immunotherapies combination strategies

IMMUNOTHERAPIES
COMBINATION STRATEGIES
Martin Reck
Department of Thoracic Oncology
LungClinic Grosshansdorf
Germany
DISCLOSURES
Member of the advisory board: Roche, Lilly, DaichiSankyo, BMS, AstraZeneca, Pfizer, BoehringerIngelheim
Honoraria for lectures: Roche ,Lilly, Daichi-Sankyo,
AstraZeneca, BMS, Boehringer-Ingelheim
SOME GOOD REASONS FOR COMBINATIONS...
FROM THE RECREATION AREA –
PLANTS VERSUS ZOMBIES
Goal: You have to keep your plants alive!
Lung Cancer
Immunotherapy
Chemotherapy
Immuno- and Chemotherapy
Combination makes sense!
Courtesy of David F. Heigener
3
THE IDEA
This is the goal!
Survival
Survival
Here we are
?
Time
Time
Control
Targeted therapies
Immune checkpoint blockade
Combinations/sequencing
Hypothetical slide illustrating a scientific concept, and is beyond data available to date
These charts are not intended to predict what may actually be observed in clinical studies
Adapted from Ribas A, presented at WCM, 2013; Ribas A, et al. Clin Cancer Res 2012;18:336–341;
Drake CG. Ann Oncol 2012;23(suppl 8):viii41–viii46
A COUPLE OF MISPERCEPTIONS:
NO INTERACTION BETWEEN IMMUNE SYSTEM AND CHEMOTHERAPY
Galluzi L, Nature Reviews 2012; 11: 215233
5
A COUPLE OF MISPERCEPTIONS:
NO INTERACTION BETWEEN IMMUNE SYSTEM AND TARGETED THERAPIES
Galluzi L, Nature Reviews 2012; 11: 215233
6
INTERESTING CONCEPTS
WHAT DO WE KNOW?
•
•
•
•
Combination with chemotherapy
Combination with targeted agents
Combination with radiotherapy
Combination of immunotherapies
7
INTERESTING CONCEPTS
WHAT DO WE KNOW?
• Combination with chemotherapy
• Combination anti-CTL4 antibodies and chemotherapy
• Combination with targeted agents
• Combination with radiotherapy
• Combination of immunotherapies
8
BREAST AND COLORECTAL CANCER
IPILIMUMAB
Jure-Kunkel M, Cancer Immunol Immunother 2013; 62: 1533-43
LUNG AND COLORECTAL
IPILIMUMAB
Jure-Kunkel M, Cancer Immunol Immunother 2013; 62: 1533-43
ANTI-CTLA-4 PLUS CHEMOTHERAPY AS FIRST-LINE TREATMENT:
PHASE 2 STUDY OF IPILIMUMAB AND PACLITAXEL/CARBOPLATIN IN NSCLC AND
ED SCLC
First-line
NSCLC1
Induction phase
Q3W
N=270
C
Concurrent
IPI + Pac/Carbo
R
1:1:1
Phaseda
IPI + Pac/Carbo
IPI
C
IPI
C
IPI
C
Maintenance phase
Q12W
C
C
C
IPI
p
p
C
C
IPI
IPI
C
IPI
IPI
p
p
C
C
p
p
C
C
C
C
C
C
p
p
p
p
p
p
IPI
IPI
IPI
aPhased
N=130
n=128
Follow-up
phase
IPI
Follow-up
phase
Control
p + Pac/Carbo
First-line ED
SCLC2
Follow-up
phase
n=41
regimen: 2 doses of paclitaxel (175 mg/m 2) /carboplatin (AUC=6) before start of ipilimumab.
AUC=area under the curve; C=chemotherapy (paclitaxel 175 mg/m2/carboplatin [AUC=6]); Carbo=carboplatin; IPI=ipilimumab (10 mg/kg IV);
p=placebo; Pac=paclitaxel; Q12W=every 12 weeks; R=randomized.
