(1) Department of Oncology, Haukeland University Hospital, Bergen, Norway; (2) Centre of Cancer Biomarkers, University of Bergen, Bergen, Norway; (3) BerGenBio ASA, Bergen, Norway

Trial update: A randomised Phase Ib/II study of the selective small molecule AXL inhibitor bemcentinib (BGB324) in combination with either dabrafenib/trametinib (D/T) or pembrolizumab in patients with metastatic melanoma

This poster was presented at the ESMO 2019 Congress, Barcelona, Spain (September 27 - October 01, 2019)This presentation is the intellectual property of the presenter. Contact them at oddbjorn.straume@helse-bergen.no for permission to reprint and/or distribute.

Oddbjørn Straume1, James Lorens2,3, David Micklem3,, Bjørn T. Gjertsen2, Cornelia Schuster2,

Background & Objective

In collaboration with:

Background & Objective

Part 2 Preliminary Results

Poster 1336TiP

60%

40%

-20%

-40%

0%

20%

-100%

-80%Pembrolizumab + bemcentinib

Pembrolizumab

80%

% change from baseline in target lesions (low tumour load)PD

PDPD

PD

PD

SDSD

SDPR

PRPR

PR

PRPR

CRFour recruited patients (3 in the pembrolizumab+bemcentinib group, 1 in pembrolizumab monotherapy group) did not receive a post-baseline scan (2 showed clinical progression before scan, 2 were taken off study before scan due to AEs) and have not been included in plot above.

BRAF

neg

aitiv

e

Discussion

Formal interim analysis of clinical safety and efficacy data (June 2019) 20 randomised patients had completed up to 12 cycles of treatment (Currently enrolled pts n= 50)

The Data Monitoring Committee (DMC) reviewed the following listing in the eCRF • AEs• SAEs• Early Response Assessment (Response rates according to Recist 1.1)

DMC conclusions• bemcentinib RP2D (200 mg daily) seems to be well tolerated in combination with both D/T and pembrolizumab with AE profiles consistent with those reported for either therapeutic approach alone. • Diarrhea and increasing liver enzymes seemed to be slightly increased in patients receiving bemcentinib. • The DMC recommended that the study continues according to protocol.

Lorem ipsum

Oddbjørn Straume MD, PhDDepartment of OncologyHaukeland University HospitalJonas Lies vei 655021 BergenNORWAY

oddbjorn.straume@helse-bergen.no

BerGenBio ASAJonas Lies vei 915009 BergenNORWAY

Contact

Oddbjørn StraumeBerGenBio ASA, poster preparation and travel grant

Cornelia SchusterBerGenBio ASA, poster preparation and travel grant

Conflicts of Interest

• Histologically confirmed advanced cutaneous non-resectable (Stage IIIc) or metastatic (Stage IV) melanoma• Measurable disease as defined by RECIST 1.1 & documented progression of ≥1 measurable lesion• Availability of fresh or archival tumour tissue sample suitable for evaluation of predictive biomarkers of response• ECOG score 0 to 2 at screening

• No prior treatment for Stage IIIb or Stage IIIc melanoma• No history of or current active autoimmune diseases• No symptomatic central nervous system metastatic lesions• No recent or ongoing systemic treatment with immunosuppressive or

immunomodulating agents

NCT02872259: Ph I/II randomised trial of selective AXL inhibitor bemcentinib in metastatic melanoma patients

Three part randomised design enrolling up to 92 patients

Key inclusion and exclusion criteria

Assessments - efficacy & safety• Response assessed q9 wks per RECIST v1.1 & irRC• Adverse events assessed by CTCAE v4.03• Safety-evaluable: ≥1 dose of study treatment as of cut-off

Biomarker analysis• Soluble protein biomarkers by liquid biopsy• PD-L1 and AXL expression per IHC• Immune cell populations by CyTOF

Endpoints• Primary: ORR• Secondary: PFS DoR OS

2:1

Part 2n=80 Part 3

2:1

2:1

Dabrafenib/trametinib+

bemcentinib

Dabrafenib/trametinib

Pembrolizumab+

bemcentinib

Pembrolizumab

Pembrolizumab+

bemcentinib

Pembrolizumab

Pembrolizumab+

bemcentinib

Pembrolizumab

Dabrafenib/trametinib+

bemcentinib

Dabrafenib/trametinib

Safe

ty/E

ffic

acy

Low

tum

our

load

High

tum

our

load

BRAF

posi

tive

BRAF

nega

tive

• Exploratory: response per irRC response by biomarker expression QoL

Status• Part 1 (dose escalation bemcentinib + dabrafenib/trametinib n=12): Completed• Part 2: Ongoing• Part 3: Ongoing

Dabrafenib/trametinib + bemcentinib

Dabrafenib/trametinib

60%

40%

-60%

-20%

-40%

0%

20%

-100%

-80%

SD

SDSD

PRPRPRPR

PR PR PR

PR

CR CROne recruited patient in the D/T + bemcentinib group did not receive a post-baseline scan (death before scan) and has not been included in plot above

% change from baseline in target lesions (high tumour load)

