AXL inhibitors as cornerstone of combination cancer therapy1 AXL inhibitors as cornerstone of...
Transcript of AXL inhibitors as cornerstone of combination cancer therapy1 AXL inhibitors as cornerstone of...
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AXL inhibitors as cornerstone of combination cancer therapyFirst-in-class medicines to treat aggressive cancers
Third Annual Immuno-Oncology Summit Europe March 22nd 2018
Julia Schoelermann (PhD, MBA), Assoc. Dir BD & Partnering
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Disclaimer
Certain statements contained in this presentation constitute forward-looking statements. Forward-looking statements are statements that are not historical facts and they can be identified by the use of forward-looking terminology, including the words "anticipate", "believe", "intend", "estimate", "expect", "will", "may", "should" and words of similar meaning. By their nature, forward-looking statements involve a number of risks, uncertainties and assumptions that could cause actual results or events to differ materially from those expressed or implied by the forward-looking statements. Accordingly, no assurance is given that such forward-looking statements will prove to have been correct. They speak only as at the date of the presentation and no representation or warranty, expressed or implied, is made by BerGenBio ASA or its affiliates ("BerGenBio"), or by any of their respective members, directors, officers or employees that any of these forward-looking statements
or forecasts will come to pass or that any forecast result will be achieved and you are cautioned not to place any undue influence on any forward-looking statement. BerGenBio is making no representation or warranty, expressed or implied, as to the accuracy, reliability or completeness of this presentation, and neither BerGenBio nor any of its directors, officers or employees will have any liability to you or any other person resulting from the use of this presentation.
Copyright of all published material, including photographs, drawings and images in this presentation remain with BerGenBio and relevant third parties, as appropriate. Consequently, no reproduction in any form of the presentation, or parts thereof, is permitted without the prior written permission, and only with appropriate acknowledgements.
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Corporate snapshot
BackgroundLeaders in developing therapeutics that target AXL, a protein that makes cancers and their environment highly aggressive and which is associated with poorer outcomes across many cancers
Diversified pipeline, lead drug is tested in several indications of high unmet medical need and large market potential
Promising efficacy with sustained treatment benefit and confirmed favourable safety
Companion diagnostic supported by biomarker tests
Bemcentinib (BGB324)First-in-class highly selective small molecule AXL inhibitor
Broad phase II proof of concept clinical trials ongoing in NSCLC, TNBC, AML/MDS, melanoma.
PipelineBemcentinib (BGB324)
AXL antibody
AXL ADC (partnered)
Immunomodulatory small molecules
OSE:BGBIORaised $50m in IPO on OSE in April ’17
$320m market cap (Feb 18th 2018)
Corporate 35 staff
Headquarters and research in Bergen, Norway; Clinical Trial Management in Oxford, UK
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Antibody programs
BGB149 Oncology
BGB601(Partnered) Metastatic cancer
Discovery Pipeline – small molecule inhibitorsBGB002/BGB003 Oncology
Discovery Preclinical Phase I Phase II Phase IIIBemcentinib – Axl kinase inhibitor
NSCLC
adenocarcinoma
mutation driven
all comers*
TNBC
Melanoma*
AML / MDS
Advancing a broad development pipeline of innovative drugs
Small molecule
Anti-Axl mAb
ADC
Phase Ib / II – Single agent / Combination
Phase Ib / II – Combination with TARCEVA® (erlotinib)
Phase II Combination with KEYTRUDA® (pembrolizumab)
Phase II Combination with KEYTRUDA® (pembrolizumab)
Phase II bemcentinib in combination with Docetaxel
Phase II bemcentinib in combination with current standard therapies, incl. CPIs
>350 Patients
*Investigator-sponsored trials
50 sites in Europe & US.