1. Lynch TJ et al. J Clin Oncol. 2012;30:2046–2054; 2. Reck M et al. Ann Oncol. 2013;24:75–83.
PHASE 2 STUDY OF IPILIMUMAB AND PACLITAXEL/ CARBOPLATIN
IN NSCLC: SURVIVAL OUTCOMES
PFS by immune-related criteria (irPFS) was significantly improved in the phased (5.7 mo)
but not concurrent (5.5 mo) schedule vs chemotherapy alone (4.6 mo)
1.0
1.0
Median irPFS, mo
(95% CI)
0.6
Phased
5.68 (4.76–7.79)
Control
4.63 (4.14–5.52)
HR = 0.72, P = 0.05
0.4
0.8
irPFS (probability)
irPFS (probability)
0.8
Median irPFS,
mo (95% CI)
0.6
Concurrent
5.52 (4.17–6.74)
Control
4.63 (4.14–5.52)
HR = 0.81, P = 0.13
0.4
0.2
0.2
0.0
0.0
0 1 2 3
4
5 6 7
8 9 10 11 12 13 14 15 16 17
Months
0 1 2 3 4
5 6
7 8 9 10 11 12 13 14 15 16 17
Months
PFS by mWHO criteria were similar to irPFS results
– OS was numerically improved in the phased (12.2 mo) and concurrent (9.7 mo) schedules vs
chemotherapy alone (8.3 mo), but the differences were not significant
HR=hazard ratio; mWHO=modified World Health Organization.
Lynch TJ, et al. J Clin Oncol. 2012;30:2046–2054.
PHASE 2 STUDY OF IPILIMUMAB AND PACLITAXEL/ CARBOPLATIN
IN ED SCLC: SURVIVAL OUTCOMES
PFS by immune-related criteria (irPFS) was significantly improved in the phased
(6.4 mo) but not concurrent (5.7 mo) schedule vs chemotherapy alone (5.3 mo)
Median irPFS,
mo (95% CI)
irPFS (probability)
0.8
Phased
6.44 (5.29–7.75)
Control
5.26 (4.67–5.72)
0.8
HR = 0.64, P = 0.03
0.6
0.4
0.0
0.0
4
6
8
10 12
Months
14
16
18
20
22
5.68 (5.19–6.87)
Control
5.26 (4.67–5.72)
HR = 0.75, P = 0.11
0.4
0.2
2
Concurrent
0.6
0.2
0
Median irPFS,
mo (95% CI)
1.0
irPFS (probability)
1.0
0
2
4
6
8
10
12
14
16
18
20
22
Months
By mWHO criteria, PFS was similar across arms
– A trend for improved OS was observed in the phased regimen (12.9 mo) vs chemotherapy
alone (9.9 mo), but it was not significant; no OS benefit over chemotherapy was observed in
the concurrent schedule (9.1 mo)
Reck M, et al Ann Oncol. 2013;24:75–83.
IPILIMUMAB: CURRENT PHASE III PROTOCOLS
Squamous Cell NSCLC
Stage IV
Primary Endpoint: OS
SCLC
Stage IV
Primary Endpoint: OS
Spigel D et al ASCO 2012, Reck M et al ASCO 2012
INTERESTING CONCEPTS
WHAT DO WE KNOW?
