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Combinations Among Different
Immunotherapies (including simultaneous
PD-(L)1 and CTLA-4 blockade)
Karen Kelly, MD
Professor of Medicine
Associate Director for Clinical Research
Jennifer Rene Harmon Tegley and Elizabeth Erica Harmon
Endowed Chair in Cancer Clinical Research
UC Davis Comprehensive Cancer Center
Royalty: UpToDate Author
Advisor: Ariad, AstraZeneca, BMS, Boehringer Ingelheim, Clovis, Genentech, Lilly
Research: AbbVie, Celgene, EMD Serono, Genentech, Gilead, Lilly, Millennium, Novartis
Disclosures
Immune Checkpoint Inhibitors and NSCLC
Single agent PD-1 inhibitors produce superior PFS and OS
compared to chemotherapy in the first and second line
treatment setting.
This treatment benefit is limited to a subset of patients.
Immune evasive pathways are nonredundant; providing an
opportunity for therapeutic immune combinations.
PD-1 inhibitor ORR DOR 1 YR PFS 1 YR OS
Nivolumab
Squamous cell
20% NR
(3-20.5 m)
21% 42%
Nivolumab
Non-squamous cell
19% 17.2 m 19% 51%
Pembrolizumab
2 mg/kg
18% NR
(4.2-10.5 m)
20% 43%
Brahmer J et al, NEJM: 373:123-35, 2015
Borghaei H et al, NEJM 373: 1627-39, 2015
Herbst RS et al, Lancet Oncol: 387, 2016
Convert a non-T-cell inflamed tumor into an inflamed tumor
Expectations of Immune Combinations
IO
combinations
Enhance immune mediated tumor cell death
IO
combinations
?Anti-PD-1
inhibitor
Immune Signature
for IO combination
Understanding the Role of the Tumor
Microenvironment and Immunotherapy
Responsiveness
Luke, JJ et al ASCO 2016 abstr #3004
T cell-inflamed tumor microenvironment by tumor type in increasing frequency
NO CORRELATION WITH MUTATIONAL BURDEN
Immunotherapy Drug Classifications
Drugs that target immune evasion
•Blockade of negative immune
regulators
•Blockade of tolerogenic enzymes
Drugs that stimulate the immune
process
• Agonist of costimulatory
receptors
• Enhancers of antigen
presentation (vaccines)
• Exogeneous recombinant
cytokines
• Oncolytic viruses
• Cell therapies
Reference
Clinical Expectations of Immune Combinations
• Increased number of responding patients
• Deeper and more durable responses
• Longer PFS and OS
• An acceptable toxicity profile
Dual Immune Checkpoint Inhibitors
CTLA-4 Blockade (Ipilimumab)PD-1 Blockade(Nivolumab)
APC – T-cellInteraction
Activation(cytokine secretion, lysis,
proliferation, migration to tumor)
TumorMicroenvironment
Dendriticcell T cell Tumor cell
MHCTCR TCR
PD-L1
PD-L2
MHC
PD-1
PD-1
B7
B7 CD28
CTLA-4
anti-CTLA-4
+++
---
+++T cell
+++
---
---anti-PD-1
anti-PD-1
•Nivolumab and ipilimumab enhance T-cell antitumor activity through distinct but complementary mechanisms
•Preclinical data suggest synergy with dual CTLA-4 and PD-1 blockade vs either agent alone
–Increased proliferation of effector CD8+ and CD4+ T cells and decreased intratumoral T-regulatory cells vs single pathway blockade