2018 Key read-outs:
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Discovery Preclinical Phase I Phase II Phase IIIBemcentinib – Axl kinase inhibitor
NSCLC adenocarcinoma
TNBC
Melanoma*
Three combination trials of bemcentinib with KEYTRUDA
Phase II Combination with KEYTRUDA® (pembrolizumab)
Phase II Combination with KEYTRUDA® (pembrolizumab)
Phase II bemcentinib in combination with current standard therapies, incl. CPIs
*Investigator-sponsored trials
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background bemcentinib Phase II PoC programme
T-cell
Successful anti-cancer therapies depend on both tumour antigenicity and immune system adjuvanticity
Tumour antigenicity /
immunogenicity
Immune system adjuvanticity
Anti-tumour therapy:• Chemotherapy• Radiotherapy• Targeted therapy• Oncolytic viruses• Anti-PD-L1
Tumour cell
DC
NKTNK
- Interferon mediated -anti-tumour immune reaction
Tumour clearance
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background bemcentinib Phase II PoC programme
T-cell
Successful anti-cancer therapies depend on both tumour antigenicity and immune system adjuvanticity
Tumour antigenicity /
immunogenicity
Immune system adjuvanticity
- Interferon mediated -anti-tumour immune reaction
Anti-tumour therapy Immune activating therapy
Tumour cell
DC
NKTNK
Tumour clearance
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background bemcentinib Phase II PoC programme
AXL is negative feedback mechanism: drives cancer immune escape via tumour intrinsic survival programme & suppression of immune adjuvanticity
Tumour survival programme
(EMT)
Tumour cell
T-cell
Innate immune suppression
DC
NKTNK
- AXL mediated -tumour immune escape
Aggressive cancer
Survival programme (EMT):• Therapy resistance• Metabolic programming• Reduced immunogenicity:
• Biophysical• PD-L1• autophagy
Immune suppression• SOCS → ↓DC • M2 macrophages• Tregs• ↓MHC
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background bemcentinib Phase II PoC programme
Successful cancer drug combination strategies…
AXL driven tumour cell plasticity and immune suppression is a negative feedback mechanism
Boost tumour antigenicity
Effectively address feedback inhibition
Boost immune adjuvanticity and concomitantly
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background bemcentinib Phase II PoC programme
AXL receptor tyrosine kinase
bemcentinibbinds the internal
kinase domain
IG-like domains
FN domains
Kinase domain
Immunosuppression & therapy resistance
• Member of the TAM (Tyro-AXL-Mer) family
• Ubiquitously expressed at low levels
• Epigenetically upregulated upon immune reaction or cellular damage (e.g. anti-cancer therapy, hypoxia)
o Innate immune checkpointo Tumour cell pro-survival programme:
Ø Therapy resistanceØ Metabolic reprogrammingØ Reduced immunogenicity
• Only TAM member that correlates with aggressive cancers
AXL is a surface receptor tyrosine kinaseAXL antibody BGB149binds IG domain
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background bemcentinib Phase II PoC programme
AXL signalling in DCs, via INF/STAT pathway, leads to
expression of DC negative regulators SOCS1/32
Antigen presentation by DCs (red) to T-
cells (green) is reduced when AXL is
active1
AXL is off-switch for DCs
AXL is an innate immune checkpoint facilitating immune escape
Innate immune activation through toll-like receptor (TLR) signalling
triggers AXL upregulation in DCs1
Ø miR-34a downregulates AXL
Ø ↓miR-34a à↑AXL
Source: (1) Kurowska-Stolarska et al Nature Comm 2017 (2) Rothlin et al Cell 2007
AXLactive inactive
Immune response trigger
DC
DC inactive
DC DC activeantigen presentation
to T-cells
Toll like receptor
signalling
AXL signalling
DC self-regulatory
cycle1
1
2
2
AXL off = DC on AXL on = DC off
AXL activation
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background bemcentinib Phase II PoC programme
AXL drives tumour cell escape from checkpoint inhibitors
Source: Chouaib, 2014; Hugo, 2016
Checkpoint inhibitors (CPIs) work only in a small proportion of patients
% r
espo
nder
s vs
non
-re
spon
ders
0 %
20 %
40 %
60 %
80 %
100 %
NSCLC TNBC Renal Cancer Head & Neck Melanoma
Responders Non-responders
AXL upregulated in CPI resistant melanomaAXL
Axl driven tumour EMT prevents CTL killing of cancer cells
EpiEpi
Epi
AJAJ
AJ
ICAM
CTL
LFA1
IS
MHC-II
TCR
• Effective synapse
• Immune mediated cell death
Robust immunological synapse between CTL and epithelial tumour cell
CTL MES
• impaired synapse
• Immune evasion
Impaired immunological synapse between CTL & mesenchymal tumour cell
AXL
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background bemcentinib Phase II PoC programme
AXL is detected in patient tumour and immune cells (BerGenBio) IHC assay
MethodsEstablishment of a validated, automated immuno-histochemistry (IHC) assay for the detection of AXL in human formalin-fixed paraffin-embedded (FFPE) tissue: IHC was implemented on the Discovery XT staining platform (Roche Diagnostics/Ventana Medical Sys-tems) using a rabbit monoclonal anti-AXL antibody. FFPE tissue samples and FFPE TMAs were sliced into 3-5 μm sections and mounted and the method was verified for linerity and precision using a semi-quantitative H-score performed by a pathologist. Between 28 and 33 patient samples of TNBC, adeno-carcinoma of the lung and squamous cell carcinoma, respectively, were pathologist scored for presence of AXL expression on either tumour tissue or tumour infil-trating immune cells.
