Combination strategies
SAMO Interdisciplinary Workshop on Chest Tumors
9th and 10th October 2015
Hotel Hermitage, Lucerne
David Carbone, MD PhD
Director, James Thoracic Center
The Ohio State University
Columbus, Ohio
USA
Disclosures
•
•
•
•
•
•
•
•
•
•
•
•
Bayer Health Care
Biodesix
Biothera
Boehringer Ingelheim
Bristol Myers-Squibb (BMS)
Clovis Oncology
Eisai Inc.
Genentech/Roche
GlaxoSmithKline (GSK)
MedImmune
Merck
Novartis
Peregrine Pharmaceuticals, Inc.
 Pfizer
 Synta Pharmaceuticals Corp.

This includes receipt of grants/research
support, receipt of honoraria or
consulting fees, and participation
in company sponsored speaker’s
bureaus.
I-O agents have a unique MoA, offering the
opportunity for combination with other agents
I-O
Drake C. Ann Oncol. 2012;23(suppl 8):viii41–viii46; Hannani D, et al. Cancer J 2011;17:351–358;
Ménard C, et al. Cancer Immunol Immunother. 2008;57:1579–1587; Ribas A, et al. Curr Opin Immunol. 2013:25:291–296.
Examples of ongoing combination trials with I-O
therapies, many more in development
Chemotherapy
Radiotherapy
Targeted
Immunotherapy
+ ipilimumab
(NCT01454102)
+ anti-KIR (NCT01714739)
+ anti-LAG3 (NCT01968109)
Nivolumab
(anti-PD-1)
+ cisplatin/gemcitabine,
cisplatin/pemetrexed or
carboplatin/paclitaxel
(NCT01454102)
NR
+ bevacizumab
or erlotinib
(NCT01454102)
Pembrolizumab
(anti-PD-1)
+ cisplatin/pemetrexed or
carboplatin/paclitaxel
(NCT01840579)
+ paclitaxel/carboplatin
± bevacizumab (NCT02039674)
+ SBRT (NCT02444741)
+ chemorads in LS SCLC
(NCT02402920
+ SBRT (NCT02492568)
+ gefitinib or
erlotinib
(NCT02039674)
+ ipilimumab
(NCT02039674)
+ INCB024360
(NCT02178722)
NR
+ gefitinib
(NCT02088112)
+ AZD9291
(NCT02143466)
+ tremelimumab
(NCT02000947,
NCT02141347)
+ ipilimumab
(NCT02174172)
MEDI-4736
(anti-PD-L1)
NR
Atezolizumab
(anti-PD-L1)
+ carbo/pac (NCT02366143)
+ carbo/nab-pac (NCT02367781)
+ gem/cis (NCT02409355)
+ carbo/pem (NCT02409342)
+ chmoRT (NCT02525757)
+ SBRT (NCT02400814)
+ erlotinib
(NCT02013219)
+ cobimetinib
(NCT01988896)
Ipilimumab
(anti-CTLA-4)
Various
(NCT00527735; NCT01165216;
NCT01285609; NCT01331525;
NCT01450761;NCT1454102)
+ stereotactic
radiosurgery*
(NCT02107755,
NCT02239900)
+ ionizing radiation
(NCT02221739)
+ erlotinib or
crizotinib
(NCT01998126)
+ nivolumab (NCT01454102)
+ pembrolizumab
(NCT02039674)
Tremelimumab
(anti-CTLA-4)
NR
NR
+ gefitinib
(NCT02040064)
+ MEDI-4736 (NCT02000947)
*Trial in patients with melanoma with metastatic disease to a visceral organ (lung, liver, brain, adrenal, nodal station outside the regional lymph
drainage of the primary, vertebral bodies).
NR = no trials reported.
www.clinicaltrials.gov. Accessed October 2015.
I-O agents have a unique MoA, offering the
opportunity for combination with other agents
I-O
Drake C. Ann Oncol. 2012;23(suppl 8):viii41–viii46; Hannani D, et al. Cancer J 2011;17:351–358;
Ménard C, et al. Cancer Immunol Immunother. 2008;57:1579–1587; Ribas A, et al. Curr Opin Immunol. 2013:25:291–296.