BRAF

pos

itive

Preliminary Efficacy - Best Overall Response

Pembrolizumab + bemcentinib

Pembrolizumab

60%

40%

-60%

-20%

-40%

0%

20%

-100%

-80%

% change from baseline in target lesions (low tumour load)PD

PD

SD SDSD

PD* PR

PRPRPRPRPRPR

CRCR* Tumour shrinkage of 33% but with new lesions

Safety

Dabrafenib/trametinib/

bemcentinib

Dabrafenib/ trametinib

Pembrolizumab/bemcentinib Pembrolizumab

n=13 n=3 n=27 n=12

n (%) e n (%) e n (%) e n (%) e

Any AE (Grade 3-5) 4 (30%) 12 1 (33%) 1 13 (48%) 20 3 (25%) 5

Treatment-related AEs (Grades 3-51) 3 (25%) 7 0 (0%) 0 8 (30%) 10 2 (17%) 2

Bemcentinib-related AEs (Grades 3-51) 3 (25%) 3 n/a n/a 7 (26%) 7 n/a n/a

1Possible, probably, definitely related

Adverse events grades 3-5 (CTCAE v4.03)

FC: 1.046P: 0.687

BGBM006

FC: 1.45P: 0.000309

FC: 1.06P: 0.461

FC: 1.588P: 0.000107

sAXL PembrolizumabPembrolizumab/bemcentinib

Biomarkers

FC: Fold Change

Pharmacodynamics: Serum AXL (sAXL) and BGBM006 increase upon treatment with pembrolizumab/bemcentinib combination.

Predictive biomarker candidates: Serum biomarkers BGBM007 and BGBM008 are predictive for patient benefit from combination treatment with bemcentinib

BGBM007 BGBM008

FC: 2.821P: 0.00018

FC: -1.59P: 0.0099

* Number of events reported on study

Most frequent AEs in patients receiving bemcentinib in combination

Dabrafenib/trametinib/bemcentinib (n=13), e*

Pembrolizumab/bemcentinib (n=27), e*

Adverse event Regardless of relation Related to Bemcentinib Regardless of relation Related to

Bemcentinib

Diarrhoea 12 8 15 3

Pyrexia 16 0 5 0

Fatigue 8 5 11 4

Rash 5 3 14 3

Hepatic enzymes increased 6 6 13 8

Nausea 7 6 5 3

Immune -related hepatitis 0 0 5 5

Study rationale

The receptor tyrosine kinase AXL promotes both intrinsic and acquired resistance to targeted agents and immune therapeutics in solid malignancies1. In addition, AXL is a key negative regulator of the innate immune response2. Hence targeting AXL by AXL inhibitors is an attractive clinical approach that serves both to activate an anti-tumourigenic immune response and to render resistant tumor cells sensitive to conventional therapy.AXL mediates tumor drug resistanceAXL is associated with epithelial-to-mesenchymal (EMT) -related phenotypic plasticity, and AXL dependent cell plasticity has been proven essential for developing resistance towards MAP kinase pathway inhibitors3. In BRAF V600E mutant melanoma, the MITFlow /AXLhigh expression ratio is associated with resistance to BRAF inhibitors4,5. Using single cell resolution analysis, evidence was found that small populations of AXL-high cells were preexistent within the tumour and that their persistence and/or proliferation drove inherent resistance6. EMT is also increasingly recognized as a major contributor to tumour immune evasion. EMT renders cells resistant to lymphocyte-mediated cell lysis7. An EMT signature is associated with a suppressive microenvironment with upregulation of several immune check points in NSCLC8. In melanoma patients resistant to anti-PD-1 therapy, AXL expression was identified as a component of the anti-PD-1 resistance program9. The drug resistant MITFlow /AXLhigh melanoma phenotype is also associated with an immune suppressive micro-environment and T cell exhaustion6.AXL mediates innate anti-tumor immune suppressionAxl is an important negative feedback regulator of the innate immune response. Tumour associated macrophages express AXL10 and AXL mediates M2-macrophage polarization11. AXL attenuates natural killer cell anti-tumor activity12, and AXL expression is associated with decreased ability of dendritic cells to activate T lymphocytes13.

The drug resistant low MITF/ high AXL melanoma phenotype is associated with an immune suppressive microenvironment.

Melanocyte

Melanoma

Melanin

Epidermis

Dermis

HypodermisMuscle Layer

AXL

Zeb1 p27 ++

MITF

ImmunoevasiveTherapy resistant

ImmunogenicTherapy sensitive

Cellular stress:hypoxiain�ammationstarvation

radiationtreatmentgrowth factors

S

tem

-like

Invasive Proliferating Di�erentiated

1Davidsen K.T et al., Springer Publishing, 351-76, 2017, 2Lemke and Rothlin, Nat Rev Immunol. 8(5) 2008.3Shaffer et al, Nature 546:431, 20174Konieczkowski et al., Cancer Discov 4:816, 20145Müller, et al., Nat. Comm 5:5712, 2014 6Tirosh et al., Science 8;352(6282), 20167Terry et al., Cancer Immun Res. doi: 10.1158/2326-6066, 20198Lou et al., Clin Can Res 22(14), 20169Hugo et al., Cell 165, 201610Ye et al., Oncogene 29, 2010.

11Chiu et al., Oral Oncology 51, 2015.12Paolino et al., Nature, 507:508, 201613Kurowska-Stolarska et al., Nat Comm 8: 15877, 2017

References

Bemcentinib

BGB324

Kinase Kinome Scan (Kd)

nM Fold

Axl 0.4 1

Mer 100 250

Tyro >1000 >1000

Selectivity ProfileBemcentinib (BGB324) is a once-a-day, highly selective, potent, orally available, AXL kinase inhibitor which is being evaluated as a therapy for solid tumours and myeloid malignancies.

Bemcentinib is being developed as monotherapy and in combination with immune, targeted and chemotherapy in NSCLC, AML/MDS and melanoma.

Phase II clinical trials are ongoing with bemcentinib in combination with pembrolizumab in adenocarcinoma of the lung (NCT03184571), and as a single agent and in combination with low dose chemotherapy in AML & MDS (NCT02488408).

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