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Combining immunotherapeutic agents
Paolo A. Ascierto, MDUnit 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, Roche-
Genentech, 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
Istituto Nazionale Tumori Fondazione “G. Pascale”, Naples, Italy
Oct-2010 Jun-2011
immunotherapy
slow acting, but possibility to
reach long-term benefit
target therapy
fast acting, rapid metabolic shutdown,
unfortunately resistance
Day 15Day 0
Ascierto ESMO 2016
Figure modified from Ribas et al., Clin Cancer Res. 2012.
Combination?
Pe
rce
nt a
live
Years
1 2 30
Immunotherapy
Pe
rce
nt a
live
Years
1 2 30
Targeted therapy
Pe
rce
nt a
live
Years
1 2 30
Raising the bar ……
Chemotherapy
Immunotherapy
Radiotherapy
Targeted therapy
Combinationapproaches
Raising the bar ……
Ascierto ESMO 2016
Chemotherapy
Immunotherapy
Radiotherapy
Targeted therapy
Combinationapproaches
Raising the bar ……
Immunotherapy+
Ascierto ESMO 2016
Components of eliciting a clinically relevant immune response
Abrogate immuno-suppressive networks
T-regs B-regs
IDO
MDSC
adenosine
arginine
TGF-β exosomes
M2 MO
IL-10
PGE2VEGF
Turn on NK cell
a-KIR
sMICAFc/CD16
IL-2
CD137
IL-15
NKG2D
sMICB
Turn on T-cellactivate inhibit
CD137
CD40
OX40
GITR CD27 BTLA
PD-1
CTLA4
TIM-3
LAG-3
Prime system• chemotherapy• radiation therapy• vaccine• intratumoral
– oncolytic virus– cytokines– TLR agonists
T & NK cell
trafficking
and
infiltration
into the
tumor
SMR 2014 BMS scientific symposium
Targeting CTLA-4 and PD-1 pathways
Wolchock J, et al. JCO 2013 Volume 31, Issue 15_suppl ; abstr 9012^
T cell Tumour cell
MHCTCR
PD-L1PD-1T cellDendritic
cell
MHCTCR
CD28
B7 CTLA-4- - -
Activation(cytokines, lysis, proliferation,
migration to tumour)
B7+++
+++
CTLA-4 pathway PD-1 pathway
Anti-CTLA-4
Anti-PD-1/PD-L1
Periphery Tumour microenvironment
+++
PD-L2PD-1
Anti-PD-1
- - -
- - -
CA209-067 study: ORR and PFS
Larkin et al. NEJM 2015Wholchok et al ASCO 2016
CA209-069 study: PFS and OS
Postow et al AACR 2016Hodi et al. Lancet Oncol. 2016 Sep 9
KEYNOTE-029: Study Design
Dose Run-In
(Part 1A)
Tolerable
based on
DLT rate?
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
Primary end point:
Safety
Secondary end points:
ORR, DOR, PFS, OS
Stop
development
No
Dose Expansion
(Part 1B)
Patients
• Advanced MEL
• ≥0 prior therapies
• No prior anti–CTLA-4,
PD-1, or PD-L1
• ECOG PS 0 or 1
Yes
Combination tolerable based on DLT rate and AE profile1,2
ClinicalTrials.gov, NCT02089685.
Long G et al ASCO 2016
Keynote 029: Best Change From Baseline in Tumor Size (RECIST v1.1, investigator review)
-100
-80
-60
-40
-20
0
20
40
60
80
100C
han
ge F
rom
Baseli
ne,
% 81%
Data cutoff date: Mar 17, 2016.
