#9553 Dynamics of tumor response in advanced melanoma patients

#9553
Dynamics of tumor response in advanced melanoma patients treated with Coxsackievirus A21
Robert Hans Ingemar Andtbacka, Brendan D. Curti, Howard Kaufman, John J. Nemunaitis, Gregory A. Daniels, Sigrun Hallmeyer, Eric D. Whitman, Jose Lutzky, Stephen Michael Schultz, Lynn E. Spitler, Zipei Feng, Christopher Paustian, Bernard A. Fox, Carlo Bifulco, Karl Zhou, Mark Grose, Roberta Karpathy, Darren Shafren
Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; Earle A. Chiles Research Institute, Providence Cancer Center, Portland, OR; Rush University Medical Center, Chicago, IL; Mary Crowley Cancer Research Centers, Dallas, TX; University of California, San Diego, Moores Cancer Center, La Jolla, CA; Oncology Specialists SC, Park Ridge, IL; Atlantic Melanoma Ctr, Morristown,
NJ; Mount Sinai Medical Center, New York, NY; American Health Network Indiana, Indianapolis, IN; St. Mary's Medical Center, Tiburon, CA; Oregon Health Sci Univ, Portland, OR; Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR; inVentiv Health Clinical, Bridgewater, NJ; Viralytics Ltd., Sydney, Australia.
CALM Study: Extension Cohort
C
D
27
C
D
28
C
D
C 40
D
40
C L
D
12
4- 2
1B
O B
X
O -40
X40
L
G
IT
R
IC
O
S
TL A
A
-4
ID
O
LA
G
3
PD
PD 1
-L
PD 1
-L
TI 2
M
-3
C
B
TL
H
3
R
7-
B
IF
2A
A
Change in RNA expression, relative units
at Day 8 compared to Day 0
1
IH
1
C
C
D
27
C
D
28
C
D
C 40
D
40
C L
D
12
4- 2
1B
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X40
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G
IT
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IC
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TL A
A
-4
ID
O
LA
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3
PD
PD 1
-L
PD 1
-L
TI 2
M
-3
TL
3
H
B
7-
R
B
2A
A
1
IT
300
p=0.037
200
100
8
D
ay
D
ay
D
C
R
PR
O
G
D
C
R
D
ay
0
ay
D
G
O
PR
0
0
8
CD40L p=0.0202
150
p= NS
100
p= NS
50
8
D
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ay
0
D
ay
8
ay
D
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PR
PR
O
G
D
D
ay
ay
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0
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RNA expression relative units
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ay
8
PR
O
G
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ay
0
ay
D
G
O
0
0
PR
p= NS
8
p= NS
RNA expression relative units
D
C
R
G
O
PR
D
C
R
p=0.0024
p= NS
200
400
D
ay
0
D
ay
8
D
ay
G
D
ay
0
RNA expression relative units
O
400
8
D
C
R
D
C
R
600
D
ay
0
D
ay
8
PR
O
G
D
ay
D
ay
0
0
G
0
PR
p= NS
O
100
CD122
RNA expression relative units
p= NS
200
PR
p= NS
200
PD-L1
p= NS
p= NS
300
8
D
C
R
G
PR
O
G
O
PR
400
p=0.026
400
D
ay
0
0
D
ay
D
ay
p=0.004
600
8
D
ay
D
C
R
D
C
R
D
ay
8
PR
O
G
D
ay
D
ay
0
0
0
RNA expression relative units
50
G
0
8
D
C
R
p= NS
100
O
p= NS
200
D
ay
0
D
C
R
D
ay
8
ay
D
PR
O
G
D
G
O
PR
p= NS
150
PR
ay
PR
O
G
D
ay
G
O
PR
p=0.0084
250
200
400
IDO
TIM-3
8
0
RNA expression relative units
p= NS
200
ay
0
0
p= NS
D
C
R
p= NS
500
600
8
1000
p=0.021
ay
p= NS
800
D
1500
8
D
ay
D
C
R
p= NS
400
p=0.034
RNA expression relative units
CXCL11
CTLA-4
IHIF1
-20
-40
-60
-80
•  A comparable ORR was observed in patients administered prior immunotherapy, 29.0% (9/31) vs other tx 27.0% (7/26).
