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