ORR = 57%
Median change:
–54.5%
PD-L1 positive
PD-L1 negative
PD-L1 unknown
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%)
Led to death 0 0
Led to ipilimumab discontinuation
only
16 (10%) 12 (8%)
Led to pembrolizumab
discontinuationb
11 (7%) 6 (4%)
Led to ipilimumab and
pembrolizumab discontinuationc
16 (10%) 11 (7%)
Long et al. ASCO 2016
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
PreviouslyUntreatedUnresectableStage III-IVMelanoma
Randomize(N = 346)
1:1
Stratify by• PD-L1
expression• M stage
Arm A (n = 173)
nivolumab 3 mg/kg IV+ ipilimumab 1 mg/kg IV
Every 3 weeks for 4 doses
Arm B (n = 173)
nivolumab 1 mg/kg IV+ ipilimumab 3 mg/kg IV
Every 3 weeks for 4 doses
Nivolumab Flat Dose 480 mg
Every 4 weeks
Nivolumab Flat Dose 480 mg
Every 4 weeks
*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 beconsidered 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
Double BlindedPart 1
Treat until progression** or unacceptable toxicity
Open-labelPart 2***
6 weeks*
CA209-511: Study Design
Changes in Target Lesions: Nivo/Ipi and Pembro/Epacadostat
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
1 mg/kg nivolumab
+ 3 mg/kg ipilimumab
First occurrence
of new lesion
Weeks since treatment initiation
Cha
ng
e in
ta
rge
t le
sio
ns fro
m b
ase
line
(%
)
–100
–80
–60
–40
–20
0
20
40
60
80
300
100
200
0 10 20 30 40 50 60 70 80 90 100 110
nivolumab + ipilimumab pembrolizumab + epacadostat
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 = 660
1:1
N = 330
N = 330
Pembrolizumab 200mg IV Q3W
T-VEC Intralesional
Pembrolizumab 200mg IV Q3W
T-VEC placebo Intralesional
Primary Endpoints: PFS and OS
R
NCT02263508
• Unresectable stage III or
IV melanoma
• Treatment naive
– Prior BRAFi allowed
• Injectable lesions
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 % and1 y-OS was 86,2%
9/9 (100%) responder patients were alive at a medianfollow 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
CD8 T cellAdhesion molecules
(CAM-1) and death
receptors (FAS)
Peptide pools
Vascular normalisation
T cell initiation
Cytokine release
CD8 T cells
T cell functionMDSC
Tregs
Activation of apoptosis
Blockage of cell cycle
TAA
Upregulates MHCI
Adhesion molecules/
death receptors
APM
CD8 T cells
(homeostatic peripheral
expansion)
MDSC
Tregs
M2 macrophages
TAA cross-
presentation
CD8 T cells
Effector immune infiltrate
Release of tumour
antigens (cascade)
Translocation of
calreticulin
Radiation
Chemotherapy Targeted therapies
Dendritic cell
Upregulation of MHCI
Uploading
of antigen
processing
machinery
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 Immunother2008;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.
Chemotherapy
Immunotherapy
Radiotherapy
Targeted therapy
Combinationapproaches
Raising the bar ……
Radiotherapy modifies the immune system
interaction with cancer
Demaria & Formenti, Front Oncol 2012
Lymphocyte-poor
Lymphocyte-rich
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
• 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
100
80
60
40
20
0
OS
(%
)
0 6 12 18 24 30 36
Months
No abscopal response
Median OS, months
(95% CI): 8.3 (7.6–9.0)
Abscopal response
Median OS, months
(95% CI): 22.4 (2.5–50.3)
Abscopal Effects of Radiotherapy in Melanoma Patients Progressing After Ipilimumab
• 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
Baseline
Post
ipilimumab
Post
radiotherapy
799 patients randomized
Site: bone mets
Dose : 8 Gy, single fraction
Time: RT within 2 days from
IPI, then anytime during IPIStudy powered to detect a 4 month
difference in median overall survival (15.8
versus 12 months)
RT
Chemotherapy
Immunotherapy
Radiotherapy
Targeted therapy
Combinationapproaches
Raising the bar ……
Combining Ipilimumab with Chemotherapy
Summary of Efficacy Results in Melanoma
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
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
Single arm
phase 2 trial of
ipilimumab
10 mg/kg +
fotemustine
Single arm
phase 2 trial of
ipilimumab
10 mg/kg +
temozolomide
Treatment-naïve Treatment-naïve
Patient population Ipi + DTIC Ipi Ipi + DTIC DTICPretreated and
Treatment-naïve Treatment-naïve
Patients, n 35 37 250 252 86 64
Median OS, months 14.3 11.4 11.2 9.1 13.3 Not reached
1-year OS, % 62 45 47.3 36.3 52.6 68
Median PFS,
monthsNot reported
24% reduction in the risk
of progression with ipi +
DTIC
5.3 5.1
Best overall
response rate, %14.3 5.4 15.2 10.3 29.1 30
Median duration of
response, months
Not reported
(durable CRs and
PRs of 20+ months)
19.3 8.1 Not reached 12+
Caution is warranted when comparing across trials
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
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.