Response Patterns for Immunotherapy
Compared With Targeted Therapy
Targeted Therapy
Percent Alive
Percent Alive
Immunotherapy
0
1
2
3
Yrs
Ribas A, et al. Clin Cancer Res. 2012;18:336-341.
0
1
2
Yrs
3
Combining Immunotherapy and Targeted
Therapies
Survival
Targeted Therapy
Combination???
Immunotherapy
Controls/
Conventional Therapy
Yrs
Adapted from Ribas A, et al. Clin Cancer Res. 2012;18:336-341.
TKI – immunotherapy combinations are
the topic of my lecture tomorrow
I-O agents have a unique MoA, offering the
opportunity for combination with other agents
I-O
Drake C. Ann Oncol. 2012;23(suppl 8):viii41–viii46; Hannani D, et al. Cancer J 2011;17:351–358;
Ménard C, et al. Cancer Immunol Immunother. 2008;57:1579–1587; Ribas A, et al. Curr Opin Immunol. 2013:25:291–296.
Anti-CTLA-4 plus chemotherapy as 1st-line treatment:
ipilimumab plus carboplatin/paclitaxel as an example
CA184-041: phase 2 study results, no prior therapy for lung cancer,
stage IIIB/IV NSCLC, ECOG PS ≤1, all histologies
Ipilimumab + concurrent chemotherapy
Ipilimumab + phased chemotherapy
1.0
irPFS, probability
irPFS, probability
1.0
0.8
0.6
0.4
0.2
0
0.8
0.6
0.4
0.2
0
0
2
4
6
8
10
12
14
16
0
2
4
Time, months
Placebo
Events/
patients
56/66
Ipilimumab 55/70
Median
irPFS,
months
4.63
5.52
95% CI
4.14, 5.52
8
10
12
14
16
Time, months
HR
4.17, 6.74 0.81
Lynch T, et al. J Clin Oncol. 2012;30:2046–2054.
6
P- value
Placebo
0.13
Events/
patients
56/66
Ipilimumab 54/68
Median
irPFS,
months
4.63
5.68
95% CI HR P -value
4.14, 5.52
4.76, 7.79 0.72
0.05
CA209-012 (CheckMate 012) Study Design:
Nivolumab in Combination With Chemotherapy
Chemotherapy-naïve patients with stage IIIB or IV NSCLC
Squamous
Non-squamous
Nivolumab 10 mg/kg IV Q3W
+ Gem 1250 mg/m2
+ Cis 75 mg/m2
(four 21-day cycles)
Nivolumab 10 mg/kg IV Q3W
+ Pem 500 mg/m2
+ Cis 75 mg/m2
(four 21-day cycles)
Any histology
Nivolumab 10 mg/kg IV Q3W
+ Pac 200 mg/m2
+ Carb AUC 6
(four 21-day cycles)
Nivolumab 10 mg/kg IV Q3W
until disease progression or unacceptable toxicity
Nivolumab 5 mg/kg IV Q3W
+ Pac 200 mg/m2
+ Carb AUC 6
(four 21-day cycles)
Nivolumab 5 mg/kg IV Q3W
until disease progression
or unacceptable toxicity
Primary objective: safety and tolerability
Secondary objectives: ORR and PFS rate at 24 weeks
Exploratory objective: OS
Carb = carboplatin; Cis = cisplatin; Gem = gemcitabine; ORR = objective response rate; OS = overall survival; Pac = paclitaxel;
Pem = pemetrexed; PFS = progression-free survival; Q3W = every three weeks
11
Efficacy Endpoints
Nivolumab
5 mg/kg
Nivolumab 10 mg/kg
Gem/Cis
(n = 12)
Pem/Cis
(n = 15)
Pac/Carb
(n = 15)
Pac/Carb
(n = 14)
ORR, %
33
47
47
43
SD, %
58
47
27
43
18-month OS rate, %
33
60
40
86
Median OS, weeks
51
83
65
NR
NR = not reached
12
Best Percent Change in Target Lesions
Change in Baseline Target Lesions (%)
100
80
60
40
20
Nivolumab
10 mg/kg
+ Gem/Cis
Nivolumab