Shown are squamous cell carcinoma FFPE patient samples stained for AXL (brown) as per BerGenBio’s proprietary AXL IHC assay
AXL expression in tumour adjacent alveolar macrophages
AXL expression in NSCLC patient tumour sample
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background bemcentinib Phase II PoC programme
AXL is independent negative prognostic factor in a broad variety of cancers
1 Gjerdrum, 2010; 2 Ishikawa, 2012; 3 Ben-Battala, 2013; 4 Song, 2010, 5 supported by > 100 publications
Therapy resistance
Breast carcinoma1
Acute Myeloid Leukaemia3 Pancreatic ductal adenocarcinoma4
Lung adenocarcinoma (NSCLC)2Astrocytic brain tumors
Breast cancer
Gallbladder cancer
GI
• Colon cancer
• Esophageal cancer
• Gastric cancer
Gynaecological
• Ovarian cancer
• Uterine cancer
HCC
HNC
Haematological
• AML
• CLL
• CML
Months after primary treatment20 40 60 80 100
0
0.2
0.4
0.6
0.8
1
Prob
abilit
y of
sur
viva
l
AXL expressionLog Rank Test, P=0.035
Strong AXL (64/11)
Weak AXL (90/6)
0 24 36 48 600
20
40
60
80
100
12Months after operation
AXL IHC high (n=29)
AXL IHC low (n=59)
P <0.001
Time after diagnosis (years)0 4 8 12
0
20
40
60
80
100
Ove
rall
surv
ival
(%)
AXL > median
AXL < median
0 100 1500
20
40
60
80
100
50Time (months)
AXL IHC high (n=38)
AXL IHC low (n=16)
P=0.02
Ove
rall
surv
ival
(%)
Prob
abilit
y of
sur
viva
l
Strong AXL expression correlates with poor survival rate Broad evidence of AXL linked with poor prognosis5
Melanoma
Mesothelioma
NSCLC
Pancreatic cancer
Sarcomas
• Ewing Sarcoma
• Kaposis sarcoma
• Liposarcoma
• Osteosarcoma
Skin SCC
Thyroid cancer
Urological
• Bladder cancer
• Prostate cancer
• RCC
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Bemcentinib, first in class highly selective AXL inhibitor
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background bemcentinib Phase II PoC programme
Bemcentinib is active throughout the complete cancer immunity cycle reversing immune suppression
Reversal of immune
suppression
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background bemcentinib Phase II PoC programme
Bemcentinib is an immune modulator that enhances anti-tumourimmunity
Source: Ludvig, Cancer Research, 2017; Guo, OncoTarget, 2017
Cytokines that mediate immune suppression
• Recruitment (CCL2, CCL3, CCL4, CCL5) and
• Activity (CCL11, IL-7, IL-1β, and IL-6)
Bemcentinib decreases immune suppression
• Recruitment (CXCL9, CXCL10 and CXCL11) and
• Functionality (IFN-γ, IL-12p40, T-bet)
While enhancing T cell responses
T cell activity increased T cell activity increased
CCL11
Cntl Gem BGB Combo
1750150012501000750500250
0
pg/m
L
IL-710
5
0
pg/m
L
Cntl Gem BGB Combo
IL-1β50
40
30
20
10
0
pg/m
L
Cntl Gem BGB Combo
IL-6350300250200150100500
pg/m
L
Cntl Gem BGB Combo
MyeloidSuppression decreased
MyeloidSuppression decreased
IC8 ovarian carcinoma
Vehiclebemcentinib
Vehiclebemcentinib
Pancreatic model
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background bemcentinib Phase II PoC programme
Bemcentinib is an immune modulator that enhances anti-tumourimmunity
Source: Guo, OncoTarget, 2017
ID8 ovarian carcinoma, 5 day bemcentinib monotherapyVehiclebemcentinib
Increased T Cell infiltration Increased T cell proliferation Increased T cell activity
Decreased myeloid
suppressors
Increased dendritic
cells
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background bemcentinib Phase II PoC programme
Bemcentinib therapy targets immune suppressive M-MDSC and tumor associated macrophages
Source: Ludvig et al., Can Research, 2017
bemcentinib monotherapy (2 wk) PDAC cells (subQ)Monocytic myeloid-derived suppressor cell immature myeloid cells with pathologic activation, immune suppressive
Tumour associated macrophagePro-tumoural macrophage, promote proliferation, invasion, and metastasis of tumour cells, and inhibit T cell response
ArginaseMetabolises L-arginine to L-ornithine and urea - myeloid cell arginase-mediated L-arginine depletion suppresses T cell responses
