While checkpoint inhibitor therapy (CPI) has improved metastatic melanoma (MM) treatment, many patients remain refractory and fail to achieve durable responses. We reasoned that combining CPI with an agent that activates antigen-presenting cells and improves T-cell priming may result in improved clinical responses. Our approach is to modulate the tumor microenvironment through intratumoral (i.t.) injection of a TRL9 agonist, IMO-2125, in combination with either ipilimumab (ipi) or pembrolizumab (pembro). In preclinical studies, i.t. administered IMO-2125 stimulated plasmacytoid dendritic cells to induce high amounts of interferon alpha and helper T cell-1 cytokines, leading to increased immune cell infiltration in the tumor microenvironment. In addition, the combination of i.t. IMO-2125 with either an anti-CTLA-4 or anti-PD-1 antibody resulted in improved systemic tumor control compared with either agent alone. Based on these data, we hypothesized that i.t. IMO-2125 will synergize with ipi or pembro to overcome tumor immune escape and improve systemic anti-melanoma activity. We initiated a Phase 1/2 clinical trial in patients with anti-PD-1 refractory MM accordingly. Here, we describe updated preliminary results for the IMO-2125 and ipi combination from the Phase 1 portion of the trial. 1 M Uemura, 1 CL Haymaker, 1 R Murthy, 1 M James, 2 J Geib, 2 S Swann, 2 K Lipford, 1 C Yee, 1 J Wargo, 1 R Amaria, 1 S Patel, 1 H Tawbi, 1 I Glitza, 1 S Woodman, 1 W Hwu, 1 MA Davies, 1 P Hwu, 1 W Overwijk, 1 C Bernatchez, and 1 A Diab 1 The University of Texas MD Anderson Cancer Center, Houston, TX; 2 Idera Pharmaceuticals, Inc., Cambridge, MA and Exton, PA Intratumoral IMO-2125, a TLR9 Agonist, is Active in Combination with Ipilimumab in PD-(L)1 Refractory Melanoma • The combination of IMO-2125 and ipilimumab is tolerable at all dose combinations studied and has clinical activity in PD-1 refractory melanoma • There is evidence for immune activation in both the injected and distant tumor biopsies that correlates with clinical outcome • Further investigation of the IMO-2125 + ipilimumab combination in PD-(L)1 refractory melanoma is warranted; the planned Phase 2 expansion will begin soon • Dose escalation of IMO-2125 + pembrolizumab is also ongoing • Study population: Adults with unresectable or metastatic melanoma that progressed during or after ≥ 12 wks PD-1-directed therapy (alone or in combination); no prior immune-related dose-limiting toxicities; accessible tumor for biopsy and injection (2 lesions) • Endpoints: • Primary: Investigator-assessed overall response using immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) • Secondary: Overall response by RECIST, duration of response (DoR), durable response rate (DRR), progression-free survival (PFS), overall survival (OS), and pharmacokinetics • Exploratory: Immunophenotyping with flow cytometry, assessment of TCR Vβ CDR3 clonal diversity using ImmunoSeq™ and NanoString gene expression analyses N (%) Age, median (range) 58 (39,78) Male 8 (62) Race Caucasian Asian 12 (92) 1 (8) Stage IIIC IV 1 (8) 12 (92) Histology Cutaneous Mucosal 11 (85) 2 (15) Brain metastases 1 (8) Visceral metastases 10 (77) Elevated LDH 3 (23) BRAF mutation 9 (69) * IMO-2125 + ipilimumab