NSCLC (Concurrent) NSCLC (Phased)
1.0
0.8
0.6
0.4
0.2
0
0 2 4 6 8 10 12 14 16
Time (months)
irP
FS
(pro
babili
ty) Events/
patientsMedian OS,
months 95% CI HR P value
Control 56/66 4.63 4.14–5.52
PhasedIpilimumab
54/68 5.68 4.76–7.79 0.72 0.05
66 59 55 41 38 28 17 13 11 5 4 3 3 3 1 1 1 0
66 59 55 41 38 28 17 13 11 5 4 3 3 3 1 1 1 0
Control
Ipilimumab
No. at risk
1.0
0.8
0.6
0.4
0.2
0
0 2 4 6 8 10 12 14 16 18 20 22
Time (months)
irP
FS
(pro
babili
ty) Events/
patientsMedian OS,
months 95% CI HR P value
Control 40/45 5.26 4.67–5.72
PhasedIpilimumab
38/42 6.44 5.29–7.75 0.64 0.03
Control
Ipilimumab
No. at risk
45 44 42 38 36 26 11 10 7 5 4 3 2 2 2 2 1 0 0 0 0 0 0
42 42 40 37 35 31 22 18 10 7 7 6 6 6 5 5 5 3 2 1 1 1 0
1.0
0.8
0.6
0.4
0.2
0
Time (months)
irP
FS
(pro
babili
ty)
Events/patients
Median OS,months 95% CI HR P value
Control 40/45 5.26 4.67–5.72
ConcurrantIpilimumab
37/43 5.68 5.19–6.87 0.75 0.11
Control
Ipilimumab
No. at risk
0 2 4 6 8 10 12 14 16 18 20 22
45 44 42 38 36 26 11 10 7 5 4 3 2 2 2 2 1 0 0 0 0 0 0 0
1.0
0.8
0.6
0.4
0.2
0
0 2 4 6 8 10 12 14 16
Time (months)
irP
FS
(pro
babili
ty) Events/
patientsMedian OS,
months 95% CI HR P value
Control 56/66 4.63 4.14–5.52
ConcurrantIpilimumab
55/70 5.52 4.17–6.74 0.81 0.13
66 59 55 41 38 28 17 13 11 5 4 3 3 3 1 1 1 0
70 62 48 44 40 34 29 20 18 9 8 6 2 1 1 0 0 0
Control
Ipilimumab
No. at risk
ED-SCLC (Concurrent) ED-SCLC (Phased)
43 38 36 31 29 26 16 12 11 10 9 9 8 5 4 3 3 2 2 2 2 2 1 0
Chemotherapy
Immunotherapy
Radiotherapy
Targeted therapy
Combinationapproaches
Raising the bar ……
Summary of Published Data of Immunotherapy in Combination with Targeted Agents
Jang, S, Atkins M. Lancet Oncol 2013;14:e60–9
Ribas A, et al. N Engl J Med 2013;368:1365–6
• The combination of ipilimumab with targeted agents could in theoryresult in synergistic effects
Effect of BRAF inhibitors on the immune system
CD4+ and CD8+ increase in
responder lesion and
decrease in lesions which
progressed
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
BRAF inhibition is
associated with increased
melanoma antigen
expression in tumours of
patients with metastatic
melanoma
↑ MHC and melanoma
antigen expression3
Antitumour activity of
combined BRAFi+MEKi
plus anti-PD-13
BRAF inhibition is associated with
increased CD8+ T-cell infiltrate in
tumours of patients with metastatic
melanoma
• The combination of ipilimumab with targeted agents could in theoryresult in synergistic effects
• Concurrent administration of vemurafenib and ipilimumab may notbe feasible
– Increased incidence of hepatotoxicity observed in a phase 1 safety study
– Toxicity may preclude adequate dosing
Summary of Published Data of Immunotherapy in Combination with Targeted Agents
Jang, S, Atkins M. Lancet Oncol 2013;14:e60–9
Ribas A, et al. N Engl J Med 2013;368:1365–6
• The combination of ipilimumab with targeted agents could in theoryresult in synergistic effects
• Concurrent administration of vemurafenib and ipilimumab may notbe feasible
– Increased incidence of hepatotoxicity observed in a phase 1 safety study