10 mg/kg
+ Pem/Cis
Nivolumab
10 mg/kg
+Pac/Carb
Nivolumab
5 mg/kg
+ Pac/Carb
0
-20
-40
-60
-80
-100
Patients
Only includes patients with baseline target lesions and at least one post-baseline target lesion assessment with non-missing value
13
Percent Change in Target Lesions
Nivolumab 10 mg/kg + Gem/Cis
Squamous
100
Change From Baseline (%)
Nivolumab 10 mg/kg + Pem/Cis
80
80
60
60
40
40
20
20
0
0
-20
-20
-40
-40
-60
-60
-80
-80
-100
-100
0
6
12
18
24
30
36
42
48
54
Nonsquamous
100
60
0
66
6
12
18
Time Since First Dose (Weeks)
60
20
0
0
-20
-20
-40
-40
-60
-60
-80
-80
-100
-100
18
24
30
36
42
48
54
60
66
72
78
84
90
96
102
Time Since First Dose (Weeks)
54
60
66
72
78
84
90
96
102
108
114
120 126
108
Squamous
Nonsquamous
60
40
12
48
80
20
6
42
100
40
0
36
Nivolumab 5 mg/kg + Pac/Carb
Squamous
Nonsquamous
80
30
Time Since First Dose (Weeks)
Nivolumab 10 mg/kg + Pac/Carb
100
24
114
120 126
0
6
12
18
24
30
36
42
48
54
60
66
72
78
84
90
96
102 108 114
Time Since First Dose (Weeks)
+ first appearance of new lesion
14
Efficacy Endpoints According to
Baseline PD-L1 Expression
Baseline PD-L1 expressiona
PD-L1+
PD-L1–
Samples sufficient for analysis, n
17
27
ORR,b %
53
41
18-month OS rate, %
59
51
Median OS, weeks
88
83
aPositivity
defined as tumor cell membrane staining with ≥5% expression in a minimum of 100 evaluable cells
PRs or CRs only (per RECIST v1.1)
bConfirmed
15
Overall Survival by Treatment Arm
Regimen
mOS (wks)
Nivolumab 10 mg/kg + Gem/Cis
51
Nivolumab 10 mg/kg + Pem/Cis
83
x Nivolumab 10 mg/kg + Pac/Carb
100
Nivolumab 5 mg/kg + Pac/Carb
65
NR
OS (%)
80
60
40
20
0
B/L
12
24
36
48
60
72
84
96
108
120
132
Time Since First Dose (Weeks)
mOS = median OS
16
Chemo-Nivo conclusions
 ORR for nivolumab plus chemotherapy in 1st-line treatment
of patients with advanced NSCLC are similar to those
previously reported for chemotherapy alone
 Nivolumab 5 mg/kg Q3W in combination with
paclitaxel/carboplatin may provide clinical benefit beyond
nivolumab monotherapy or single modality chemotherapy
– Encouraging 18-month OS rate of 86% with a lack of
progressive disease at first restaging
 Responses were observed regardless of tumor PD-L1
expression
 Nivolumab plus chemotherapy demonstrates a manageable
safety profile, reflecting additive toxicities of individual
agents
 These data support further evaluation of nivolumab 5
mg/kg Q3W in combination with chemotherapy
17
Epigenetic Priming for
Chemotherapy and PD-1 Blockade
Tumor-intrinsic effects of combination
epigenetic therapy
entinostat
Synergy
azacitidine
Epigenetic lung cancer study - trial
schema
MS275
entinostat
5-Aza
5-aza
Day
•
•
•
•
•
•
11
8
8
15
15 22
2929
36 36
Single-arm phase II
Simon two-stage design
5AC dosing = 40 mg/m2 SQ daily on days 1-6 and 8-10
Entinostat dosing = 7 mg PO days 3 & 10
Cycle length = 28 days
3% RR, Median Survival 8.6 months
Juergens R et al Cancer Disc 2011