M-MDSC
TAM
Arg1
Source: Ludvig, Cancer Research, 2017
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background bemcentinib Phase II PoC programme
Bemcentinib promotes dendritic cell tumour-infiltration and activation
ID8 ovarian carcinoma, 5 day bemcentinib monotherapy
Control bemcentinib
Source: Guo, OncoTarget, 2017
Control bemcentinib Control bemcentinib
Peripheral, cross-presenting dendritic cell (DC)
Mature DC
IL-12 secreting DC
CD103+ DC
CD40+CD86+ DC
IL-12p40+ DC
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background bemcentinib Phase II PoC programme
Orthotopic 4T1 in Balb/c
! CTLA4/PD1 CTLA4/PD1 + BGB324!Lung Liver Spleen Lung Liver Spleen
Non-responders! 11/15 10/15 12/15 14/16 9/16 10/16
Responders! 0/1 0/1 0/1 3/8 0/8 1/8
!!! CTLA4 CTLA4 + BGB324!
Lung Liver Spleen Lung Liver Spleen Non-responders! 6/8 5/8 5/8 6/7 5/7 4/7
Responders na na na 0/2 0/2 0/2
!
P=0.0009P=0.006 P=0.02
Bemcentinib enhances immune checkpoint inhibitor efficacyM
emb
ran
e ex
pre
ssio
n
AX
L
0
2
4
6
8
10
CTLA4/P
D-1
Control
Source: Davidsen ,Wnup-Lipinska, et al, in prep
100
Perc
ent s
urvi
val
50
00 10 20 30 40 50
Time (days)
Anti-CTLA + Anti-PD1 + bemcentinibAnti-CTLA-4 + Anti-PD1Control
re-challenge
Checkpoint inhibitor treatment induces aggressive tumour AXL
programmeAbrogation of metastases in
respondersDurable response to bemcentinib +
CPI treatment
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Bemcentinib phase II PoCprogramme:
designed to evaluate potential of bemcentinib to increase efficacy of anti-cancer therapies
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background bemcentinib Phase II PoC programme
Bemcentinib recently reported interim PoC Phase II data
Bemcentinib (BGB324) foundation therapy
monotherapy
BGBIL006: Melanoma
BGBC007: TNBC
BGBC008: NSCLC
BGBC004: NSCLC
BGBIL006: Melanoma
BGBIL005: NSCLC
BGBC003: AML
BGBC003: AML/MDS
+ chemotherapy+ checkpoint inhibitors + targeted therapy
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AXL inhibition to increase efficacy of anti-PD-1 therapy
BGBC007, BGBC008, BGBIL006
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science bemcentinib Phase II PoC programme
Combination with bemcentinib to increase efficacy of anti-PD1 therapy
BerGenBio trials including anti-PD1 therapy
TNBCNSCLC Melanoma
2nd line (no prior CPIs) 1st & 2nd line2nd line
(no prior CPIs)
Combination therapy: bemcentinib + KEYTRUDA to increase response rates
AXL driven immune evasion and drug resistance
• A significant proportion (up to 95% in 2L TNBC) of patients do not respond to checkpoint inhibitor therapy
• Non-responders to checkpoint therapy have been shown to express AXL at higher rates
• Inhibiting AXL may increase the number of patients responding to checkpoint therapy
• Comprehensive biomarker programme analysing AXL, PD-L1 and immune signature
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science bemcentinib Phase II PoC programme
ASCO-SITC Clinical IO Symposium 2018Favourable safety reported for bemcentinib / pembro combo across all three trials
Source: Yule et al ASCO-SITC Clinical IO Symposium (January 2018)
• 34 patients evaluable for safety
• SAE profile of combination similar to pembro alone
TNBCNCT03184558
NSCLCNCT03184571
Melanoma*NCT02872259 total
19 9 6 34
SOC n n n n %
Skin and subcutaneous tissue disorders 4 0 0 4 12
General disorders and administration site conditions 3 0 1 4 12
Gastrointestinal disorders 3 0 0 3 9
Investigations 3 3 9
Blood and lymphatic system disorders 1 0 0 1 3
Cardiac disorders 1 0 0 1 3
Hepatobiliary disorders 0 1 0 1 3
Respiratory, thoracic and mediastinal disorders 1 0 0 1 3
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BGBC008 trial in NSCLCKeytruda monotherapy showed 18% response rate in previously treated NSCLC patients. PD-L1 negative patients remain particularly challenging.
