Download Combining immunotherapeutic agents

Combining immunotherapeutic agents
Paolo A. Ascierto, MD
Unit Melanoma, Cancer Immunotherapy and Innovative Therapies
Istituto Nazionale Tumori – Fondazione “G. Pascale”, Napoli, Italy
Disclosure
•
Employment or Leadership Position: None
•
Consultant/Advisory Role: Bristol-Meyers Squibb,
Roche-Genentech, Merck Sharp & Dohme, Novartis,
Amgen, Array, Merck Serono
•
Stock Ownership: None
•
Research Funding: Bristol-Meyers Squibb, RocheGenentech, Array
•
Expert Testimony: None
•
Other Remuneration: None
The goals for treatments ……
early and fast
responses
Long-term
benefit
cure the patients
Ascierto ESMO 2016
Two different drugs... Two different concepts
immunotherapy
slow acting, but possibility to
reach long-term benefit
Oct-2010
Ascierto ESMO 2016
Jun-2011
target therapy
fast acting, rapid metabolic shutdown,
unfortunately resistance
Day 0
Day 15
Istituto Nazionale Tumori Fondazione “G. Pascale”, Naples, Italy
Raising the bar ……
Targeted therapy
Combination?
Percent alive
Percent alive
Percent alive
Immunotherapy
0
1
2
Years
3
0
1
2
Years
3
0
1
2
3
Years
Figure modified from Ribas et al., Clin Cancer Res. 2012.
Raising the bar ……
Chemotherapy
Radiotherapy
Combination
approaches
Immunotherapy
Targeted therapy
Ascierto ESMO 2016
Raising the bar ……
Chemotherapy
Radiotherapy
Combination
approaches
Immunotherapy
+
Immunotherapy
Targeted therapy
Ascierto ESMO 2016
Components of eliciting a clinically relevant immune response
Abrogate immuno-suppressive networks
T-regs
B-regs
Turn on NK cell
Turn on T-cell
activate
IDO
•
•
•
•
CD137
CD40
CD137
VEGF
chemotherapy
radiation therapy
vaccine
intratumoral
arginine
CTLA4
sMICB
– oncolytic virus
– cytokines
– TLR agonists
PD-1
OX40
M2 MO
LAG-3
GITR
CD27
BTLA
T & NK cell
trafficking
and
infiltration
into the
tumor
PGE2
TIM-3
Fc/CD16
sMICA
IL-2
TGF-β
NKG2D
Prime system
a-KIR
MDSC
inhibit
IL-15
exosomes
adenosine
IL-10
SMR 2014 BMS scientific symposium
Targeting CTLA-4 and PD-1 pathways
Periphery
Tumour microenvironment
Activation
(cytokines, lysis, proliferation,
migration to tumour)
MHC
Dendritic
cell
B7
B7
TCR
TCR
+++
+++
CD28
CTLA-4
+++
---
T cell
Anti-CTLA-4
MHC
T cell
PD-1
PD-L1
---
Tumour cell
Anti-PD-1/PD-L1
PD-1
PD-L2
--Anti-PD-1
CTLA-4 pathway
PD-1 pathway
Wolchock J, et al. JCO 2013 Volume 31, Issue 15_suppl ; abstr 9012^
CA209-067 study: ORR and PFS
Larkin et al. NEJM 2015
Wholchok et al ASCO 2016
CA209-069 study: PFS and OS
Postow et al AACR 2016
Hodi et al. Lancet Oncol. 2016 Sep 9
KEYNOTE-029: Study Design
Dose Expansion
(Part 1B)
Dose Run-In
(Part 1A)
Patients
• Advanced MEL,
≥0 prior therapies
OR
• Advanced RCC,
≥1 prior therapy
Pembro
2 mg/kg Q3W
up to 24 months
+
Ipi 1 mg/kg Q3W
x 4 doses
Tolerable
based on
DLT rate?