•  BTB of the 57 pts in the CALM study was 3.9 cm (95% CI 4.3, 6.5).
4500
•  A BTB ≤ median was associated with: superior ORR (39.3 vs 17.2 %), superior DRR (35.7 vs 6.9 %), and greater OS (Log Rank : p = 0.003).
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•  CVA21 treatment facilitated notable changes within the tumor microenvironment by inducing increases in immune cell infiltrates (CD3+CD8+) and
expression of PD-L1, in particular within lesions displaying stable disease or response.
1500
-100
ASCO 2016, June 3-7, Chicago USA: Corresponding author, Robert Andtbacka: [email protected]
8
ay
0
•  CVA21 treatment significantly up-regulated a number of interferon-response and immune checkpoint inhibitory genes in injected melanoma
lesions, including CXCL10, CXCL11, CTLA-4, PD-L1, LAG-3, TIM-3 and IDO.
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0
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+#
:D
ay
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R
Study Days
:D
337
ay
253
PR
*, Investigator assessed
#,3 CR responses unconfirmed at time of data cut-off
+Durable response is a response lasting continuously for ≥ 6 months as assessed by irRECIST criteria
169
C
127
D
85
:D
43
0
0
0
0
G
75.4% (43/57 pts) Patients (n=6)
PD-L1+
6000
ay
*
B
O
26.7 months (95% CI: 17.4, 34.5) 0
:D
1-year survival rate:
5.7 months (95% CI: 2.8, 11.1) CD27
CD28
CD40
CD40L
CD122
4-1BB
OX-40
OX-40L
GITR
ICOS
•  Three patients exhibited progression (> 25% by irRECIST criteria) prior to response.
CD3+CD8+
PR
Median Overall survival *
G
Median irPFS 3.4 months (95% CI: 1.5, 4.2) 20
O
Median Time to response onset 400
350
300
250
200
150
100
50
0
-50
-100
•  Responses were observed in injected lesions, non-injected non-visceral lesions and in distant non-injected visceral lesions
PR
21.1% 40
cells/mm2
28.1% (16/57 pts) [8CR + 8PR] # % Change in sum of Target lesions
relative to baseline
Overall response rate (ORR)*
(CR+PR, irRECIST 1.1): Durable response rate (DRR)+ • Female: Stage IIIC
with melanoma to back
• Prior treatment with ipilimumab
and talimogene laherparepvec
*
Secondary endpoints A2AR
B7-H3
BTLA
CTLA-4
IDO
LAG3
PD-1
PD-L1
PD-L2
TIM-3
Conclusions
60
38.6% (22/57 pts)
400
350
300
250
200
150
100
50
0
-50
-100
*, n=3; + n=6
Primary endpoint
irPFS 6 months (CR+PR+SD)
0
D
C
R
600
D
Changes in tumor burden of responding patients
Patient response data
CD27
CD28
CD40
CD40L
CD122
4-1BB
OX-40
OX-40L
GITR
ICOS
Patients (n=3)
Patients (n=6)
2000
D
ay
Pt 03-­‐044 800
p=0.024
D
C
R
LAG-3
0
Study Months
• Female: Stage IIIC
with melanoma to legs
• Prior treatment with ipilimumab
and pembrolizumab
+
D
ay
0
16%
21%
G
*
D
C
R
10
O
BTB ≤ Median vs BTB > Median
Log Rank: p=0.0034***
20
D
ay
8
D
ay
30
RNA expression relative units
0
8
9
12
500
0
IV M1b
IV M1c
40
p= NS
0
39%
25%
Pt 04-­‐015 1000
PR
22
14
50
p= NS
ay
IIIC
IV M1a
Disease Control
1500
D
98%
2%
0
2000
G
56
1
500
p=0.056
O
Caucasian
Asian
1000
2500
PR
63%
37%
RNA expression relative units
36
21
60
RNA expression relative units
Male
Female
1500
CXCL10
40
75%
25%
2000
400
350
300
250
200
150
100
50
0
-50
-100
A2AR
B7-H3
BTLA
CTLA-4
IDO
LAG3
PD-1
PD-L1
PD-L2
TIM-3
35
43
14
30
0
1
CXCL10
CXCL11
IFIH1
IFIT1
Patients (n=6)
70
25
57
(28-94)
20
Stage at screening
80
15
Race
90
10
Sex
Day 8 (post-­‐treatment) • Male: Stage IIIC
with melanoma to the neck
• Prior treatment with ipilimumab
Patients with BTB ≤
Median
Patients with BTB >
Median
5
ECOG status
Day 0 (pre-­‐treatment) Change in RNA expression, relative units
at Day 8 compared to Day 0
All Patients
0
Mean (yrs)
(range)
Percent (%)
Percentage survival
Age
A
Disease
Control
Pt 03-­‐042 100
Number
(n=57)
Progression
400
350
300
250
200
150
100
50
0
-50
-100
Immune checkpoint stimulatory
molecules
Patients (n=3)
IF
Levels of lesion T-cell infiltrates following Coxsackievirus A21 injection:
Multispectral Images (A) Obtained and Enumerated (B) with PerkinElmer Vectra
imaging system and InForm Software
Kaplan-Meier curve of Interim overall survival
Patient Characteristics
Change in RNA expression, relative units
at Day 8 compared to Day 0
Patient Identification
*Tx include radiotherapy, chemotherapy, surgery and kinase inhibitors.