• Combination with chemotherapy
• Combination anti-CTL4 antibodies and chemotherapy
• Combination anti-PD1/anti-PDL1 antibodies and
chemotherapy
• Combination with targeted agents
• Combination with radiotherapy
• Combination of immunotherapies
15
COMBINATION OF ANTI-PDL1 AND CHEMOTHERAPY
Tumour rechallenge
MC38 colorectal model
2000
500
Anti-PDL1
Control
10% PR
ChemoRx
Naive mice
Tumour volume (mm3)
Tumour volume (mm3)
400
1500
1000
500
Anti-PDL1/ChemoRx
40% CR
300
200
Tumours failed to grow
in 4/4 mice
100
% of IFN-γ+ T cells
0
0
0
10
20
30
Day
40
50
60
>90 days
0
10
20
30
40
Day
No additional drug therapy
Irving. 1st Annual Expert Forum on Immuno-oncology, 2013
ANTI-PD-1 PLUS CHEMOTHERAPY AS FIRST-LINE TREATMENT:
NIVOLUMAB PLUS PLATINUM-BASED REGIMENS AS AN EXAMPLE
Change in Baseline Target Lesions (%)
CA209-012: phase 1 study interim results, chemotherapy-naïve,
stage IIIB or IV NSCLC, ECOG PS ≤1, all histologies
100
80
60
Nivolumab 10 mg/kg
+ Gem/Cis
(squamous)
Nivolumab 10 mg/kg
+ Pem/Cis
(non-squamous)
Nivolumab 10 mg/kg
+ Pac/Carbo
(any histology)
Nivolumab 5 mg/kg
+ Pac/Carbo
(any histology)
40
20
0
-20
-40
-60
-80
-100
Patients
Nivolumab 10 mg/kg
Nivolumab 5 mg/kg
Gem/Cis (n = 12)
Pem/Cis (n = 15)
Pac/Carbo (n = 15)
Pac/Carbo (n = 14)
ORR, %
33
47
47
43
18-month OS rate, %
33
60
40
86
Median OS, weeks
51
83
65
NR
Any grade treatment-related AEs in 95% of patients
– Most common: fatigue (71%), nausea (46%), decreased appetite (36%)
Grade 3–4 treatment-related AEs in 41% of patients; grade 4 events included decreased neutrophil count (n=1),
pneumonitis and neutropenia (n=1 each)
Pneumonitis reported in 13% (any grade) and 7% (grade 3-4) of patients
21% discontinued due to drug-related AEs
Cis=cisplatin; Gem=gemcitabine; Pem=pemetrexed.
Antonia S, et al. Oral presentation at CMSTO 2014.
ONGOING COMBINATION TRIALS
Agent
Phase
Design
Study population
Enrollment
NCT
Ipilimumab
III
Ipilimumab +
Paclitaxel/Carboplatin vs.
Placebo +
Paclitaxel/Carboplatin
Squamous NSCLC
920
NCT01285609
Ipilimumab
III
Ipilimumb + Eto/Carbo, Cis vs
Placebo + Eto/Carbo, Cis
SCLC
816 events
NCT01450761
Nivolumab
I
Nivolumab + Gem/Cis,
Pem/Cis, Pac/Carbo, Erlotinib,
Bev, Ipi
NSCLC
412
NCT01454102
Pembrolizumab
I/II
Pembrolizumab + Pac/Carbo,
Pac/Carbo/Bev, Pem/Carbo,
Ipi, Erlotinib, Gefitinib
NSCLC
320
NCT02039674
MPDL3280A
III
MPDL3280A + Pac/Carbo/Bev
vs Placebo + Pac/Carbo/Bev
Non sq. NSCLC
1200
NCT02366143
MPDL3280A
III
MPDL3280A + Nab-Pac/Carbo
vs Placebo + Nab-Pac/Carbo
Squamous NSCLC
1200
NCT02367794
MPDL3280A
III
MPDL3280A + Nab-Pac/Carbo
vs Placebo + Nab-Pac/Carbo
Non sq. NSCLC
500
NCT02367781
INTERESTING CONCEPTS
WHAT DO WE KNOW?
•
•
•
•
Combination with chemotherapy
Combination with targeted agents
Combination with radiotherapy
Combination of immunotherapies
20
EXAMPLE EGFR-TKIS
CONFLICTING PRECLINICAL DATA
In Tumors with EGFR oncogenic signalling upregulation of PD-1,
PD-L1 and CTLA-41
Effect of TKI?
Immunosuppressive effects:
– Inhibition of T-Cell proliferation
– Release of Th1 cytokine
– Prevention of dermal hypersensitivity response2
Immunoactivating effects:
– Activation of Lymphocate Migration and Accumulation in the skin3
– Indirect T-cell activation by increase of soluble IL-1 receptor4
Akbay EA, Cancer Discovery 2013; Luo Q Toxicol Appl Parmacol 2011; Yamamoto N, Mol Pharmacol 2011;
21
Kanazawa S, J Cancer Res Clin Oncoll 2006
CLINICAL DATA?