No
Stop
development
Combination tolerable based on DLT rate and AE
profile1,2
Yes
Patients
• Advanced MEL
• ≥0 prior therapies
• No prior anti–CTLA-4,
PD-1, or PD-L1
• ECOG PS 0 or 1
Primary end point:
Safety
Secondary end points:
ORR, DOR, PFS, OS
ClinicalTrials.gov, NCT02089685.
Long G et al ASCO 2016
Keynote 029: Best Change From Baseline in Tumor Size
Change From Baseline, %
(RECIST v1.1, investigator review)
100
80
60
40
20
0
-20
-40
-60
-80
-100
PD-L1 positive
PD-L1 negative
PD-L1 unknown
81%
ORR = 57%
Median change:
–54.5%
Data cutoff date: Mar 17, 2016.
Long et al. ASCO 2016
Keynote 029: AE Summary
Category
Treatment
Related
N = 153
Immune
Mediateda
N = 153
Any grade
145 (95%)
89 (58%)
Grade 3-4
64 (42%)
38 (25%)
0
0
16 (10%)
12 (8%)
11 (7%)
6 (4%)
16 (10%)
11 (7%)
Led to death
Led to ipilimumab discontinuation
only
Led to pembrolizumab
discontinuationb
Led to ipilimumab and
pembrolizumab discontinuationc
Long et al. ASCO 2016
CA209-511: Study Design
Phase IIIb/IV, Randomized, Double Blinded, Study of Nivolumab 3 mg/kg in Combination with Ipilimumab 1 mg/kg vs Nivolumab 1 mg/kg in Combination with
Ipilimumab 3 mg/kg in Subjects with Previously Untreated, Unresectable or Metastatic Melanoma
Double Blinded
Part 1
6 weeks*
Open-label
Part 2***
Arm A (n = 173)
Previously
Untreated
Unresectable
Stage III-IV
Melanoma
Randomize
(N = 346)
1:1
Stratify by
• PD-L1
expression
• M stage
nivolumab 3 mg/kg IV
+ ipilimumab 1 mg/kg IV
Nivolumab Flat Dose
480 mg
Every 4 weeks
Every 3 weeks for 4 doses
Arm B (n = 173)
nivolumab 1 mg/kg IV
+ ipilimumab 3 mg/kg IV
Nivolumab Flat Dose
480 mg
Every 4 weeks
Every 3 weeks for 4 doses
*6 weeks from last dose in part 1 to Part 2 monotherapy flat dose
**Treatment beyond initial investigator-assessed RECIST 1.1-defined progression will be
considered in subjects experiencing investigator assessed clinical benefit and tolerating study therapy. Such subjects must discontinue
therapy when further progression is documented.
*** The treatment arm assigned in Part 1 will no be revealed until the end of the study
Treat until
progression** or
unacceptable
toxicity
Changes in Target Lesions: Nivo/Ipi and Pembro/Epacadostat
nivolumab + ipilimumab
pembrolizumab + epacadostat
1 mg/kg nivolumab
+ 3 mg/kg ipilimumab
300
Change in target lesions from baseline (%)
200
First occurrence
of new lesion
100
80
60
40
20
0
–20
–40
–60
–80
–100
0
10
20
30
40
50
60
70
80
90
100
110
Weeks since treatment initiation
Wolchok JD, et al. J Clin Oncol 2013;31(suppl): abstract 9012^;
Sznol M, et al. J Clin Oncol 2013;31(suppl): abstract CRA9006^
Hamid et al. SMR November 21, 2015
T-VEC + ipilimumab
Puzanov et al JCO 2016; 34:2619-2626
T-VEC + pembrolizumab
Long et al SMR 2015
MASTERKEY-265 Phase 3 Study Design
N = 330
N = 660
T-VEC Intralesional
• Unresectable stage III or
IV melanoma
• Treatment naive
– Prior BRAFi allowed
• Injectable lesions
Pembrolizumab 200mg IV Q3W
R
1:1
T-VEC placebo Intralesional
Pembrolizumab 200mg IV Q3W
N = 330
Primary Endpoints: PFS and OS
NCT02263508
Long et al SMR 2015
Mozzillo N, Simeone E, et al.Oncoimmunology 2015 in press
Survival results
All cohort 6 months-OS was 93,3 % and
1 y-OS was 86,2%
9/9 (100%) responder patients were alive at a median
follow up of 16,2 months.
