combinations among different immunotherapies (including ... · brahmer j et al, nejm: 373:123-35,...
TRANSCRIPT
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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
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Royalty: UpToDate Author
Advisor: Ariad, AstraZeneca, BMS, Boehringer Ingelheim, Clovis, Genentech, Lilly
Research: AbbVie, Celgene, EMD Serono, Genentech, Gilead, Lilly, Millennium, Novartis
Disclosures
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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
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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
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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
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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
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Clinical Expectations of Immune Combinations
• Increased number of responding patients
• Deeper and more durable responses
• Longer PFS and OS
• An acceptable toxicity profile
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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
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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)
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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)
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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)
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Nivolumab + Ipilimumab
Increased number of responding patients
Deeper and more durable responses
Longer PFS (q 12 wk schedule)
? Longer OS
- An acceptable toxicity profile
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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
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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
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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
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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
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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
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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)
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Dual Immune Checkpoint Agonist and Antagonist
Infante J et al. ASCO 2016 abst #101
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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)
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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
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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
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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
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Understanding Mechanisms of
Immune Evasion
Spranger S et al Nature 2015
Luke JJ et al. J Clin Oncol, 2016 (suppl; abstr 3004)