PD-1 INHIBITION + EGFR-TKI IN EGFR MUTANT PATIENTS?
• 21 Patients (20 patients refractory after previous
EGFR TKI)
• 7 Patients T790M mutation
• RR 19%
• PFS-Rate 24w: 50%, med PFS: 29.4 w
• 18 months OS-rate: 64%
• Grade 3 AEs: 24% (10% Diarrhea, 10% AST, 8% ALT)
• Discontinuation due to AE: 19%
• Option for patients without T790M mutation?
Gettinger S, CMSTO 2014
Combination VEGF Inhitibition and anti PDL-1
an interesting concept
• Enhanced effector memory CD8+ T cells
observed in patients treated with ipilimumab
+ bevacizumab combination2
Anti-VEGF combination
Cloudman melanoma1
2000
Pre-treatment
AntiPDL1
Control
1500
Anti-VEGF
CCR7
1000
Anti-PDL1 +
anti-VEGF
500
0
0
10
20
30
40
36.5
%
20.6%
50
36.5%
CCR7
Post-treatment
Tumour volume (mm3)
Ipilimumab +
bevacizumab
Ipilimumab
79.8
%
26.5%
79.8%
Day
CD45RO
1. Irving. 1st Annual Expert Forum on Immuno-oncology, 2013
2. Hodi et al. J Clin Oncol 2011;29(15S):abstr 8511
INTERESTING CONCEPTS
WHAT DO WE KNOW?
•
•
•
•
Combination with chemotherapy
Combination with targeted agents
Combination with radiotherapy
Combination of immunotherapies
24
COMBINATION OF RADIOTHERAPY AND IMMUNOTHERAPY
A COUPLE ARGUMENTS
• Tumor regression and long term survival by
combination of fractionated RTx and anti-CTL4 in breast
cancer model (Dewan MZ, Clin Cancer Res 2009)
• Increase of PDL-1 Expression bei Radiotherapy (Deng L,
J Clin Invest 2014)
• Increase of Inflammatory Cell Death and Antigen
Release by RTx – RTx as priming intrinsing vaccine?
(Tang C, Cancer Immunol Res 2014)
• Supporting early Phase I results in Melanoma, RCC and
B-Cell Lymphoma
25
THE INTERESTING ABSCOPAL EFFECT..
•
64 year old Caucasian patient
•
Stage IV adenocarcinoma
•
PD after Carbo/Pem, Pem Maint., Gem/Vino
•
Ipilimumab (EAP) and RTX of liver mets
August 2012
January 2013
Golden EB, Cancer Immunol Res 2013
26
THE INTERESTING ABSCOPAL EFFECT...
August 2012
January 2013
August 2012
Golden EB, Cancer Immunol Res 2013
January 2013
27
EFFICACY DEPENDANT ON TUMOR TYPE?
•
Prostate Cancer:
• Ipilimumab vs Placebo after RTx in patients with refractory
prostate cancer and bone metastasis
• No difference in OS but potential benefit in subgroups
•
Melanoma
• RTx after PD following Ipilimumab
• 62% response, 38% stable disease
• Potential predictive quality of abscopal effect (OS +/abscopal effect: 22.4 m vs 8.3 m)
• Exploratory uncontrolled analysis
•
Lung
• Trials ongoing...
Kwon ED, Lancet Oncology 2014; Grimaldi AM Oncoimmunology 2014
28
INTERESTING CONCEPTS
WHAT DO WE KNOW?
