD-L1, programmed death ligand 1; TCR, T cell receptor; TH1, T helper 1; TIL, tumour infiltrating lymphocyte; Treg, regulatory T cell.
Teng MWL et al. Cancer Res. 2015;75(11):2139-2145.
Tumour Microenvironment Types Based on TILs and PD-L1
TILs+
PD-L1+
Type I
TILs-
PD-L1-
Type II
PD-L1-
TILs+
Type IV
PD-L1+
TILs-
Type III
EGFR mutant NSCLC
ALK rearranged NSCLC
Non–PD-1/PD-L1 suppression
pathways
Tolerance (other suppressors?)
1. Antigen recognition
4
2
TILs
CTL
TH1
TCR
MHC-peptide
PD-1
PD-L1
IFN-γ
3. Induction of PD-L1
TILs
Blood vessel
CTL TH1
M2
MDSC
Treg
Blood vessel
Blood vessel
Blood vessel
Macrophage
Macrophage APC
PD-L1
Macrophage
Macrophage
APC
Adaptive immune resistance
Immunological ignorance
Intrinsic induction
Oncogenic pathway induction
of PD-L1
TUMOUR CELLS
TUMOUR CELLS
TUMOUR CELLS
TUMOUR CELLS
Tumour microenvironment across solid tumors
100
75
50
25
0
Imm
un
e T
yp
e (
%)
IV: PD-L1↓ CD8A↑
III: PD-L1↑ CD8A↓
II: PD-L1↓ CD8A ↓
I: PD-L1↑ CD8A↑
TMIT
Bra
in lo
wer-
gra
de g
liom
a
Pro
sta
te a
denocarc
inom
a
Adre
nocort
ical cancer
Ute
rin
e c
arc
inosarc
om
a
Liv
er
hepato
cellu
lar
carc
inom
a
Glio
bla
sto
ma m
ultiform
e
Kid
ney c
hro
mophobe
Acute
myelo
id le
ukem
ia
Pheochro
mocyto
ma &
Para
ganglio
ma
Ute
rin
e c
orp
us e
ndom
etr
ioid
carc
inom
a
Uveal m
ela
nom
a
Chola
ngio
carc
inom
a
Kid
ney p
apill
ary
cell
carc
inom
a
Ovaria
n s
ero
us c
ysta
denocarc
inom
a
Sarc
om
a
Colo
recta
l adenocarc
inom
a
Bla
dder
uro
thelia
l carc
inom
a
Bre
ast cancer
Mesoth
elio
ma
Pancre
atic a
denocarc
inom
a
Esophageal carc
inom
a
Th
yro
id c
arc
inom
a
Skin
cuta
neous m
ela
nom
a
Te
sticula
r germ
cell
tum
our
Sto
mach a
denocarc
inom
a
Cerv
ical cancer
Head &
neck s
quam
ous c
ell
carc
inom
a
Lung s
quam
ous c
ell
carc
inom
a
Kid
ney c
lear
cell
carc
inom
a
Lung a
denocarc
inom
a
Diffu
se la
rge B
-cell
lym
phom
a
Th
ym
om
a
Ock CY et al. Clin Cancer Res. 2016;22(9):2261-2270.
47
Atezolizumab-treated NSCLC patient benefit
by pretreatment IFNγ mRNA signature
Fehrenbacher et al., Lancet oncol 2016
Overall survival in bTMB subgroups in OAK
BEP, biomarker-evaluable population; HR, hazard ratio; ITT, intention-to-treat.