safety population (N=13). Data cut-off 5 Jan 2017 AE preferred term All grade, N (%) Grade 3, N (%) Grade 4, N (%) Any 13 (100) 6 (46) 1 (8) Anemia 6 (46) 1 (8) - Pyrexia 6 (46) 1 (8) - Nausea 6 (46) 1 (8) - Vomiting 6 (46) 1 (8) - Decreased WBC 4 (31) - - Increased ALT 4 (31) 1 (8) - Increased TG 4 (31) - - Diarrhea 4 (31) 2 (15) - Fatigue 3 (23) - - Headache 3 (23) - - Increased AST 3 (23) - 1 (8) Chills 3 (23) - - Urinary Tract Infection 3 (23) 1 (8) - *TEAE in >20% of IMO-2125 + ipilimumab safety population (N=13). Data cut-off 5 Jan 2017 IMO-2125 dose 4 mg (N=3) 8 mg (N=4) 16 mg (N=3) 32 mg (N=3) Total (N=13) ≥ 1 TEAE 1 3 (100%) 4 (100%) 3 (100%) 3 (100%) 13 (100%) Related TEAE 1 2 (67) 4 (100) 3 (100) 3 (100) 12 (100) ≥ 1 SAE 2 2 (67) 2 (50) 2 (67) 1 (33) 7 (54) Discontinued for AE 3 0 0 0 0 0 Death from AE 3 0 0 0 0 0 DLT 4 0 0 0 0 0 irAE 5 1 (33) 1 (25) 2 (67) 0 4 (31) 1 treatment-emergent adverse event 2 serious adverse event 3 adverse event 4 dose-limiting toxicity 5 immune-related adverse event: hypophysitis (2), adrenal insufficiency (1), autoimmune hepatitis (1) * IMO-2125 + ipilimumab safety population (N=13). Data cut-off 5 Jan 2017 IMO-2125 dose mg (N) # IMO-2125 injections Median (range) # ipilimumab infusions Median (range) # Discontinuations (reasons) 4 (3) 6 (3,6) 3 (1,4) 2 (insurance, death) 8 (4) 6 (5,6) 4 (3,4) 1 (withdrawal) 16 (3) 5 (3,6) 2 (1,4) 1 (withdrawal) 32 (3) 5 (4,5) 3 (2,3) 0 Ipilimumab dose = 3 mg/kg Q3wks x 4 * IMO-2125 + ipilimumab safety population (N=13). Data cut-off 5 Jan 2017 N (%) PD-(L)1 inhibitor 12 (92) CTLA-inhibitor 7 (54) BRAF inhibitor 5 (39) MEK inhibitor 4 (31) Interferon 5 (39) IL-2 1 (8) Other systemic therapy 3 (23) Radiation 5 (39) * IMO-2125 + ipilimumab safety population (N=13). Data cut-off 5 Jan 2017 Dose-finding: IMO-2125 + ipilimumab SAFETY ASSESSMENT COMPLETED Dose-finding: IMO-2125 + pembrolizumab ONGOING Phase 2 IMO-2125 + ipilimumab and IMO-2125 + pembrolizumab PLANNED “Backfill” cohort(s): IMO-2125 + ipilimumab ONGOING Dosing: IMO-2125 4, 8, 16, or 32 mg single i.t. injection week 1, 2, 3, 5, 8, 11 Ipilimumab and pembrolizumab are administered per label beginning week 2 *Recommended Phase 2 dose RP2D* = collection of biopsy Pre-dose 24 hours post intratumoral IMO-2125 injection Week 8 5 doses of IMO-2125 and 3 doses of ipilimumab Injected lesion Un-injected lesion Injected lesion Injected lesion Un-injected lesion Fresh flow cytometry Formalin - IHC RNA (TCRseq and NanoString) Tumor biopsy mDC1 vs. mDC2 vs. pDC CD8 T cell: Treg ratio T cell proliferation via Ki67 of both Tregs and CD8+ T cells Immune subsets ratio (T cell vs. B cell vs. NK cells) Injected lesion Un-injected lesion Week 13 Tumor-specific antigens CD8+ T-cells Dendritic cells NK cells TLR9 Intratumoral administration of IMO-2125 Increased TIL infiltration Draining lymph node Primed T-cells migrate to distant tumor sites Metastases are targeted by primed T-cells IFN- α IMO-2125 IFN- and Th1-type immune response T-cells mDCs B-cells Macrophages Neutrophils NK cells pDCs B-cells pDCs Blockade with CPIs 1 2 Tumor microenvironment Distant metastases 3 4 Immune cell infiltration and activation DC maturation Migration and expansion of T-cells 2. Induction of interferon gamma (IFN-γ) Serum IFNγ (pg/ml) 45 30 15 0 60 C2W5 C3W8 C4W11 Patient timepoint C1W1 C1W2 4. Expansion of top T-cell clones in distant (untreated) lesion Frequency of total T cell clones 20% 10% 0 C3W8 predose 3. T-cell activation following 6 doses of IMO-2125 (4mg) + 3 doses of ipilimumab % CD56 + of CD8 + cells 60 40 20 0 80 100 predose C3W8 Injected Tumor Distant Tumor CD56+ of CD8+ cells Ki67+ of CD8+ cells CD45+ cells CD45+ cells % Ki67 + of CD8 + cells % CD45 + live cells CD45 + live cells 60 40 20 0 80 100 predose C3W8 60 40 20 0 80 100 6 4 2 8 10 predose C3W8 60 40 20 0 80 100 predose C3W8 1. Dendritic cell mDC1 maturation in the injected tumor Pre-dose 24 hours post i.t. IMO-2125 injection Comp-FITC-A :: CD1c 10 4 10 3 0 -10 3 10 5 10 4 10 5 Comp-APC-A :: CD303 0 10 3 Comp-FITC-A :: CD1c 10 4 10 3 0 -10 3 10 5 10 4 10 5 Comp-APC-A :: CD303 0 10 3 Comp-FITC-A :: CD1c 10 4 10 3 0 -10 3 10 5 10 4 10 5 Comp-APC-Cy7-A :: HLA-DR 0 10 3 Data cut-off date: 13 Feb 2017 Ipi + IMO-2125 4mg Ipi + IMO-2125 8mg Ipi + IMO-2125 16mg Ipi + IMO-2125 32mg 0 2 Weeks 4 26 28 10 18 20 12 14 16 22 24 6 8 30 38 40 32 34 36 46 48 42 44 50 52 54 56 Treated Subjects Confirmed Response Start Ongoing Unconfirmed Response Start Efficacy Evaluable Subjects -100 -80 -60 0 20 -40 -20 Maximum % decrease in target lesions (sum of longest diameters) Ipi + IMO-2125 4mg Ipi + IMO-2125 8mg Ipi + IMO-2125 16mg Ipi + IMO-2125 32mg Dose Cohort Presented at the ASCO-SITC Clinical Immuno-Oncology Symposium, February 2017 Abstract No. 136 Patient and disease characteristics Prior treatment Exposure Design of the phase 1/2 clinical trial IMO-2125-204 (NCT02644967) Immune response monitoring Safety summary Proof of mechanism in responding patient 003 CONCLUSIONS Most frequent TEAE Patient time on study and RECIST v1.1 responses by dose cohort Maximum decrease in target lesions by RECIST v1.1 BACKGROUND DISCUSSION
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While checkpoint inhibitor therapy (CPI) has improved metastatic melanoma (MM) treatment, many patients remain refractory and fail to achieve durable responses. We reasoned that combining CPI with an agent that activates antigen-presenting cells and improves T-cell priming may result in improved clinical responses.
Our approach is to modulate the tumor microenvironment through intratumoral (i.t.) injection of a TRL9 agonist, IMO-2125, in combination with either ipilimumab (ipi) or pembrolizumab (pembro). In preclinical studies, i.t. administered IMO-2125 stimulated plasmacytoid dendritic cells to induce high amounts of interferon alpha and helper T cell-1 cytokines, leading to increased immune cell infiltration in the tumor microenvironment. In addition, the combination of i.t. IMO-2125 with either an anti-CTLA-4 or anti-PD-1 antibody resulted in improved systemic tumor control compared with either agent alone.
Based on these data, we hypothesized that i.t. IMO-2125 will synergize with ipi or pembro to overcome tumor immune escape and improve systemic anti-melanoma activity. We initiated a Phase 1/2 clinical trial in patients with anti-PD-1 refractory MM accordingly. Here, we describe updated preliminary results for the IMO-2125 and ipi combination from the Phase 1 portion of the trial.