– Toxicity may preclude adequate dosing
Summary of Published Data of Immunotherapy in Combination with Targeted Agents
Jang, S, Atkins M. Lancet Oncol 2013;14:e60–9
Ribas A, et al. N Engl J Med 2013;368:1365–6
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
• The combination of ipilimumab with targeted agents could in theoryresult in synergistic effects
• Concurrent administration of vemurafenib and ipilimumab may notbe 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 + ipilimumabwith or without trametinib are not associated with hepatotoxicity
Summary of Published Data of Immunotherapy in Combination with Targeted Agents
• The combination of ipilimumab with targeted agents could in theoryresult in synergistic effects
• Concurrent administration of vemurafenib and ipilimumab may notbe 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 + ipilimumabwith or without trametinib are not associated with hepatotoxicity
• The triplo combo ipilimumab/dabrafenib/trametinib is not feasibledue 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
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
• The combination of ipilimumab with targeted agents could in theoryresult in synergistic effects
• Concurrent administration of vemurafenib and ipilimumab may notbe 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 + ipilimumabwith or without trametinib are not associated with hepatotoxicity
• The triplet combo ipilimumab/dabrafenib/trametinib is not feasibledue to the increase of gastro-intestinal toxicity (bowel perforation)
• Sequential treatment with ipilimumab and targeted therapies maybe a more appropriate therapeutic approach
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
Summary of Published Data of Immunotherapy in Combination with Targeted Agents
Sullivan R et al SMR 2015
• What about the combo anti-PD-1/PD-L1 with Target Therapy ?
• We know that anti-PD-L1can be combined with BRAFi
Summary of Published Data of Immunotherapy in Combination with Targeted Agents
Sullivan R et al SMR 2015
• 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 !
Summary of Published Data of Immunotherapy in Combination with Targeted Agents
Ribas et al. ASCO 2015
• 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 !
Summary of Published Data of Immunotherapy in Combination with Targeted Agents
Hwu P et al. ESMO 2016
• Primary endpoint: PFS
• Interim Analysis for early efficacy signal
KEYNOTE-022 Phase 2 Trial Design
Advanced melanoma
• BRAFi/MEKi , anti-
PD-1/L1, IPI naïve
• N=120 Placebo +
Dabrafenib + Trametinib
Pembrolizumab +
Dabrafenib + Trametinib
1:1
Clinicaltrials.gov NCT02130466
50
100
1 2
PFS curves may predict long-term benefit …
% P
rogr
essi
on
-Fre
e
Years
Anti-PD-1
Combo target
Ascierto & Long. Lancer Oncol. 2016
50
100
1 2
PFS curves may predict long-term benefit …
% P
rogr
essi
on
-Fre
e
Years
Anti-PD-1
Combo Target
Ascierto & Long. Lancer Oncol. 2016
Via Mariano Semmola, 80131, Napoli, Italy
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Email: [email protected]