METHODS

A PHASE 2A TRIAL TO ASSESS THE SAFETY AND EFFICACY OF BL-8040AND PEMBROLIZUMAB IN PATIENTS WITH METASTATIC PANCREATIC ADENOCARCINOMA (PDAC)

Manuel Hidalgo1, Ron Epelbaum2, Brian M. Wolpin3, Salomon M. Stemmer4, Ravit Geva5, Talia Golan6, Erkut Borazanci7, Mitesh J. Borad8, Katrina S. Pedersen9, Joon Oh Park10,Robert Ramirez11, Amnon Peled12, Tzipi Lustig13, Osnat Bohana Kashtan12, Olivia Rosenfeld12, Ella Sorani12, Katia Schlienger14, Abi Vainstein12, Daniel Von Hoff15

RESULTS

37 pa�ents were enrolled in the study of which 29 were evaluable (i.e. received at least one dose of combina�on and have a post baseline CT) and 17 received one previous treatment line (2L) (Table 1).PDAC treatment with BL-8040 and Pembrolizumab was found to be safe and tolerable. The most common adverse event was mild to moderate injec�on site reac�on (Table 2).

RESULTS – MOA

REFERENCES

CONCLUSIONS

Median OS in all pa�ents (N=37) was 3.3 months with a 6-month survival rate of 34.4% (Figure 3A). Interes�ngly, in the sub-popula�on of pa�ents that received the study drugs as a second-line treatment (N=17), the median OS was 7.5 months with a 6-month survival rate of 51.5% (Figure 3B).

1Beth Israel Deaconess Medical Center, Boston, MA, USA; 2Rambam Medical Center, Haifa, Israel; 3Dana-Farber Cancer Institute, Boston, MA, USA; 4Rabin Medical Center, Petah Tikva, Israel; 5Sourasky Medical Center, Tel Aviv, Israel; 6Sheba Medical Center, Ramat-Gan, Israel; 7HonorHealth, Scottsdale, AZ, USA; 8Mayo Clinic, Phoenix, AZ, USA; 9Washington University School of Medicine, St Louis, MO, US; 10Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; 11Ochsner Medical Center, New Orleans, LA, USA; 12Hebrew University Hospital, Jerusalem, Israel; 12BioLineRx Ltd., Modi'in, Israel; 14Merck & Co., Inc., Kenilworth, NJ, USA; 15Translational Genomics Research Institute, Phoenix, AZ, USA

The combina�on of BL-8040 and pembrolizumab is safe and well tolerated.BL-8040 and pembrolizumab produced encouraging disease control in a significant number of PDAC pa�ents and extended overall survival in pa�ents receiving the study drugs as a second-line treatment in a tumor-type that is largely unresponsive to immune checkpoint inhibitors alone.Median OS in all pa�ents (N=37) was 3.3 months and 7.5 months in pa�ents receiving the study drugs as a second-line treatment (N=17). This compares favorably with historical mOS data of 6.1 months for the only currently approved second-line PDAC treatment (a chemotherapy combina�on of Onivyde®, 5-FU and leucovorin).Clinical ac�vity correlated with pharmacodynamic results: - BL-8040 treatment promoted an increase in the number of infiltra�ng ac�vated cytotoxic T cells that was accompanied by pronounced decrease in the number of tumor cells, as well a decrease in MDSCs. - The most pronounced changes in tumor microenvironment were observed following combina�on treatment of BL-8040 and pembrolizumab and were correlated with stable disease for 8 cycles of treatment. These encouraging results support further development of this combina�on as part of the treatment in pancrea�c cancer pa�ents.

Hidalgo et al. Evalua�on of pharmacodynamic (PD) biomarkers in pa�ents with metasta�c pancrea�c cancer treated with BL-8040, a novel CXCR4 antagonist. J. Clin. Oncol. 36, 88–88 (2018).Gerdes et al. Highly mul�plexed single-cell analysis of formalin-fixed, paraffin-embedded cancer �ssue. PNAS 110, 11982-11987 (2013) Corresponding Author: Abi Vainstein Abiv@biolinerx.com