1. Gandara DR, et al. ASCO 2017 48
Interaction P = 0.75
Months Months
bTMB ≥16 bTMB <16
Atezolizumab (N = 216) Docetaxel (N = 209)
+ Censored
Atezolizumab (N = 77) Docetaxel (N = 81)
+ Censored
• The OS benefit observed was consistent between the bTMB ≥16 population and the BEP
• This result may reflect the impact of subsequent therapies post-PD1
• Median OS for the bTMB ≥16 subgroup was 13.5 months in the atezolizumab arm
and 6.8 months in the docetaxel arm
Overa
ll S
urv
iva
l (%
)
Overa
ll S
urv
iva
l (%
)
Increasing Atezolizumab benefit with higher bTMB cut-points
in OAK Trial
BEP, biomarker-evaluable population; ITT, intention-to-treat. 49
Progression-Free Survival – OAK Overall Survival – OAK
• Enrichment of PFS benefit was observed in the bTMB ≥16 subgroup, while
OS was consistent between the bTMB ≥16 subgroup and the BEP
CHICAGO, IL 2018
CT077
CheckMate 227
Nivolumab + Ipilimumab vs Platinum-Doublet Chemotherapy as First-line Treatment for Advanced
Non-Small Cell Lung Cancer: Initial Results From CheckMate 227
Matthew D. Hellmann,1 Tudor-Eliade Ciuleanu,2 Adam Pluzanski,3 Jong Seok Lee,4 Gregory A. Otterson,5
Clarisse Audigier-Valette,6 Elisa Minenza,7 Helena Linardou,8 Sjaak Burgers,9 Pamela Salman,10
Hossein Borghaei,11 Suresh S. Ramalingam,12 Julie Brahmer,13 Martin Reck,14 Kenneth J. O’Byrne,15
William J. Geese,16 George Green,16 Han Chang,16 Joseph Szustakowski,16 Prabhu Bhagavatheeswaran,16
Diane Healey,16 Yali Fu,16 Faith Nathan,16 Luis Paz-Ares17
1Memorial Sloan Kettering Cancer Center Hospital, New York, NY, USA; 2Prof. Dr. Ion Chiricuta Institute of Oncology and Universitatea de Medicina si Farmacie Iuliu Hatieganu, Cluj-napoca, Romania; 3Centrum Onkologii–Instytut im. Marii Sklodowskiej-Curie, Warsaw, Poland;
4Seoul National University Bundang Hospital, Seoul, South Korea; 5The Ohio State University, Columbus, OH, USA; 6Hôpital Sainte Musse, Toulon, France; 7Ospedale Santa Maria della Misericordia, Perugia, Italy; 8First Department of Oncology, Metropolitan Hospital, Athens,
Greece; 9Antoni Van Leeuwenhoek Ziekenhuis, Amsterdam, the Netherlands; 10Fundación Arturo López Pérez, Santiago, Chile; 11Fox Chase Cancer Center, Philadelphia, PA, USA; 12Winship Cancer Institute, Emory University, Atlanta, GA, USA; 13Sidney Kimmel Comprehensive
Cancer Center at Johns Hopkins, Baltimore, MD, USA; 14LungenClinic Grosshansdorf, Airway Research Center North, German Center for Lung Research, Grosshansdorf, Germany; 15Princess Alexandra Hospital, Brisbane, QLD, Australia; 16Bristol-Myers Squibb, Princeton, NJ, USA;
17Hospital Universitario 12 de Octubre, Centro Nacional de Investigaciones Oncológicas, Universidad Complutense, & CiberOnc, Madrid, Spain
CheckMate 227: Nivo + Ipi in 1L NSCLC With High TMB (≥10 mut/Mb)
CheckMate 227 Part 1 Study Designa
Database lock: January 24, 2018; minimum follow-up: 11.2 months
N = 1189
<1% PD-L1 expression
N = 550
Nivolumab 3 mg/kg Q2W Ipilimumab 1 mg/kg Q6W
n = 396
Histology-based chemotherapyb
n = 397
Nivolumab 240 mg Q2W n = 396
Nivolumab 3 mg/kg Q2W Ipilimumab 1 mg/kg Q6W
n = 187
Histology-based chemotherapyb
n = 186
Nivolumab 360 mg Q3W + histology-based chemotherapyb
n = 177
R
1:1:1
Key Eligibility Criteria •Stage IV or recurrent NSCLC
•No prior systemic therapy
•No known sensitizing