Mozzillo N, Simeone E, et al.Oncoimmunology 2015
Heppt et al. Cancer Immunol Immunother. 2016 Aug;65(8):951-9
Rationale for investigating opportunities to combine immunotherapy
with other therapeutic modalities
Multiple mechanisms of potential synergy between the different treatment modalities
Radiation
Adhesion molecules
(CAM-1) and death
receptors (FAS)
Peptide pools
CD8 T cell
Upregulation of MHCI
Uploading
of antigen
processing
machinery
Chemotherapy
Targeted therapies
Vascular normalisation
T cell initiation
Effector immune infiltrate
Release of tumour
antigens (cascade)
Cytokine release
Translocation of
calreticulin
CD8 T cells
TAA crosspresentation
Dendritic cell
MDSC
Tregs
M2 macrophages
TAA
Upregulates MHCI
Adhesion molecules/
death receptors
APM
CD8 T cells
(homeostatic peripheral
expansion)
MDSC
CD8 T cells
T cell function
Tregs
Activation of apoptosis
Blockage of cell cycle
1. Adapted from Hodge JW. Semin Oncol 2012;39:323–39; 2. Drake CG Ann Oncol 2012;23 Suppl 8:viii41–6; 3. Ménard C, et al. Cancer Immunol Immunother
2008;57:1579-87; 4. Hannani D, et al. Cancer J 2011;17:351–58; 5. Ribas A at al. Curr Opin Immunol 2013:25:291–96.
Raising the bar ……
Chemotherapy
Radiotherapy
Combination
approaches
Immunotherapy
Targeted therapy
Radiotherapy modifies the immune system
interaction with cancer
Lymphocytepoor
Lymphocyterich
Demaria & Formenti, Front Oncol 2012
Radiation + ipilimumab
• A patient with melanoma received ipilimumab and radiotherapy
• The target and other lesions regressed
• Regression of distant lesions may be due to an enhanced systemic response
Figure adapted from Postow M, et al. N Engl J Med 2012; 366(10): 925–931.
Abscopal Effects of Radiotherapy in Melanoma Patients
Progressing After Ipilimumab (cont’d)
• Patient survival according to abscopal responses
100
OS (%)
80
Abscopal response
Median OS, months
(95% CI): 22.4 (2.5–50.3)
No abscopal response
Median OS, months
(95% CI): 8.3 (7.6–9.0)
60
40
20
0
0
6
12
18
Months
24
30
36
• Abscopal response was present in 11 patients and absent in 10 patients
• Groups were compared using the log-rank test; p=0.002
Grimaldi AM, et al. Oncoimmunology 2014;3:e28780
Abscopal Effects of Radiotherapy in Melanoma Patients Progressing After Ipilimumab
Baseline
Post
ipilimumab
Post
radiotherapy
• 54-year old patient
• Received 4 cycles of
ipilimumab 3 mg/kg
• Followed by palliative
whole brain radiotherapy
• Post RT follow-up CT
scans indicative of
abscopal response
Grimaldi AM, et al. Oncoimmunology 2014;3:e28780
799 patients randomized
RT
Site:
bone mets
Dose : 8 Gy, single fraction
Study powered to detect a 4 month
difference in median overall survival (15.8
versus 12 months)
Time: RT within 2 days from
IPI, then anytime during IPI
Raising the bar ……
Chemotherapy
Radiotherapy
Combination
approaches
Immunotherapy
Targeted therapy