IT
35.7% vs 6.9 % Immune checkpoint inhibitory
molecules
Patients (n=3)
1
DRR with BTB < median 3.9 cm (95% CI 4.3, 6.5) IF
39.3% vs 17.2 % 0
IH
ORR with BTB ≤ median 500
IF
40.0% (2/5) 1000
C
XC
L1
1
ORR: Pts with prior talimogene
laherparepvec (T-VEC)
Baseline tumor burden (BTB) 26.7% (4/15) 1500
C
XC
L1
1
29.0% (9/31) vs 27.0% (7/26) Progression
CXCL10
CXCL11
IFIT1
IFIH1
2000
C
XC
L1
0
ORR: Pts with prior immunotherapy vs
other Tx* ORR: Pts with prior ipilimumab Disease control
(CR + PR+ SD)
C
XC
L1
0
100
80
60
40
20
0
-20
-40
-60
-80
-100
03
-0
45
12
-0
10
03
-0
42
04
-0
14
03
-0
43
03
-0
44
04
-0
15
03
-0
48
03
-0
46
Exploratory endpoints
Interferon-induced genes CXCL10, CXCL11
and viral RNA response genes IFIH1, IFIT1
Progression
Percentage change from baseline
to final tumor measurement
Phase 2 CALM Study
Coxsackievirus A21 injection up-regulates interferon-induced genes and immune checkpoint molecules within the micro-environment
of melanoma lesions (NanoString analysis Pan Cancer Immune Profiling Panel)
Change in RNA expression, relative units
at Day 8 compared to Day 0
Coxsackievirus A21 injected individual lesion data
(investigator assessed)
Change in RNA expression, relative units
at Day 8 compared to Day 0
CAVATAK, an oncolytic immunotherapy, is a bio-selected oncolytic strain of Coxsackievirus A21 (CVA21). Intratumoral (IT) injection of CVA21 induces lytic tumor cell infection,
up-regulation of immune checkpoint molecules and increased immune-cell infiltration. The Phase II CALM study investigated the efficacy and safety of IT CVA21 in 57 pts with
advanced melanoma resulting in a confirmed ORR of 28.1% and DRR (continuously > 6 mths) of 21.1%. The CALM extension study (13 pts) investigated CVA21 induced
changes in immune cell infiltrates within the tumor-microenvironment (TME). We describe factors regarding the nature of clinical responses in 70 pts with stage IIIC-IV
melanoma given IT CVA21.
Change in RNA expression, relative units
at Day 8 compared to Day 0
Introduction
*, n=3; + n=5
#, Data from Pt 03-048 were excluded for analysis in this
section due to cell counts exceeding upper limits of detection.
•  CVA21 treatment can potentially increase the “immunological heat” within the tumor micro-environment
•  Up-regulation of immune cell infiltrates and/or immune checkpoint inhibitory molecules in CVA21-treated lesions may be predictive of future tumor
response, particularly in combination with immune checkpoint blockade strategies.
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