The BGBC008 trial is designed to test the hypothesis whether AXL inhibition can
Enhance responses to immunotherapy
when given in combination with pembrolizumab in previously treated, immunotherapy-naïve NSCLC patients.
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science bemcentinib Phase II PoC programme
Bemcentinib increases immune checkpoint inhibitor efficacy in NSCLC models in vivo
Bemcntinib reverses CPI induced EMT
0.7
0.8
0.9
1.0
1.1
1.2
0.0
0.5
1.0
1.5Vimentin N-cadherin
mR
NA
fold
cha
nge
(rela
tive
to c
ontro
l)
mR
NA
fold
cha
nge
(rela
tive
to c
ontro
l)
Bemcentinib PD1/PDL1 Bemcentinib + PD1/PDL1 Bemcentinib PD1/PDL1 Bemcentinib +
PD1/PDL1
**
Tum
our v
olum
es (m
m3 )
0
300
600
900
1200
1500
1800
Control Bemcentinib PD1/PDL1
PD1/PDL1Bemcentinib
Bemcentinib increases CPI efficacy
Source: Wnuk-Lipinska et al AACR 2017 – LLC model
*******
****
0
0.5
1
1.5
2
2.5
CD
3+
CD
8+
CD
4-
Control BGB324PD1/PDL1PD1/PDL1BGB324
Tumour CTLs
*******
Control BGB324PD1/PDL1PD1/PDL1BGB324
0
0.5
1
1.5
2
2.5
CD
3+
NK
p4
6+ 3
3.5
NKT cells
*
mMDSCs
Control BGB324PD1/PDL1PD1/PDL1BGB324
0
20
40
60
CD
11
b+
Ly6
G L
y6C
hig
h
Bemcentinib reverses immunosuppression in tumour microenvironment
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science bemcentinib Phase II PoC programme
BGBC008: Phase II trial in NSCLC of bemcentinib in combination with KEYTRUDA
BGBC008 Phase 2 – NSCLC Adenocarcinoma of the lung
Initial read-out expected 2H 2018
Previously treated, unresectable adenocarcinoma of the lung
up to 48 ptsany PD-L1 expressionany AXL expressionno prior IO
Simon two stage (interim after 22 pts)
ORR
Safety, DoR, TtP, OS at 12 mo, response by biomarker expression
Expected readout
Single arm
bemcentinib 200mg/dKeytruda 200mg/3w
Mandatory pre-treatment biopsies
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BGBC007 trial in TNBCKEYTRUDA monotherapy showed 4% response rate in previously treated TNBC patients.
The BGBC007 trial is designed to test the hypothesis whether AXL inhibition with bemcentinib can
Enhance responses to immunotherapy
when given in combination with pembrolizumab in previously treated, immunotherapy-naïve TNBC patients.