1M Uemura, 1CL Haymaker, 1R Murthy, 1M James, 2J Geib, 2S Swann, 2K Lipford, 1C Yee, 1J Wargo, 1R Amaria, 1S Patel, 1H Tawbi, 1I Glitza, 1S Woodman, 1W Hwu, 1MA Davies, 1P Hwu, 1W Overwijk, 1C Bernatchez, and 1A Diab
1The University of Texas MD Anderson Cancer Center, Houston, TX; 2Idera Pharmaceuticals, Inc., Cambridge, MA and Exton, PA
Intratumoral IMO-2125, a TLR9 Agonist, is Active in Combination with Ipilimumab in PD-(L)1 Refractory Melanoma
• The combination of IMO-2125 and ipilimumab is tolerable at all dose combinations studied and has clinical activity in PD-1 refractory melanoma
• There is evidence for immune activation in both the injected and distant tumor biopsies that correlates with clinical outcome
• Further investigation of the IMO-2125 + ipilimumab combination in PD-(L)1 refractory melanoma is warranted; the planned Phase 2 expansion will begin soon
• Dose escalation of IMO-2125 + pembrolizumab is also ongoing
• Study population: Adults with unresectable or metastatic melanoma that progressed during or after ≥12 wks PD-1-directed therapy (alone or in combination); no prior immune-related dose-limiting toxicities; accessible tumor for biopsy and injection (2 lesions)
• Endpoints:
• Primary: Investigator-assessed overall response using immune-related Response Evaluation Criteria in Solid Tumors (irRECIST)
• Secondary: Overall response by RECIST, duration of response (DoR), durable response rate (DRR), progression-free survival (PFS), overall survival (OS), and pharmacokinetics
• Exploratory: Immunophenotyping with flow cytometry, assessment of TCR Vβ CDR3 clonal diversity using ImmunoSeq™ and NanoString gene expression analyses
N (%)
Age, median (range) 58 (39,78)Male 8 (62)Race Caucasian Asian
12 (92)1 (8)
Stage IIIC IV
1 (8)12 (92)
Histology Cutaneous Mucosal
11 (85)2 (15)
Brain metastases 1 (8)Visceral metastases 10 (77)Elevated LDH 3 (23)BRAF mutation 9 (69)
* IMO-2125 + ipilimumab safety population (N=13). Data cut-off 5 Jan 2017
AE preferred term All grade, N (%)
Grade 3, N (%)
Grade 4, N (%)
Any 13 (100) 6 (46) 1 (8)
Anemia 6 (46) 1 (8) -
Pyrexia 6 (46) 1 (8) -
Nausea 6 (46) 1 (8) -
Vomiting 6 (46) 1 (8) -
Decreased WBC 4 (31) - -
Increased ALT 4 (31) 1 (8) -
Increased TG 4 (31) - -
Diarrhea 4 (31) 2 (15) -
Fatigue 3 (23) - -
Headache 3 (23) - -
Increased AST 3 (23) - 1 (8)
Chills 3 (23) - -
Urinary Tract Infection 3 (23) 1 (8) -
*TEAE in >20% of IMO-2125 + ipilimumab safety population (N=13). Data cut-off 5 Jan 2017
IMO-2125 dose 4 mg(N=3)
8 mg(N=4)
16 mg(N=3)
32 mg (N=3)
Total(N=13)
≥ 1 TEAE1 3 (100%) 4 (100%) 3 (100%) 3 (100%) 13 (100%)
Related TEAE1 2 (67) 4 (100) 3 (100) 3 (100) 12 (100)
≥ 1 SAE2 2 (67) 2 (50) 2 (67) 1 (33) 7 (54)
Discontinued for AE3 0 0 0 0 0
Death from AE3 0 0 0 0 0
DLT4 0 0 0 0 0
irAE5 1 (33) 1 (25) 2 (67) 0 4 (31)1treatment-emergent adverse event2serious adverse event3adverse event4dose-limiting toxicity5immune-related adverse event: hypophysitis (2), adrenal insufficiency (1), autoimmune hepatitis (1)
* IMO-2125 + ipilimumab safety population (N=13). Data cut-off 5 Jan 2017
IMO-2125 dose mg (N)
# IMO-2125 injections
Median (range)
# ipilimumab infusions
Median (range)
# Discontinuations (reasons)
4 (3) 6 (3,6) 3 (1,4) 2 (insurance, death)
8 (4) 6 (5,6) 4 (3,4) 1 (withdrawal)
16 (3) 5 (3,6) 2 (1,4) 1 (withdrawal)
32 (3) 5 (4,5) 3 (2,3) 0
Ipilimumab dose = 3 mg/kg Q3wks x 4
* IMO-2125 + ipilimumab safety population (N=13). Data cut-off 5 Jan 2017
N (%)
PD-(L)1 inhibitor 12 (92)CTLA-inhibitor 7 (54)BRAF inhibitor 5 (39)MEK inhibitor 4 (31)