•Combination FDA approved for untreated metastatic melanoma
CheckMate 012 Study Design: Nivolumab Plus Ipilimumab in First-line NSCLC
Primary endpoint: safety and tolerability
Secondary endpoints: ORR (RECIST v 1.1) and PFS rate at 24 wks
Exploratory endpoints: OS; efficacy by PD-L1 expression
Stage IIIB/IV NSCLC (any histology); no prior chemotherapy for advanced disease; ECOG PS 0 or 1
Nivo 3 mg/kg IV Q2W until
disease progression or
unacceptable toxicity
Nivo 1 mg/kg IV Q3W x 4
+
Ipi 1 mg/kg IV Q3W x 4
Nivo 1 mg/kg IV Q2W
+
Ipi 1 mg/kg IV Q6W
Nivo 3 mg/kg IV Q2W
+
Ipi 1 mg/kg IV Q12W
Nivo 3 mg/kg IV Q2W
+
Ipi 1 mg/kg IV Q6W
Until disease progression or unacceptable toxicity
Dual Immune Checkpoint Inhibitors
Hellman MD et al, J Clin Oncol 34, 2016 (suppl; abstr 3001)
Nivo 3 Q2W + Ipi 1 Q12W
(n = 38)
Nivo 3 Q2W + Ipi Q6W
(n = 39)
Nivo 3 Q2W
(n = 52)
Any
Grade
Grade
3-4
Any
Grade
Grade
3-4
Any
Grade
Grade
3-4
Treatment-related AEs, % 82 37 72 33 71 19
Treatment-related AEs
leading to discontinuation, %11 5 13 8 10 10
Dual Immune Checkpoint Inhibitors
Safety Profile
Hellman MD et al, J Clin Oncol 34, 2016 (suppl; abstr 3001)
Dual Immune Checkpoint Inhibitors
Nivo 3 Q2W + Ipi 1 Q12W
(n = 38)
Nivo 3 Q2W + Ipi Q6W
(n = 39)
Nivo 3 Q2W
(n = 52)
Confirmed ORR, % (95% CI) 47 (31, 64) 39 (23, 55) 23 (13, 37)
Median duration of response, mo (95% CI) NR (11.3, NR) NR (8.4, NR) NR (5.7, NR)
Median length of follow-up, mo (range) 12.9 (0.9-18.0) 11.8 ( 1.1-18.2) 14.3 (0.2-30.1)
Best overall response, %
Complete response
Partial response
Stable disease
Progressive disease
Unable to determine
0
47
32
13
8
0
39
18
28
15
8
15
27
38
12
Median PFS, mo (95% CI) 8.1 (5.6, 13.6) 3.9 (2.6, 13.2) 3.6 (2.3, 6.6)
1-year OS rate, % (95% CI) NC 69 (52, 81) 73 (59, 83)
Hellman MD et al, J Clin Oncol 34, 2016 (suppl; abstr 3001)
Nivolumab + Ipilimumab
Increased number of responding patients
Deeper and more durable responses
Longer PFS (q 12 wk schedule)
? Longer OS
- An acceptable toxicity profile
Randomized Phase III Trials of Dual Immune Checkpoint Inhibitors
CheckMate 227
Primary endpoints OS and PFS
Nivolumab monotherapy
Ran
do
miz
e
Tumor PD-L1> 1%
Nivolumab + Ipilimumab3 mg/kg q 2wks + I mg/kg q 6 wks
Chemotherapy
Non-SQ: Pemetrexed + cisplatin
or carboplatin
SQ: Gemcitabine + cisplatin
or carboplatin
Treatmentuntil disease progression or unacceptable toxicity
Nivolumab + SOC
Ran
do
miz
e
Nivolumab + Ipilimumab3 mg/kg q 2 wks+ 1 mg/kg q 6 wks
Chemotherapy
Pemetrexed + cisplatin or carboplatin
Gemcitabine + cisplatin or carboplatin
Paclitaxel + carboplatin
Treatmentuntil disease progression or unacceptable toxicity
Tumor PD-L1< 1%
Treatment-naïvepatients withstage IVor recurrentNSCLC
Anticipatedenrollment:approximately1980
