BLU-945, a highly potent and selective 4th-generation EGFR ...
嚜篙h
4 -generation
BLU-945, a highly potent and selective
EGFR+/T790M/C797S resistant NSCLC
EGFR TKI for the treatment of
1296P
Stefanie Schalm1, Tom Dineen1, Sun Min Lim2, Chae-Won Park2, John Hsieh1, Rich Woessner1, Zhuo Zhang1, Kevin Wilson1, Meredith Eno1, Doug Wilson1, Brett Williams1, John Campbell1, Chris De Savi1, Faith Stevison1, Caitlin Utt1, Timothy Guzi1, Marion Dorsch1, Klaus Hoeflich1, Byoung Chul Cho2
Medicines Corporation, Cambridge, Massachusetts, USA; 2Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea
C797S
T790M
1.2
129.5
544.4
21.5
2.9
4.4
140.6
5.9
6655.5
4524.8
Gefitinib
4679.8
1.8
16.5
4.6
6707.7
4864.7
4.7
2.1
115.9
11.0
7754.6
>10,000
Osimertinib
450
0
300
1
100
BLU-945
1000
300
100
0
Drug concentration (nM)
10
300
100
10
Osimertinib
6 hrs
pEGFR (Y1068)
EGFR
EGFR
pAKT (S473)
pAKT (S473)
AKT
AKT
pERK
pERK
ERK
ERK
pS6
pS6
S6
S6
GAPDH
GAPDH
Ba/F3 L858R/T790M/C797S
BLU-945 has antitumor activity on EGFR+/T790M and
EGFR+/T790M/C797S driven cancers
Figure 3: Oral administration of BLU-945 showed significant tumor regression in
(A) NCI-H1975 NSCLC CDX (L858R/T790M) tumor model similar to covalent drug osimertinib
and (B) an osimertinib resistant Ba/F3 CDX (ex19del/T790M/C797S) model;
(C) PD analysis for 3A
A.
1000
NCI-H1975 (L858R/T790M)
B.
1000
Table 1: BLU-945 is a subnanomolar EGFR+/T790M/C797S and EGFR+/T790M
inhibitor with >900-fold selectivity over EGFR WT
Mean tumor volume (mm3) ㊣ SEM
Mean tumor volume (mm3) ㊣ SEM
Highly potent inhibitor of EGFR+/T790M/C797S and EGFR+/T790M resistant mutants
Excellent EGFR WT and overall kinome selectivity
BLU-945 only inhibits 1% of the kinome >90% at a concentration of 3 ?M
Selectivity profile enables combinations to cover wide spectrum of resistant mechanisms
Compound
BLU-945
7.1
ex19del
(746每750)
ex19del/
T790M
ex19del/
T790M/C797S
EGFR WT
0.4
0.5
71.4
0.8
0.8
736.3
750
500
250
0.3
3132.7
5654.7
0.2
1394.7
1906.6
9.8
Gefitinib
0.1
1667.2
3921.8
0.1
632.7
1219.7
3.5
Osimertinib
0.9
0.6
5461.6
ATP, adenosine triphosphate; IC50, half maximal inhibitory concentration.
0.8
0.6
649.9
0
T790M (p14)
1.6
5
C797S (p14)
*
TGC ↙ TCC
C.
5
10
Days post treatment initiation
Vehicle
2h
15
BLU-945, 30 mg/kg BIDa
2h
6h
12 h
Vehicle
2h
A.
p-EGFR
p-EGFR
p-ERK
p-ERK
GAPDH
GAPDH
BID, twice daily; PD, pharmacodynamic; QD, once daily; SEM, standard error of the mean. aDosed for 3 days.
15
2h
6h
12 h
Vehicle
6h
300
250
200
150
100
50
0
1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39
Days post treatment initiation
? PDX (ex19del/T790M/C797S) model developed from patient with NSCLC (poorly-moderately
differentiated adenocarcinoma) who progressed through >5 lines of therapy, including
chemotherapy, icotinib, erlotinib, and osimertinib
每 RNA-seq analysis of PDX model suggested EGFR amplification and allelic heterogeneity
B.
LUPF104 (ex19del/T790M/C797S)
LUPF104 (ex19del/T790M/C797S)
BLU-945 + osimertinib
BLU-945 + gefitinib
1500
1250
1000
750
500
250
?
?
?
?