EGFR/ALK alterations
•ECOG PS 0–1
Stratified by SQ vs NSQ
R
1:1:1
7
aNCT02477826 bNSQ: pemetrexed + cisplatin or carboplatin, Q3W for ≤4 cycles, with optional pemetrexed maintenance following chemotherapy or nivolumab + pemetrexed maintenance following nivolumab + chemotherapy; SQ: gemcitabine + cisplatin, or gemcitabine + carboplatin, Q3W for ≤4 cycles; cThe TMB co-primary analysis was conducted in the subset of patients randomized to nivolumab + ipilimumab or chemotherapy who had evaluable TMB ≥10 mut/Mb
≥1% PD-L1 expression
Nivolumab + ipilimumab n = 396
Chemotherapyb
n = 397
Patients for PD-L1 co-primary analysis
Co-primary endpoints: Nivolumab +
ipilimumab vs chemotherapy
• OS in PD-L1–selected populations
• PFS in TMB-selected populations
Nivolumab + ipilimumab n = 139
Chemotherapyb n = 160
Patients for TMB co-primary analysisc
CheckMate 227: Nivo + Ipi in 1L NSCLC With High TMB (≥10 mut/Mb)
TMB and Tumor PD-L1 Expression Identify Distinct and Independent Populations of NSCLC
Tumor PD-L1 expression
11 aSymbols (dots) in the scatterplot may represent multiple data points, especially for patients with <1% tumor PD-L1 expression. The black line shows the relationship between TMB and PD-L1
expression as described by a linear regression model; bAmong patients in the nivolumab +ipilimumab and chemotherapy arms; TMB ≥10 mut/Mb, n = 299; TMB <10 mut/Mb, n = 380
TMB and tumor PD-L1 expressiona
PD-L1 expression (%)
TM
B (
nu
mb
er
of
mu
tati
on
s/M
b)
0
20
40
60
80
100
160
120
140
0 20 40 60 80 100
TMB ≥10 mut/Mbb
TMB <10 mut/Mbb
<1%
29% ≥1%
71%
<1%
29% ≥1%
71%
<1%
29% ≥1%
71%
<1%
29% ≥1%
71%
CheckMate 227: Nivo + Ipi in 1L NSCLC With High TMB (≥10 mut/Mb)
54
Poor (inverse?) of correlation between TMB and PD-L1 expression
111 94 47 60 n =
CheckMate 227: Nivo + Ipi in 1L NSCLC With High TMB (≥10 mut/Mb)
Co-primary Endpoint: PFS With Nivolumab + Ipilimumab vs Chemotherapy in Patients With High TMB (≥10 mut/Mb)a
55
Nivo + ipi 139 85 66 55 36 24 11 3 0
Chemo 160 103 51 17 7 6 4 0 0
Nivo + ipi
(n = 139)
Chemo
(n = 160)
Median PFS,b mo 7.2 5.4
HRc
97.5% CI
0.58
0.41, 0.81
P = 0.0002
Months
0
20
40
60
80
100
0 6 12 18 3 9 15 21 24
PF
S (
%)
Chemotherapy
Nivolumab + ipilimumab
1-y PFS = 43%
1-y PFS = 13%
aPer blinded independent central review (BICR); median (range) of follow-up in the co-primary analysis population was 13.6 mo (0.4, 25.1) for nivo + ipi and 13.2 mo (0.2, 26.0) for chemo;
b95% CI: nivo + ipi (5.5, 13.2 mo), chemo (4.4, 5.8 mo); c95% CI: 0.43, 0.77 mo; dThe P-value for the treatment interaction was 0.0018
No. at risk
• In patients with TMB <10 mut/Mb treated with nivo + ipi vs chemo, the HR was 1.07 (95% CI: 0.84, 1.35)d
CheckMate 227: Nivo + Ipi in 1L NSCLC With High TMB (≥10 mut/Mb)
Presented By Hossein Borghaei at 2018 ASCO Annual Meeting
CheckMate 227: Nivo + Ipi in 1L NSCLC With High TMB (≥10 mut/Mb)
Presented By Hossein Borghaei at 2018 ASCO Annual Meeting
Nivolumab +
Chemotherapy
Chemotherapy
• TMB ≥10 mut/Mb: ORR was 60.5% with nivo + chemo and 20.8% with chemo
• TMB <10 mut/Mb: ORR was 27.8% with nivo + chemo and 22.0% with chemo
43 36 21 14 9 5 2 0 No. at risk
48 30 16 4 1 1 1 0 Chemo
Nivo + chemo
(n = 43)
Chemo
(n = 48)
Median PFS,a mo 6.2 5.3
HR
(95% CI)
0.56
(0.35, 0.91)
Nivolumab +
chemotherapy
Months
Chemotherapy