Charlie Rudin et al, 2013
Immunotherapy After Epigenetic Therapy
Epigenetic Therapy Followed by
Anti-PD-L1: An example of response
10/2011
12/2011
Pt 010-6084 – History 64 y/o Diagnosed with IIIB adenoca Rx
with XRT+ Tax/carbo, pemetrexed + carbo, Entinostat + 5aza x 6
cycles
M. Brock, C. Rudin, J. Brahmer, S. Baylin
Synergy between Epigenetic Modulation and PD-1 pathway
blockade - Unleashing the Perfect Storm against Tumors
AZA/HDACi Rx
Intratumoral
pro-inflammatory
responses: IL-1,IL-18,
IFN pathway, HLA
Adaptive Resistance:
PD-L1
PD-1 Blockade
Tumor
De novo antigen
expression:
ie C-T Antigens
Enhanced Antitumor Response
T cells
De-repression
of g-IFN promoter
in tolerant T cells
PD-1 from
promoter
demethylation
PD-1 Blockade
Epigenetic Priming Study Design
Study population
Metastatic
NSCLC
1 – 2 prior
therapies
Epigenetic priming
1
R
Nivolumab
Azacitidine 40
mg/m2 SC d 1-6, 810
Entinostat 7mg PO
days 3 + 10
28 day cycle × 2
Nivolumab
3 mg/kg IV q 2
weeks
Until progression
ECOG PS 0 - 1
1
Nivolumab
3 mg/kg IV q 2
weeks
Until progression
CC-486 300 mg PO
d1-21
28 day cycle × 2
Biopsy
Biopsy
(CC-486 is an oral azacytidine)
I-O agents have a unique MoA, offering the
opportunity for combination with other agents
I-O
Drake C. Ann Oncol. 2012;23(suppl 8):viii41–viii46; Hannani D, et al. Cancer J 2011;17:351–358;
Ménard C, et al. Cancer Immunol Immunother. 2008;57:1579–1587; Ribas A, et al. Curr Opin Immunol. 2013:25:291–296.
Mechanism of Action of PD-1 and CTLA-4
Blockade
MHC = major histocompatibility complex; TCR = T-cell receptor
Brahmer JR, et al. J Clin Oncol 2010,Wang C, et al. Cancer Immunol Res 2014, Pardoll DM. Nat
Rev Cancer 2012;12:252–64.
27
CA209-012 Study Design: Nivolumab Plus
Ipilimumab
Stage IIIB or IV NSCLC, no prior chemotherapy for advanced NSCLC,
and Eastern Cooperative Oncology Group performance status 0 or 1
Sq
Non-sq
Nivolumab 1 mg/kg IV Q3W
+ ipilimumab 3 mg/kg IV Q3W
(four 21-day cycles)
Sq
Non-sq
Nivolumab 3 mg/kg IV Q3W
+ ipilimumab 1 mg/kg IV Q3W
(four 21-day cycles)
Nivolumab 3 mg/kg IV Q2W until disease progression
or unacceptable toxicitya
Primary objective: safety and tolerability
Secondary objectives: ORR (by RECIST v1.1)b and PFS rate at 24 wks
Exploratory objective: OS
aPts
were permitted to continue study treatment beyond RECIST v1.1-defined progression if they were considered
to be deriving clinical benefit and tolerating study treatment
bResponse was assessed at wks 10, 17, and 23, and every 3 months thereafter until disease progression
non-sq = non-squamous; Q2W = every two wks; Q3W = every three wks; RECIST = Response Evaluation Criteria
In Solid Tumors; sq = squamous; wks = weeks
28
Safety
 While active, q3wk ipi was toxic
 The majority of toxicity occurred during the induction
phase (nivolumab + ipilimumab Q3W for four cycles)
as compared with the maintenance phase