© BioLineRx Ltd. 2018 – All Rights Reserved – Not for Distribu�on

ABSTRACT

Study Design: Open label, mul�center Phase 2aStudy Regimen: BL-8040 (1.25 mg/kg, SC) monotherapy on Days 1-5 of week one, followed by repeated three-week cycles of Q3W administra�on of pembrolizumab (200 mg, IV) and TIW administra�ons of BL-8040 (1.25 mg/kg, SC) on non-consecu�ve days for up to two years (Figure 1). Study Endpoints: Efficacy endpoints including among others response, disease control and survival. Objec�ve response rate (ORR) was assessed according to RECIST 1.1. Disease control rate (DCR) is defined as the percentage of pa�ents with response (complete and par�al) and stable disease (SD) as compared to baseline.Biopsy Analysis: Serial tumor biopsies were taken from metasta�c lesions before treatment (at screening) and on Day 5 of BL-8040 monotherapy or a�er two cycles of the BL-8040 and pembrolizumab combina�on. Tumor biopsies were processed to FFPE sec�ons and analyzed using the Mul�Omyx™ Hyperplexed Immunofluoresence Assay (Neogenomics; Gerdes et al., 2013), with panels designed to iden�fy pancrea�c tumor, CXCR4, tumor infiltra�ng lymphocytes (TILs) and myeloid-derived suppressor cells (MDSCs). Tumor regions of interest on the slides were selected by a board cer�fied pathologist prior to staining and analysis. 5 selected paired biopsies were analyzed.

Current treatment op�ons for PDAC pa�ents are limited by poor response rate and survival. Immune checkpoint inhibitors (ICIs) targe�ng the PD-1/PD-L1 axis are successful in trea�ng several cancer types; however, PDAC remains refractory. In PDAC mouse models, blockade of the CXCR4/CXCL12 axis promotes tumor infiltra�on of T cells and synergis�c an�-tumor effects when combined with an�-PD-1/an�-PD-L1

The COMBAT study is a Phase 2a, mul�-center, open label clinical trial to assess the safety and efficacy of the high-affinity CXCR4 antagonist BL-8040 in combina�on with pembrolizumab (KEYTRUDA®) in pa�ents with metasta�c pancrea�c cancer (NCT02826486). We have previously shown that BL-8040 given as monotherapy promoted infiltra�on of T cells into metasta�c lesions in PDAC pa�ents (Hidalgo et al., 2018). Here, we report top-line results from this Phase 2a clinical trial as well as in depth analyses of biopsies taken at screening and following BL-8040 monotherapy or 2 cycles of the BL-8040 and pembrolizumab combina�on.

RESULTS

Treatment with BL-8040 and pembrolizumab combina�on resulted in increased numbers of T cells and ac�vated CD8 cytotoxic T cells in metasta�c lesion biopsies, pronounced decrease in the number of tumor cells and decreased numbers of granulocyte like MDSCs (G-MDSCs) (Figure 4).

Figure 4: BL-8040 and pembrolizumab combina�on increases ac�vated CD8 T cell infiltrate (CD8+GranzymeB+) and decreases MDSCs (CD11b+CD15+) and tumor cell number in the tumor microenvironment of PDAC pa�ents, leading to reduc�on in tumor cell numbers. Shown are representa�ve Mul�Omyx data from Pa�ent 202-05 that achieved stable disease for 8 treatment cycles of the combina�on.

Figure 1: COMBAT Trial Study Design

Table 1: Pa�ent Demographics Table 2: Treatment-Related Adverse Events

A. B.

Poster Session 1133PD

A.

75.0

68.4

64.4

50.0

45.7

43.5

33.3

32.6

31.5

30.8

12.2

11.1

9.8

8.4

7.9

0.0

-6.9

-8.6

-10.

3

-39.

7

44.9

35.5

23.1

-1.5

-2.2

-3.7

-7.7

-8.1

-13.

3

-50

-40

-30

-20

-10

0

10

20

30

40

50

60

70

80

90

Max

imal

% C

hang

e fr

om B

asel

ine

Stable Disease (N=9)Partial Response (N=1)Progression (N=19)

Study COMBAT - mITT Analysis Set (N=29) - Sum Longest DiametersMaximal % Change from Baseline by Best Response according to RECIST1.1

Max % Change: Max decrease was used for subjects with decreases, Max increase was used for subjectswith increases only

B.

C.

Figure 3: Overall survival in pa�ents receiving the BL-8040 and pembrolizumab combina�on. (A) All inten�on to treat (ITT) pa�ents (N=37). (B) A subgroup of pa�ents from the ITT that received only 1 prior treatment before the BL-8040 and pembrolizumab combina�on

Figure 2: Response in pa�ents receiving the BL-8040 and pembrolizumab combina�on. (A) Swimmer plot analysis for all inten�on to treat (ITT) pa�ents (N=37). (B) Waterfall plot analysis for evaluable pa�ents (mITT; N=29). (C) Spider plot analysis for ITT pa�ents (N=37).

Response by RECIST1.1 for the evaluable popula�on (mITT; N=29) showed 1 subject that was MSS (3.4%) with par�al response demonstra�ng ~40% reduc�on in tumor burden and 9 subjects (31%) with stable disease, yielding 34.5% (N=10) with disease control (Figure 2). Median treatment �me was 72 days (range 37-267).