Interferon 5 (39)IL-2 1 (8)
Other systemic therapy 3 (23)Radiation 5 (39)
* IMO-2125 + ipilimumab safety population (N=13). Data cut-off 5 Jan 2017
Dose-finding:IMO-2125 + ipilimumabSAFETY ASSESSMENT COMPLETED
Dose-finding:IMO-2125 + pembrolizumabONGOING
Phase 2 IMO-2125 + ipilimumab and IMO-2125 + pembrolizumabPLANNED
“Backfill” cohort(s):IMO-2125 + ipilimumabONGOING
Dosing: IMO-2125 4, 8, 16, or 32 mg single i.t. injection week 1, 2, 3, 5, 8, 11 Ipilimumab and pembrolizumab are administered per label beginning week 2
*Recommended Phase 2 dose
RP2D*
= collection of biopsy
Pre-dose
24 hours post intratumoral IMO-2125 injection
Week 8 5 doses of IMO-2125 and
3 doses of ipilimumab
Injected lesion
Un-injected lesion
Injected lesion
Injected lesion
Un-injected lesion
Fresh flow cytometry
Formalin - IHC
RNA (TCRseq and NanoString)
Tumor biopsy
mDC1 vs. mDC2 vs. pDCCD8 T cell: Treg ratioT cell proliferation via Ki67 of both Tregs and CD8+ T cellsImmune subsets ratio (T cell vs. B cell vs. NK cells)
Injected lesion
Un-injected lesion
Week 13
Tumor-specific antigens CD8+ T-cells Dendritic cells NK cells
TLR9
Intratumoraladministrationof IMO-2125
Increased TILinfiltration
Draining lymph node
Primed T-cellsmigrate to distant
tumor sites
Metastases are targetedby primed T-cells
IFN-α
IMO-2125
IFN- and Th1-type
immune response T-cells
mDCs
B-cells
Macrophages
Neutrophils
NK cells
pDCs B-cells
pDCs
Blockade with CPIs
1 2
Tumor microenvironment Distant metastases
3 4
Immune cell infiltration and activation
DC maturation
Migration and expansion of T-cells
2. Induction of interferon gamma (IFN-γ)
Seru
m IF
Nγ
(pg/
ml)
45
30
15
0
60
C2W5C3W8
C4W11
Patient timepointC1W1
C1W2
4. Expansion of top T-cell clones in distant (untreated) lesion
Freq
uenc
y of
tota
l T c
ell c
lone
s
20%
10%
0C3W8predose
3. T-cell activation following 6 doses of IMO-2125 (4mg) + 3 doses of ipilimumab
% C
D56
+ of C
D8+ c
ells
60
40
20
0
80
100 predoseC3W8
Injected Tumor Distant Tumor
CD56+ of CD8+ cells
Ki67+ of CD8+ cells
CD45+ cells CD45+ cells
% K
i67+ o
f CD
8+ cel
ls
% C
D45
+ liv
e ce
lls
CD
45+ l
ive
cells
60
40
20
0
80
100 predoseC3W8
604020
0
80100
642
810
predoseC3W8
60
40
20
0
80
100 predoseC3W8
1. Dendritic cell mDC1 maturation in the injected tumor
Pre-dose 24 hours post i.t. IMO-2125 injection
Com
p-FI
TC-A
:: C
D1c
104
103
0
-103
105
104 105
Comp-APC-A :: CD303
0 103
Com
p-FI
TC-A
:: C
D1c
104
103
0
-103
105
104 105
Comp-APC-A :: CD303
0 103
Com
p-FI
TC-A
:: C
D1c
104
103
0
-103
105
104 105
Comp-APC-Cy7-A :: HLA-DR
0 103
Data cut-off date: 13 Feb 2017
Ipi + IMO-2125 4mgIpi + IMO-2125 8mgIpi + IMO-2125 16mgIpi + IMO-2125 32mg
0 2
Weeks4 26 2810 18 2012 14 16 22 246 8 30 38 4032 34 36 46 4842 44 50 52 54 56
Trea
ted
Subj
ects
Confirmed Response Start
OngoingUnconfirmed Response Start
Efficacy Evaluable Subjects
-100
-80
-60
0
20
-40
-20
Max
imum
% d
ecre
ase
in ta
rget
lesi
ons
(sum
of l
onge
st di
amet
ers)
Ipi + IMO-2125 4mg
Ipi + IMO-2125 8mg
Ipi + IMO-2125 16mg
Ipi + IMO-2125 32mg
Dose Cohort
Presented at the ASCO-SITC Clinical Immuno-Oncology Symposium, February 2017
Abstract No. 136
Patient and disease characteristics
Prior treatment
Exposure
Design of the phase 1/2 clinical trial IMO-2125-204 (NCT02644967)
Immune response monitoring
Safety summary Proof of mechanism in responding patient 003
CONCLUSIONS
Most frequent TEAE
Patient time on study and RECIST v1.1 responses by dose cohort
Maximum decrease in target lesions by RECIST v1.1
BACKGROUND DISCUSSION
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