Combining Ipilimumab with Chemotherapy
Summary of Efficacy Results in Melanoma
Randomised
phase 2 trial of
ipilimumab 3 mg/kg +
DTIC vs ipilimumab
alone
Randomised
phase 3 trial of
ipilimumab 10 mg/kg +
DTIC vs DTIC alone
Treatment-naïve
Treatment-naïve
Patient population Ipi + DTIC
Patients, n
Median OS, months
1-year OS, %
Median PFS,
months
Best overall
response rate, %
Median duration of
response, months
35
14.3
62
Ipi
Ipi + DTIC
DTIC
37
11.4
45
250
11.2
47.3
252
9.1
36.3
Not reported
14.3
5.4
Not reported
(durable CRs and
PRs of 20+ months)
24% reduction in the risk
of progression with ipi +
DTIC
Single arm
phase 2 trial of
ipilimumab
10 mg/kg +
fotemustine
Single arm
phase 2 trial of
ipilimumab
10 mg/kg +
temozolomide
Pretreated and
Treatment-naïve Treatment-naïve
86
13.3
52.6
64
Not reached
68
5.3
5.1
15.2
10.3
29.1
30
19.3
8.1
Not reached
12+
Caution is warranted when comparing across trials
Robert C, et al. N Engl J Med 2011;364(26):2517–26
Di Giacomo AM, Lancet Oncol 2012;13(9):879–86
Patel SP, et al. Presented at ESMO 2012. P1126
Langer et al ESMO 2016
Phase 2 trial to evaluate CTLA-4 T cell checkpoint inhibition with ipilimumab in combination
with chemotherapy (carboplatin/paclitaxel) in lung cancer
1.0
NSCLC (Phased)
Events/ Median OS,
patients
months
95% CI
HR P value
0.8
Control
56/66
4.63
4.14–5.52
0.6
Concurrant
Ipilimumab
55/70
5.52
4.17–6.74 0.81
0.13
0.4
0.2
irPFS (probability)
irPFS (probability)
NSCLC (Concurrent)
0
4
6
8
10
Time (months)
Control
66 59 55 41 38 28 17 13 11 5
Ipilimumab 70 62 48 44 40 34 29 20 18 9
4
8
12
14
0.8
0.6
95% CI
HR P value
Control
56/66
4.63
4.14–5.52
Phased
Ipilimumab
54/68
5.68
4.76–7.79 0.72
0.05
0.4
0.2
16
0
3
2
3
1
1
1
1
0
1
0
0
0
6
8
10
Time (months)
4
4
12
3
3
3
3
14
3
3
1
1
16
1
1
1
1
0
0
ED-SCLC (Phased)
1.0
Events/ Median OS,
patients
months
0.6
4
Control
66 59 55 41 38 28 17 13 11 5
Ipilimumab 66 59 55 41 38 28 17 13 11 5
ED-SCLC (Concurrent)
0.8
2
No. at risk
3
6
95% CI
HR P value
Control
40/45
5.26
4.67–5.72
Concurrant
Ipilimumab
37/43
5.68
5.19–6.87 0.75
0.4
0.2
0
0.11
irPFS (probability)
2
No. at risk
irPFS (probability)
Events/ Median OS,
patients
months
0
0
1.0
Events/ Median OS,
patients
months
95% CI
HR P value
0.8
Control
40/45
5.26
4.67–5.72
0.6
Phased
Ipilimumab
38/42
6.44
5.29–7.75 0.64
0.4
0.2
0
0
No. at risk
1.0
2
4
6
8
10 12 14
Time (months)
16
18
20
22
Control
45 44 42 38 36 26 11 10 7 5 4 3 2 2 2 2 1 0 0 0 0 0 0 0
Ipilimumab 43 38 36 31 29 26 16 12 11 10 9 9 8 5 4 3 3 2 2 2 2 2 1 0
Data from trial CA184-041.
aStatistically significant per protocol-stipulated one-sided =0.1; P values not adjusted for multiple comparisons.
HR = hazard ratio; Ipi = ipilimumab; irPFS = PFS by immune-related response criteria (irRC);
mWHO-PFS = PFS by modified WHO criteria (mWHO); Pbo = placebo; PFS = progression-free survival.