– Across arms, grade 3–4 AEs were reported in 32–
50% of pts and 21–27% of pts during induction and
maintenance, respectively
 Thus q6 wk and q 12 wk schedules were added
29
Ipi-Nivo Response rates
Hellman et al, ECCO 2015
Ipi-Nivo waterfall plot
Hellman et al, ECCO 2015
Hellman et al, ECCO 2015
Response by smoking status
Hellman et al, ECCO 2015
Ipi-nivo Response by EGFR mutation status
Hellman et al, ECCO 2015
Ipi-Nivo Response by PDL1 status
Hellman et al, ECCO 2015
Ipi-Nivo AE grades
Hellman et al, ECCO 2015
Ipi-Nivo AE types
Hellman et al, ECCO 2015
PFS and OS in NSCLC pts Treated With
Nivolumab Plus Ipilimumab
PFS
Nivolumab 1 mg/kg +
ipilimumab 3 mg/kg
(mPFS 16.1 wks)
100
80
Nivolumab 3 mg/kg +
ipilimumab 1 mg/kg
(mPFS 14.4 wks)
60
PFS rate at 24 wks = 44%
40
20
100
80
1-year OS rate = 65%
OS (%)
PFS (%)
OS
PFS rate at
24 wks = 33%
60
1-year OS rate = 44%
40
Nivolumab 1 mg/kg +
ipilimumab 3 mg/kg
(mOS NR)
20
0
Nivolumab 3 mg/kg +
ipilimumab 1 mg/kg
(mOS 47.9 wks)
0
B/L
12
24
36
48
60
72
B/L
Time Since First Dose (Weeks)
12
24
36
48
60
72
84
Time Since First Dose (Weeks)
Number of Pts at Risk
Number of Pts at Risk
Nivolumab 1 mg/kg
+ ipilimumab 3 mg/kg
24
10
8
6
3
1
0
Nivolumab 1 mg/kg
+ ipilimumab 3 mg/kg
24
22
21
19
15
11
2
0
Nivolumab 3 mg/kg
+ ipilimumab 1 mg/kg
25
14
8
4
3
2
0
Nivolumab 3 mg/kg
+ ipilimumab 1 mg/kg
25
20
17
14
12
10
2
0
mOS = median OS; mPFS = median PFS
38
Hellman et al, ECCO 2015
CheckMate 032 Study Design
SCLC (n = 128) with progressive disease after ≥1 prior line of therapy,
including a platinum-based regimen in first line
(unselected by PD-L1 expression)
Nivolumab 3 mg/kg IV Q2W
(n = 40)
Nivolumab 1 mg/kg +
Ipilimumab 1 mg/kg IV Q3W
for 4 cycles (n = 3)
Nivolumab 1 mg/kg +
Ipilimumab 3 mg/kg IV Q3W
for 4 cycles (n = 47)
Nivolumab 3 mg/kg IV Q2W
Primary objective: ORR per RECIST v1.1
Secondary objective: safety
Exploratory objectives: PFS, OS, biomarker analysis
Database lock: February 16, 2015
aData
from this cohort will be presented at a later time.
aNivolumab
3 mg/kg +
Ipilimumab 1 mg/kg IV Q3W
for 4 cycles (n = 38)
Treatment-related AEs in ≥5% Patients
Nivolumab 3 (n = 40)
Any Grade, %
4, %
Grade 3–
Nivolumab 1 + Ipilimumab 3
(n = 47)
Any Grade, %
4, %
Grade 3–
Total Treatment-related
53
15
77
34
AEs
Fatigue
18
2.5
21
0
Diarrhea
13
0
23
8.5
Nausea
10
0
13
2.1
Vomiting
2.5
0
8.5
4.3
Decreased appetite
10
0
4.3
0
Pruritus
7.5
0
19
2.1
Rash
2.5
0
21
4.3
Rash maculopapular
0
0
13
4.3
Hypothyroidism
2.5
0
15
0
Hyperthyroidism
2.5
0
13
0
AST increased
5.0
0
4.3
0
Amylase increased
2.5
2.5
6.4
2.1
Lipase
increased
0 n = 1; nivolumab 1 + ipilimumab
0 3, n = 1) and resolved11with immunosuppressive6.4
Limbic
encephalitis
of grade 2 occurred in 2 pts (nivolumab,
treatment. One
pt (nivolumab, n = 1) had grade 4 limbic encephalitis which did not resolve with immunosuppressive treatment.