CheckMate 032 Study Design: Nivolumab Plus Ipilimumab in Recurrent SCLC
Primary endpoint: ORR per RECIST v1.1
Secondary endpoints: Safety
Exploratory endpoints: PFS, OS, biomarker analysis
Patients with SCLC with progressive disease after ≥ 1 prior line of therapy, including a
platinum-based regimen in first line (unselected by PD-L1 expression) (N = 183)
Until disease progression or unacceptable toxicity
Nivo 1 mg/kg IV Q2W
+
Ipi 3 mg/kg IV Q4W
Dual Immune Checkpoint Inhibitors
Nivo 3 mg/kg IV Q2W
Nivo 3 mg/kg IV Q2W
+
Ipi 1 mg/kg IV Q4W
Antonia S et al, Lancet Oncol 17, 883-95
Nivo 3 Q2W
(n = 98)
Nivo 1 Q2W + Ipi 3 Q4W
(n = 61)
Nivo 3 Q2W + Ipi Q4W
(n = 54)
Grade
1-2
Grade
3
Grade
4
Grade
1-2
Grade
3
Grade
4
Grade
1-2
Grade
3
Grade
4
Treatment-related AEs, % 39 (40%) 9 (9%) 4 (4%) 30 (49%) 14 (23%) 4 (7%) 30 (56%) 8 (15%) 2 (4%)
Treatment-related AEs
leading to discontinuation, %
Dual Immune Checkpoint InhibitorsSafety Profile
Nivolumab 3 mg/kg
(n=98)
Nivolumab 1 mg/kg plus
ipilimumab 3 mg/kg (n=61)
Nivolumab 3 mg/kg plus
ipilimumab 1 mg/kg (n=54)
Objective response; 95% CI 10 (10%; 5-18) 14 (23%; 13-36) 10 (19%; 9-31)
Best overall response
Complete response 0 1 (2%) 0
Partial response 10 (10%) 13 (21%) 10 (19%)
Stable disease 22 (22%) 13 (21%) 9 (17%)
Progressive disease 52 (53%) 23 (38%) 29 (54%)
Unable to determine 12 (12%) 8 (13%) 6 (11%)
Med Dor NR (4.4-NR) 7.7 mos 4.4 mos
1 YR PFS 11% 19% NE
1 YR OS 33% 43% 35%
Antonia S et al, Lancet Oncol 17, 883-95
Efficacy
Randomized Phase III Trials of Dual Immune Checkpoint Inhibitors
CheckMate 451
Primary endpoints OS and PFS
Nivolumab
Ran
do
miz
e
Nivolumab + Ipilimumab
Placebo
Treatmentuntil disease
progression or unacceptable
toxicity
ES SCLC with a response or stable disease after 4 cycles platinum-based therapy
N = 810
Randomized Phase III Trials of Dual Immune Checkpoint Inhibitors
Treatment-naïvepatients with stage IV or recurrent NSCLC
Anticipated enrollment:approximately 1092
Durvalumab monotherapy
Ran
do
miz
e
Tumor PD-L1assessmentat screening
Durvalumab + Tremelimumab
Pemetrexed + cisplatin or carboplatin
Gemcitabine + cisplatin or carboplatin
Paclitaxel + carboplatin
Treatmentuntil disease progression or unacceptable toxicity
Primary endpoints OS and PFS
MYSTIC
Durvalumab 20 mg/kg q 4 wks
and Tremelimumab 1 mg/kg
N=18
Treatment related AEs (any Grade)
Treatment related AEs (Grade 3-4)
11 (61%)
3 (17%)
Treatment related AEs leading to
discontinuation
3 (17%)
There was one treatment related death due to a pericardial effusion
Durvalumab 10-20 mg/kg every 2 wks
or 4 wks + tremelimumab 1 mg/kg
All evaluable patients with ≥ 24 weeks of follow-up
Objective response 6/26 (23% [9-44])
Disease control 9/26 (35% [17-56])
PD-L1 positive (≥ 25%)
Objective response 2/9 (22% [3-60])
Disease control 3/9 (33% [8-70])
PD-L1 negative (< 25%)