1. Lynch TJ, et al. J Clin Oncol. 2012;30:2046–2054; 2. Reck M, et al. Ann Oncol. 2013;24:75–83.
0
No. at risk
2
4
6
8 10 12 14
Time (months)
16
18
20
22
Control
45 44 42 38 36 26 11 10 7 5 4 3 2 2 2 2 1 0 0 0 0 0 0
Ipilimumab 42 42 40 37 35 31 22 18 10 7 7 6 6 6 5 5 5 3 2 1 1 1 0
0.03
Raising the bar ……
Chemotherapy
Radiotherapy
Combination
approaches
Immunotherapy
Targeted therapy
Summary of Published Data of Immunotherapy in Combination with Targeted Agents
• The combination of ipilimumab with targeted agents could in theory
result in synergistic effects
Jang, S, Atkins M. Lancet Oncol 2013;14:e60–9
Ribas A, et al. N Engl J Med 2013;368:1365–6
Effect of BRAF inhibitors on the immune system
BRAF inhibition is
associated with increased
melanoma antigen
expression in tumours of
patients with metastatic
melanoma
Antitumour activity of
combined BRAFi+MEKi
plus anti-PD-13
CD4+ and CD8+ increase in
responder lesion and
decrease in lesions which
progressed
↑ MHC and melanoma
antigen expression3
BRAF inhibition is associated with
increased CD8+ T-cell infiltrate in
tumours of patients with metastatic
melanoma
Wilmott JS, et al. Clin Cancer Res 2011;18:1386–94, Reprinted from Clinical Cancer Research 2012, with permission from AACR
Frederick DT, et al. Clin Cancer Res 2013;19:1225–31, Reprinted from Clinical Cancer Research 2013, with permission from AACR
3. From Hu-Lieskovan S et al. Sci Transl Med 2015;7:279ra41., Reprinted with permission from AAAS
Summary of Published Data of Immunotherapy in Combination with Targeted Agents
• The combination of ipilimumab with targeted agents could in theory
result in synergistic effects
• Concurrent administration of vemurafenib and ipilimumab may not
be feasible
–
Increased incidence of hepatotoxicity observed in a phase 1 safety study
–
Toxicity may preclude adequate dosing
Jang, S, Atkins M. Lancet Oncol 2013;14:e60–9
Ribas A, et al. N Engl J Med 2013;368:1365–6
Summary of Published Data of Immunotherapy in Combination with Targeted Agents
• The combination of ipilimumab with targeted agents could in theory
result in synergistic effects
• Concurrent administration of vemurafenib and ipilimumab may not
be feasible
–
Increased incidence of hepatotoxicity observed in a phase 1 safety study
–
Toxicity may preclude adequate dosing
Jang, S, Atkins M. Lancet Oncol 2013;14:e60–9
Ribas A, et al. N Engl J Med 2013;368:1365–6
Summary of Published Data of Immunotherapy in Combination with Targeted Agents
• The combination of ipilimumab with targeted agents could in theory
result in synergistic effects
• Concurrent administration of vemurafenib and ipilimumab may not
be feasible
–
Increased incidence of hepatotoxicity observed in a phase 1 safety study
–
Toxicity may preclude adequate dosing
• Phase 1 data show that combinations of dabrafenib + ipilimumab
with or without trametinib are not associated with hepatotoxicity
Jang, S, Atkins M. Lancet Oncol 2013;14:e60–9
Ribas A, et al. N Engl J Med 2013;368:1365–6
Puzanov I, et al. J Clin Oncol 2014;32(suppl 5s): abstract 2511
Summary of Published Data of Immunotherapy in Combination with Targeted Agents
• The combination of ipilimumab with targeted agents could in theory
result in synergistic effects
• Concurrent administration of vemurafenib and ipilimumab may not
be feasible
–
Increased incidence of hepatotoxicity observed in a phase 1 safety study
–