Pneumonitis
5.0
0
2.1
2.1
Summary of Clinical Activity
ORR, %
Complete response, %
Partial response, %
Stable disease, %
Disease control rate, %
Progressive disease, %
Death prior to first response assessment,
%
Not evaluable (no tumor assessment
follow-up), %
Median time to objective response, mos
Median DOR, mos (95% CI)
Range
Nivolumab
(n = 40)
18
0
18
20
38
53b
Nivolumab +
Ipilimumaba
(n = 46)
17
2.2
15
37
54
37
10
6.5c
0
2.2d
1.6
NR
4.1–11+
2.2
6.9 (1.5, NR)
1.5–11.1+
• Of 17 patients with SD (nivolumab + ipilimumab), 7 had confirmed PR after DBL, resulting in an updated
ORR of 32.6%; no additional responses occurred in the nivolumab monotherapy arm
aCombined
data for nivolumab 1 +iIpilimumab 1 and nivolumab 1 + ipilimumab 3 cohorts. In the nivolumab 1 + ipilimumab 3 cohort, 4 pts had not
reached first tumor assessment at DBL. b1 pt had PD in spine requiring surgery. c1 pt died due to unrelated AE, 1 pt died due to treatment-related
myasthenia gravis, 1 pt died due to PD. d1 pt had unrelated AE leading to permanent discontinuation and had no post baseline tumor assessment.
Changes in Tumor Burden
Nivolumab + Ipilimumaba
Nivolumab
100
100
Nivolumab 3
Percentage Change From Baseline (%)
75
Nivolumab 1 + Ipilimumab 1
75
Nivolumab 1 + Ipilimumab 3
50
First occurrence of new lesion
Confirmed PR or CR
50
Patients still on treatment
25
25
0
0
-25
-25
-50
-50
-75
-75
-100
-100
0
6
12
18
24
30
36
Time (weeks)
aCombined
42
48
54
60
66
% change truncated to 100%
0
6
12
18
24
30
36
42
48
Time (weeks)
data for nivolumab 1 + ipilimumab 1 and nivolumab 1 + ipilimumab 3 cohorts. Only pts with target lesion at baseline and ≥1
on-treatment tumor assessment are included (nivolumab, n = 34, nivolumab + ipilimumab, n = 40).
54
60
66
Tumor Responses (PD-L1 expression)
125
150
Nivolumab
100
Best Reduction from Baseline in
Lesion (%)
Target
150
Nivolumab + Ipilimumaba
125
100
<1% PD-L1
75
75
≥1% PD-L1
50
50
Not evaluableb
25
25
Confirmed responders
0
0
-25
-25
-50
-50
-75
-75
-100
-100
Evaluable samples
(40 of 90)
aCombined
PD-L1 expression level, n
(%)
<1%
≥1%
Nivolumab (n = 22)
15 (68)
7 (32)
Nivolumab + Ipilimumab (n
= 18)
12 (67)
6 (33)
data for nivolumab 1 + ipilimumab 1 and nivolumab 1 + ipilimumab 3 cohorts. bNot evaluable due to specimens that are not quantifiable, indeterminate, or not yet obtained;
10 nonevaluable samples and 8 not yet obtained in the nivolumab arm, 6 nonevaluable samples and 26 not yet obtained in the nivolumab 1 + ipilimumab 3 arm. Only pts with target
lesion at baseline and ≥1 on-treatment tumor assessment are included (nivolumab, n = 34, nivolumab + ipilimumab, n = 40).
Overall Survival
100
90
mOS,
mos
(95% CI)
80
70
Nivolumab
(n = 40)
Nivolumab +
Ipilimumaba
(n = 50)
4.4
(2.9, 9.4)
8.2
(3.7, NR)
OS (%)
60
50
Nivolumab + Ipilimumab
40
Nivolumab
30
mOS = 4.4 mos
20
mOS = 8.2 mos
10
0
0
3
6
9
12
15
Time (months)
Number of Patients at Risk
Nivolumab
40
26
16
7
3
0
Nivolumab +
Ipilimumab
50
25
10
5
2
0
aCombined
data for nivolumab 1 + ipilimumab 1 and nivolumab 1 + ipilimumab 3 cohorts
Novel immune
combinations:
T-cell activation
is a multiple
signal process
Many possible combination
partners with PD-1 targeted
therapies
Mahoney et al, Nature Reviews 2015
Immunological targets under clinical development
Immunological
pathway