Objective response 4/14 (29% [8-58])
Disease control 6/14 (43% [18-71])
PD-L1 negative (0%)
Objective response 4/10 (40% [12-74])
Disease control 5/10 (50% [19-81])
PD-L1 status unknown
Objective response 0/3 (0% [0-71])
Disease control 0/3 (0% [0-71])
Antonia S et al, Lancet Oncol 17, 883-95
Pembrolizumab + Ipilimumab in Second Line NSCLC
Gubens M et al. ASCO 2016 #9027
Ipilimumab 4 doses
Week 0 3 6 9 12 15 18 21 24 27 30 33 // 105
Pembrolizumab 2 or 10 mg/kg Q3W for up to 2 years
Pembrolizumab and Ipilimumab Dosing
Pembrolizumab 2 mg/kg + Ipilimumab 1 mg/kg (n=44)
Total population
n=44
TPS ≥50%
n=6
TPS ≥1%
n=24
TPS <1%
n=20
ORR, n (%) [95% CI] 11 (25) [13-40] 1 (17) [<1-64] 7 (29) [13-51] 4 (20) [6-44]
DCR, n (%) [95 % CI] 28 (64) [48-78] 2 (33) [4-78] 14 (58) [37-78] 14 (70) [46-88]
Best overall response, n (%)
CR 2 (5) 1 (17) 1 (4) 1 (5)
PR 9 (21) 0 6 (25) 3 (15)
SD 17 (39) 1 (17) 7 (29) 10 (50)
PD 8 (18) 1 (17) 4 (17) 4 (20)
No assessment 8 (18) 3 (50) 6 (25) 2 (10)
Duration of response,
median (range), months13.8 (1.8+ to 13.8) 3.5 (3.5 to 3.5) NR (1.8+ to 12.7+) 13.8 (2.5+ to 13.8)
Dual Immune Checkpoint Agonist and Antagonist
Infante J et al. ASCO 2016 abst #101
Dual Immune Checkpoint Agonist and Antagonist
Agonist Antagonist N GR 3 AE ORR Comment
OX40
MOXR 0916
.8-1200mg q 3 wk
Atezolizumab
1200mg IV q 3 wk
51
9 prior PD/PDL1
4 prior OX40
1-pneumonitis 4%
2/51 durable
NO DLT
NO DDI
4-IBB/CD137
Utomilumab
.045 – 5 mg/kg q 3 wk
Pembrolizumab
2 mg/kg q 3 wk
23
6-NSCLC
1-SCLC
Prior ICI allowed
1-adrenal
insufficiency
1 hypokalemia
26%
6/23 durable
NO DLT
NO DDI
PD-L1 Modulation
pembrolizumab)
Drug Class of Agonist Combination ASCO Session
MOXR0916 OX40 + atezolizumab Abstract 101 CSS 6/4
MEDI0562 OX40 + tremelimumab
+ durvalumab
-
GSK3174998 OX40 + pembrolizumab Abstract 3017 6/5
PF-04518600 OX40 + utolomumab Abstract 3079 6/5
MEDI6383 OX40 ligand
fusion protein
+ durvalumab -
Utomilumab IBB + pembrolizumab Abstract 3002
Dual Immune Checkpoint Agonist and Antagonist
Immune Checkpoint Inhibitors + IDO Inhibitors
ORR 53% (8/15 pts) ORR 17% (2/12 pts)
Indoximod 1200 mg po bid daily, Ipilimumab 3 mg/kg
x 4 doses, Standard anti- PD-1 administration
Yousef Z, et al. ASCO 2016 #3075Adverse event data not reported
Responses with Indoximod and Ipilimumab
Immune Checkpoint Inhibitors + Vaccines
TG4010 – MVA-MUC1-IL2 vaccine
TIME Trial
Quoix E. et al Lancet Oncology 2016
Primary endpoint: ORR
UC Davis, UCSF, COH and UCSD
Previously treated
advanced stage
nonsquamous cell
NSCLC
(N=
Cycles 1-3
TG4010 q weekly
+ Nivolumab
q 2 weekly
Subsequent Cycles
TG4010 q 2 weekly
+ Nivolumab
q 2 weekly
Progression
Understanding Mechanisms of
Immune Evasion
Spranger S et al Nature 2015
Luke JJ et al. J Clin Oncol, 2016 (suppl; abstr 3004)
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