Toxicity may preclude adequate dosing
• Phase 1 data show that combinations of dabrafenib + ipilimumab
with or without trametinib are not associated with hepatotoxicity
• The triplo combo ipilimumab/dabrafenib/trametinib is not feasible
due to the increase of gastro-intestinal toxicity (bowel perforation)
Jang, S, Atkins M. Lancet Oncol 2013;14:e60–9
Ribas A, et al. N Engl J Med 2013;368:1365–6
Puzanov I, et al. J Clin Oncol 2014;32(suppl 5s): abstract 2511
Summary of Published Data of Immunotherapy in Combination with Targeted Agents
• The combination of ipilimumab with targeted agents could in theory
result in synergistic effects
• Concurrent administration of vemurafenib and ipilimumab may not
be feasible
–
Increased incidence of hepatotoxicity observed in a phase 1 safety study
–
Toxicity may preclude adequate dosing
• Phase 1 data show that combinations of dabrafenib + ipilimumab
with or without trametinib are not associated with hepatotoxicity
• The triplet combo ipilimumab/dabrafenib/trametinib is not feasible
due to the increase of gastro-intestinal toxicity (bowel perforation)
• Sequential treatment with ipilimumab and targeted therapies may
be a more appropriate therapeutic approach
Ackerman A, et al. J Clin Oncol 2012; 30 (suppl): abstract 8569
Ascierto PA, et al. J Transl Med 2012;10: Epub ahead of print
Jang, S, Atkins M. Lancet Oncol 2013;14:e60–9
Ribas A, et al. N Engl J Med 2013;368:1365–6
Puzanov I, et al. J Clin Oncol 2014;32(suppl 5s): abstract 2511
Summary of Published Data of Immunotherapy in Combination with Targeted Agents
• What about the combo anti-PD-1/PD-L1 with Target Therapy ?
Summary of Published Data of Immunotherapy in Combination with Targeted Agents
• What about the combo anti-PD-1/PD-L1 with Target Therapy ?
• We know that anti-PD-L1can be combined with BRAFi
Sullivan R et al SMR 2015
Summary of Published Data of Immunotherapy in Combination with Targeted Agents
• What about the combo anti-PD-1/PD-L1 with Target Therapy ?
• We know that anti-PD-L1can be combined with BRAFi
Sullivan R et al SMR 2015
Summary of Published Data of Immunotherapy in Combination with Targeted Agents
• What about the combo anti-PD-1/PD-L1 with Target Therapy ?
• We know that anti-PD-L1can be combined with BRAFi
• What about the triplet ?
Summary of Published Data of Immunotherapy in Combination with Targeted Agents
•
•
•
•
What about the combo anti-PD-1/PD-L1 with Target Therapy ?
We know that anti-PD-L1can be combined with BRAFi
What about the triplet ?
It’s feasible !
Ribas et al. ASCO 2015
Summary of Published Data of Immunotherapy in Combination with Targeted Agents
•
•
•
•
What about the combo anti-PD-1/PD-L1 with Target Therapy ?
We know that anti-PD-L1can be combined with BRAFi
What about the triplet ?
It’s feasible !
Hwu P et al. ESMO 2016
KEYNOTE-022 Phase 2 Trial Design
Advanced melanoma
• BRAFi/MEKi , antiPD-1/L1, IPI naïve
• N=120
Pembrolizumab +
Dabrafenib + Trametinib
1:1
Placebo +
Dabrafenib + Trametinib
•
Primary endpoint: PFS
•
Interim Analysis for early efficacy signal
Clinicaltrials.gov
NCT02130466
PFS curves may predict long-term benefit …
% Progression-Free
100
Anti-PD-1
Combo target
50
1
2
Years
Ascierto & Long. Lancer Oncol. 2016
PFS curves may predict long-term benefit …
% Progression-Free
100
Anti-PD-1
Combo Target
50
1
2
Years
Ascierto & Long. Lancer Oncol. 2016
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