Examples in clinical
trials
Ipilimumab
CTLA4
Tremelimumab
Pembrolizumab (PD1)
Nivolumab (PD1)
Atezolizumab (formerly
MPDL3280A) (PDL1)
PD1–PDL1
MEDI4736 (PDL1)
Avelumab (PDL1)
PDR001 (PD1)
TNF and TNFR superfamilies
4-1BB–4-1BB ligand
Urelumab, PF-05082566
OX40–OX40 ligand
MEDI6469
GITR
TRX518
CD27
Varlilumab
TNFRSF25–TL1A
CD40–CD40 ligand
CP-870893
HVEM–LIGHT–LTA
Most advanced stage of
clinical development
FDA approved
Phase III
FDA approved
FDA approved
HVEM–BTLA–CD160
IgSF
LAG3
TIM3
Preclinical
BMS-986016
Phase III
Phase III
Phase I
Phase I
Phase II
Phase II
Phase I
Phase II
Preclinical
Phase I
Preclinical
Phase I
Preclinical
Natural killer cell targets
KIRs
Lirilumab
Phase II
ILTs and LIRs
Preclinical
NKG2D and NKG2A IPH2201
Phase I
MICA and MICB
Preclinical
CD244
Preclinical
Suppressive myeloid cells
CSF1R
Emactuzumab
Soluble mediators
IDO
INCB024360
TGFβ
Galunisertib
Adenosine–CD39–
CD73
Ulocuplumab,
CXCR4–CXCL12
BKT140
Other
Bavituximab
Phosphatidylserine
Siglecs
B7 and CD28‐related proteins
ICOS–ICOS ligand
B7-H3
MGA271
B7-H4
Preclinical
SIRPA–CD47
Preclinical
Phase I
Preclinical
VEGF
VISTA
Preclinical
HHLA2–TMIGD2
Butyrophilins,
including BTNL2
CD244–CD48
TIGIT and PVR family
members
Preclinical
Preclinical
Neuropilin
CC-90002
Bevacizumab
MNRP1685A
Phase I
Phase II
Phase I
Preclinical
Phase I/II*
Phase II/III
Phase I
FDA approved
Phase I
Mahoney et al, Nature Reviews 2015
Preclinical
Preclinical
47 |
I-O agents have a unique MoA, offering the
opportunity for combination with other agents
I-O
Drake C. Ann Oncol. 2012;23(suppl 8):viii41–viii46; Hannani D, et al. Cancer J 2011;17:351–358;
Ménard C, et al. Cancer Immunol Immunother. 2008;57:1579–1587; Ribas A, et al. Curr Opin Immunol. 2013:25:291–296.
Radiation and Immunotherapy
Tang et al, Cancer Immunol Res, 2(9); 831–8. 2014
Potential of anti-CTLA-4 plus radiation:
ipilimumab in one patient with melanoma as an example
•
•
The target and other lesions regressed
Regression of distant lesions may be due to an enhanced systemic
response
A
B
August 2009
C
D
November 2010
January 2011
E
April 2011
October 2011
Ipilimumab
F
Recurrence of
unresectable cancer
Induction
Maintenance
Stable
December 2010
Aug.
2009
A
Sept.
2009
Radiation
Maintenance
Slow Progression
Dec.
2009
Figure adapted from Postow M, et al. N Engl J Med. 2012;366(10): 925–931.
Nov.
2010
A
Response
Dec.
2010
B
Jan.
2010
C
Stable
April
2010
D
Oct.
2010
E
STIMILI: A randomized phase II trial of consolidation ipilimumab vs
placebo in limited-stage SCLC after chemoradiotherapy
• Biomarker collaboration: G Coukos, Lausanne
52 |
Early Stage disease
Combination with surgery
ETOP | Name Project | Title Presentation | Zurich, July 27, 2009
SOC preoperative
evaluation
Early Stage Disease:
Neoadjuvant therapy
D1
D21
D42
Treatment
Atezolizumab
Atezolizumab
Surgery
Evaluation
CT + PET/CT
CT + PET/CT
Biomarkers
Tumor biopsy
blood
Tumor sample
blood
SOC
adjuvant
therapy
Combinations and new directions
• Combinations are being studied with
everything imaginable
– PD-1 and chemotherapies, first and later lines
– PD-1 and targeted therapies, up-front or upon
resistance
– Neoadjuvant/Adjuvant
– Radiation therapy
– PD-1 and anti-CTLA4 or other immune modulators
– Vaccines
• We have a lot to learn about the optimal use
of these agents!