Clinical collaboration with Merck & Co. (MSD)
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science bemcentinib Phase II PoC programme
Bemcentinib increases immune checkpoint inhibitor efficacy in TNBC models in vivo
Bemcntinib reverses CPI induced EMT – correlates with response Bemcentinib increases CPI efficacy
Source: Wnuk-Lipinska et al AACR 2017 – 4T1 model
Bemcentinib reverses immunosuppression in tumour microenvironment
0
2
4
6
8
10
mR
NA
fold
cha
nge
(rel
ativ
e to
Ctrl
)
Non-responders Responders
*
0
2
4
6
8 Non-responders Responders
mR
NA
fold
cha
nge
(rel
ativ
e to
Ctrl
)
VimentinAXL
CTLA4/PDL1 Bemcentinib + CTLA4/PDL1 CTLA4/PDL1 Bemcentinib +
CTLA4/PDL1
0 10 20 30 40 50 60 70 130 140 1500
50
100
*********
control
Bemcentinib mono
anti-CTLA4/PD-1
anti-CTLA4/PD-1 + bemcentinib
0
2
4
6
CD
3+,
CD
8a
+,
CD
4-
Ctr Bemcentinib CTLA4/PD1
CTLA4/PD1Bemcentinib
Tumour CTLs
0
0.02
0.04
0.06
0.08
0.10
CD
4- , C
D3
- , N
Kp
46
+ 0.12
Tumour NK cells
splenicmMDSCs
0
2
0
6
CD
11
b+,
Ly6
G,
Ly6
Ch
igh
Ctr Bemcentinib CTLA4/PD1
CTLA4/PD1Bemcentinib Ctr Bemcentinib
CTLA4/PD1CTLA4/
PD1Bemcentinib
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science bemcentinib Phase II PoC programme
BGBC007: Phase II trial in TNBC of bemcentinib in combination with KEYTRUDA
BGBC007 Phase 2 – TNBC
Initial read-out expected 2H 2018
Previously treated, unresectable or metastatic TNBC
up to 56 ptsany PD-L1 expressionany AXL expressionno prior IO
Simon two stage (interim after 28 pts)
ORR
Safety, DoR, TtP, OS at 12 mo, response by biomarker expression
Expected readout
Single arm
bemcentinib 200mg/dKeytruda 200mg/3w
Mandatory pre-treatment biopsies
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BGBIL006 trial in melanomaAlthough responses to TKIs are rapid, resistance ultimately emerges. Monotherapy checkpoint inhibitor responses can be further improved.
The BGBIL006 trial is designed to test the hypothesis whether AXL inhibition can
Enhance responses to immunotherapyEnhance responses to targeted therapy
when given in combination with pembrolizumab or dabrafenib/trametinib in treatment naïve melanoma patients
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science bemcentinib Phase II PoC programme
Dabrafenib+trametinib
+/- bemcentinib200mg/d
Treatment naïve,
BRAF mutant (high tumourburden)
up to 40 pts
BRAF mutation driven
any AXL expression
BGBIL006 : Randomised Phase II trial of BGB324 in combination with targeted and I/O therapies in Melanoma
Source: Straume et alWorld Conference on Melanoma (October 2017)
BGBIL006 Phase II – Melanoma, randomised SoC (Keytruda or BRAF/MEKi) +/- BGB324
Initial read-out expected 2H 2019
First Line
ORR
Safety, DoR, TtP, OS at 12 mo, response by biomarker expression
Expected readoutEndpointsSecond Line
Pembrolizumab200mg/3w
+/- bemcentinib200mg/d
Dabrafenib+trametinib
+/- bemcentinib200mg/d
Pembrolizumab 200mg/3w
+/- bemcentinib200mg/d
R
Treatment naïve,
BRAF mutant (low tumourburden), BRAF-
up to 40 pts
any AXL expression
any PD-L1 expression
R
*
* Only BRAF mutant pts will be allowed to cross-over at progression on first line KEYTRUDA +/- bemcentinib)
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Summary
The potential of bemcentinib to enhance efficacy of KEYTRUDA is being explored in three phase II trials in NSCLC, TNBC and melanoma with interim readouts expected during the coming months
AXL drives tumour immune evasion & immune suppression = negative feedback
Bemcentinib synergises with ICB in preclinical models
Bemcentinib is a first-in-class selective AXL inhibitor in phase II clinical development
Interim PoC clinical data available for bemcentinib monotherapy and in combination with targeted- and chemotherapy
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Thank you.For further information please visit www.bergenbio.com