•
•
•
•
Combination with chemotherapy
Combination with targeted agents
Combination with radiotherapy
Combination of immunotherapies
29
BACKGROUND
• Improved efficacy for combination
of ipilimumab and nivolumab
patients with advanced melanoma
• Response rate: 40%
• Cinical activity: 65%
• Optimal dose:
• Concurrent treatment
• Ipilimumab: 3 mg/kg (4
doses)
• Nivolumab: 1 mg/kg (8 doses)
• Subsequent treatment cykles
• Grade 3,4 AEs: 53%
Wolchok JD, NEJM 2013; 369: 122-33
PRINCIPLES OF COMBINATIONS
(FOUR WAYS TO SAVE THE WORLD...)
• Dual T-cell checkpoint inhibition
(anti-PD1/anti-PDL-1 + anti-CTLA4; anti LAG-3 + anti-PD1)
• T-cell checkpoint inhibition + T-cell activation
(anti-CTLA4 + CD 40; other agonistic antibodies in development)
• T-cell checkpoint inhibition + stimulation innate immune response
(anti-CTL4 and anti-PD1/anti-PDL-1 + anti-KIR antibody (activation NK))
• Others
Combination + Cytokines, + IDO inhibitors,+ vaccines...
• Numerous trials in development and on the way in different
tumor diseases…
Modified from Antonia SJ, Clin Cancer Res 2014
31
WE HAVE TO BE CAREFUL BY INTERACTING WITH
THE IMMUNE SYSTEM – THE TGN1412 STORY
6/6 volunteers got critical ill by systemic inflammatory reaction
within hours after infusion of anti-CD28 antibody TGN1412, which
directly stimulates T-cells.
Suntharalingam G et al, NEJM 2006
32
WHAT DATA DO WE HAVE?
NIVOLUMAB + IPILIMUMAB
Change in Baseline Target Lesions (%)
CA209-012: phase 1 study interim results, chemotherapy-naïve,
non-squamous/squamous stage IIIB/IV NSCLC
200
180
160
140
120
100
80
60
40
20
0
-20
-40
-60
-80
-100
Nivolumab 1 mg/kg + ipilimumab 3 mg/kg
Nivolumab 3 mg/kg + ipilimumab 1 mg/kg
Patients
Nivolumab 1 mg/kg + ipilimumab 3 mg/kg
(n=24)
Nivolumab 3 mg/kg + ipilimumab 1 mg/kg
(n=25)
3 (13) [3, 32]
5 (20) [7, 41]
PFS rate at 24 weeks, % (95% CI)
44 (22, 64)
33 (16, 52)
1-year OS rate, % (95% CI)
65 (42, 81)
44 (24, 62)
Confirmed ORR, n (%) [95% CI]
Any grade treatment-related AEs in 88% of patients
– Most common: fatigue (49%), diarrhea (35%), rash (25%)
Grade 3–4 treatment related AEs in 51% of patients
Pneumonitis reported in 12% (any grade) and 6% (grade 3–4) of patients
37% discontinued due to drug-related AEs, including n=4 with pneumonitis, and n=3 each with colitis, diarrhea,
or ALT/AST increased
Antonia S, et al. Poster presented at CMSTO 2014.
WHAT DATA DO WE HAVE?
TREMELIMUMAB + MEDI4736
•
•
•
•
•
No dose-limitating toxicity
Most frequent AEs: Fatigue, Increase Amylase, Nausea, Increase ALT, Diarrhea
33% =/> Grade 3 AEs: Colitis, Increase AST, Increase Amylase, Diarrhea,
Pneumonitis, Mysthenia gravis and other
Treatment discontinuation due to drug related AEs in three patients (17%): Colitis,
pneumonitis, ALT elevation
1 fatal complication by complications of myasthenia gravis
Antonia S, et al. Poster presented at ESMO 2014 [1327P]
34
CONCLUSIONS
• Fascinating and cool concept
• A couple of good arguments to combine
immuntherapies with other treatments
• Clinical development has somewhat overtaken the
science behind – proper translational research will
be crucial
• We are interfering with the most powerful system
of our organism – never forget safety, a couple of
things may happen
• Having said that....
15.04.2015
35
SET OFF THE AVALANCHE OF IMMUNOTHERAPIES...

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