0
20
40
60
80
100
0 6 12 18 3 9 15 21
TMB ≥10 mut/Mb and <1% Tumor PD-L1 Expression
1-y PFS = 27%
1-y PFS = 8%
Months
TMB <10 mut/Mb and <1% Tumor PD-L1 Expression
Nivo + chemo
(n = 54)
Chemo
(n = 59)
Median PFS,b mo 4.7 4.7
HR
(95% CI)
0.87
(0.57, 1.33)
0
20
40
60
80
100
0 6 12 18 3 9 15 21
1-y PFS = 18%
1-y PFS = 16%
54 38 19 13 6 3 0 0 59 39 16 6 6 3 1 0
Nivo + chemo
No. at risk
Chemo
PF
S (
%)
Nivo + chemo
Slide 12
Relevance of a specific genomic aberration on the immune landscape
Kras + LKB1 mutation LKB1 co-mutation determines the microinviroment and response to PD-1/PD-L1 agents in Kras mutant Advanced NSCLC
Skoulidis et al. Cancer Discovery 2015
& ASCO 2017
• Pre-treated patients
• First line and earlier stages
• Further patient selection
• The future
Agenda
New Combinations
ORR=30%; DCR=85%
N=34 (Non-Sq NSCLC)
ORR=29,4%
DCR=67,6%
PFS=6,9 m
N=40 (Non-Sq NSCLC)
ORR=35%
DCR=63%
PFS=6,9 m
Pembrolizumab-
Ramurizumab
Herbst R & Paz-Ares L.
ESMO 2016
Pembrolizumab-
Necitumumab
Gil M, et al. IASCL 2016
Pembro+Epacadostat
Gangadhar TC, et al.
ASCO 2017
Balance between inhibitory and stimulatory
receptors dictates T-cell activity
B7.1
B7.1
MHC I
PD-L1
CDI37-L
OX40-L
CD40-L
CD70
Light
CTLA-4
CD28
TCR
PD-1
CDI37
OX40
CD40R
CD27
HVEM
Tumour cell or APC T cell
CD28
OX40
GITR
CD137
CD27
HVEM
CTLA-4
PD-1
TIM-3
BTLA
VISTA
LAG-3
T cell targets for modulating activity
Activating
Receptors
Inhibitory
Receptors
T cell
stimulation
Agonistic
Antibodies
Blocking
Antibodies
Mellman Nature 2011; Pardoll Nat Rev Cancer 2012
CD73 and driver oncogene
• 642 resected
NSCLC tissue
microarray
• CD73 and A2AR
expression by IHC
• CD73 high
expression is more
common in EGFR
mutant protein
expression and ALK
+ NSCLC
Inoue et al Oncotarget 2017
High CD73 as poor prognostic biomarker
Inoue et al., Oncotarget 2017
Should we investigate the combination of MEDI9447 + Durvalumab in EGFR mutation
positive/T790M negative/CD73 high expression tumor after failing first line EGFR TKI?
CEA-TCB induces potent T-cell–mediated killing of tumor cells, with enhanced activity in combination with atezolizumab
Commensal microbiota: Bifidobacterium species
can improve anti-tumor immunity and response to
anti-PD-L1 antibody in vivo
Get Cold Tumors Inflammed
Microbiota
Sivan et al., Science 2015
Patients who had received antibiotics showed decreased PFS and OS following anti-PD-1/PD-L1 treatment
Derosa et al., Science 2018
Targeting CD19+ CLL with CAR-Modified T cells
• Gene transfer (lentiviral
vector) to stably express
CAR on T cells confers
novel antigen specificity
• CAR modified T cells can
now recognize and kill
CD19+ cells
CAR, chimeric antigen receptor; TCR, T-cell receptor.
Lentiviral vector
T cell
CD19
Native TCR
Tumor cell
CTL019 cell
Dead tumor cell
Anti-CD19
CAR construct
Blank CU et al. Science 2016; 352:658
Conclusions
• We are at the beginning of the IO revolution in lung cancer
• PD-1/PD-L1 inhibitors have proven a role on the treatment of advanced
tumors
• Pretreated: Nivo, Atezo, Pembro (PD-L1 +)
• Front-line:
• Pembro Monotherapy (PD-L1 high) & combo with chemo (all comers)
• Following Chemo-radiation (Stage III): Durva
• New options and combinations of IO are in the horizon (IO-IO, …)
• Personalized strategies for IO therapeutics will be developed
Gracias