1250
Vehicle
BLU-945, 100 mg/kg BID
Osimertinib, 25 mg/kg QD
Gefitinib, 18.75 mg/kg QD
BLU-945 100 mg/kg +
osimertinib 5 mg/kg
BLU-945 100 mg/kg +
gefitinib 18.75 mg/kg
1000
750
500
250
1750
1500
1500
1500
1250
1000
750
500
250
0
5
10
15
0
Days post treatment initiation
1250
1000
750
500
250
0
5
10
15
0
Days post treatment initiation
1250
1000
750
500
250
0
0
5
10
20
30
40
Days post treatment initiation
50
10
15
Days post treatment initiation
? In preclinical models, BLU-945 demonstrated potent, robust EGFR
pathway inhibition and antitumor activity at well-tolerated doses in the
NCI-H1975 CDX model and osimertinib-resistant CDX and PDX models
of NSCLC
? Combination of BLU-945 with either 1st-generation (gefitinib) or
3rd-generation (osimertinib) EGFR TKI showed enhanced antitumor
activity compared with single agent treatment in an
EGFR+/T790M/C797S-driven PDX model, suggesting potential for
monotherapy and/or combination therapy in the clinical setting
? BLU-945 demonstrated robust antitumor activity in an NCI-H1975
L858R/T790M-luc intracranial model
? Clinical development of BLU-945 monotherapy is expected to begin with
an international phase 1 dose-escalation trial in patients with
EGFR-driven NSCLC in the first half of 2021, and future clinical
development of BLU-945 in combination with other TKIs across multiple
treatment settings is planned
References
0
0
BLU-945,100 mg/kg BID
350
Figure 5: BLU-945 showed significant tumor regression in combination with osimertinib (A)
or (B) gefitinib, in a NSCLC PDX (ex19del/T790M/C797S) model with EGFR amplification and
allelic heterogeneity
0
Vehicle
6h
1750
? BLU-945 is a potentially best-in-class oral, selective, potent,
4th-generation EGFR TKI with activity against the
EGFR+(L858R or ex19del)/T790M/C797S triple mutants
250
a
1750
BLU-945 combination with 1st-and 3rd-generation EGFR TKIs resulted in
further improved tumor regression compared with BLU-945 alone
Vehicle, BID
BLU-945, 30 mg/kg BID
BLU-945, 150 mg/kg QD
BLU-945, 100 mg/kg BID
Osimertinib, 25 mg/kg QD
5
10
Days post treatment initiation
Osimertinib,
25 mg/kg QD
Conclusions
750
0
BLU-945,
100 mg/kg BID
? Oral administration of BLU-945 (100 mg/kg BID) was sufficient for tumor regression in this
PDCX model
? BLU-945 was well tolerated in the PDCX animal model
Ba/F3 ex19del/T790M/C797S
500
Vehicle,
BID
Vehicle BID (n=6)
Osimertinib, 25mg/kg QD (n=7)
BLU-945, 100mg/kg BID (n=6)
400
? PDCX model developed from patient who
progressed on gefitinib and osimertinib
? RNA sequencing (RNA-seq) analysis of PDX
model suggests EGFR amplification and
allelic heterogeneity
0
0
Erlotinib
4
Years
Enzyme activities IC50 (nM) at 1 mM ATP with enzyme-inhibitor pre-incubation
L858R/
T790M/C797S
3
1500
BLU-945 is a highly potent and selective EGFR+ T790M/C797S inhibitor
L858R/
T790M
2
ACG ↙ ATG
10
B.
BLU-945
1
1000
300
Drug concentration (nM)
100
Osimertinib
Ba/F3 ex19del/T790M/C797S
L8585R
1
Figure 2: BLU-945, but not osimertinib, inhibits the EGFR pathway in
(A) ex19del/T790M/C797S and (B) L858R/T790M/C797S driven Ba/F3 cell lines
A.
500
ex19del/T790M/C797S
*
BLU-945
Results
ex19del/
T790M/C797S
3.9
C797S
? BLU-945 activity on EGFR mutants and EGFR wild-type (WT) was tested in biochemical assays
and cellular phosphorylation-specific EGFR AlphaLisa assays
? The in vivo antitumor activity of BLU-945 was evaluated in an NCI-H1975 cell line-derived tumor
xenograft (CDX) model, as well as in osimertinib-resistant CDX-derived and patient-derived
xenograft (PDX) models of NSCLC
L858R/
T790M/C797S
>10,000
pEGFR (Y1068)
Methods
?
?
?
?
L858R
Erlotinib
Blueprint
EGFR+ C797S
Osimertinib
A431
(EGFR WT)
del19/T790M
Mean tumor volume (mm3) ㊣ SEM
EGFR TKI
T790M
Osimertinib
PC-9
(ex19del)
BLU-945
C797S
1st-generation
NCI-H1975
(L8585R/T790M)
del19
YU-1097 (ex19del/T790M/C797S)
Bioluminescence photons/sec / 106
Compound
Engineered Ba/F3 cell lines
B.
PDC
Osimertinib
Gefitinib
Figure 6: Oral administration of BLU-945 100 mg/kg resulted in intracranial activity in a
NCI-H1975 L858R/T790M-luc intracranial model
Bioluminescence photons/sec / 106
Cell lines
Figure 1: Rationale for the development of BLU-945 targeting EGFR+/T790M/C797S
T790M
A.
Cellular pEGFR inhibition IC50 (nM)
10
? Osimertinib, a 3rd-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor
(TKI), has favorably impacted the treatment of patients with EGFR-driven non-small cell lung
cancer (NSCLC) and extended overall survival compared with older EGFR TKIs, including the
1st-generation agent gefitinib1
? The C797S mutation is the most frequent on-target resistance mechanism to osimertinib and
there are no targeted therapies approved for patients with disease progression2
? We are developing targeted agents to treat C797S-driven resistance with the goal of improving
patient outcomes and prolonging clinical benefit
每 BLU-945 (Figure 1) is a 4th-generation EGFR TKI designed to target the
EGFR+(L858R or ex19del)/T790M/C797S triple mutant following treatment with a
1st-line 1st-generation EGFR TKI and 2nd-line osimertinib3,4
每 A second 4th-generation EGFR TKI aims to target the EGFR+/C797S double mutant following
treatment with 1st-line osimertinib3
? Here we describe preclinical data for BLU-945 supporting initiation of clinical development in
EGFR-driven NSCLC
BLU-945 demonstrates intracranial activity when administered orally
Bioluminescence photons/sec / 106
Table 2: BLU-945 potently inhibits EGFR+/T790M/C797S and EGFR+/T790M autophosphorylation
Mean tumor volume (mm3) ㊣ SEM
Background
Figure 4: In an (A) osimertinib-resistant EFGR ex19del/T790M/C797S patient-derived cell line
xenograft (PDCX) model, (B) oral administration of BLU-945 led to significant tumor regression
Mean tumor volume (mm3) ㊣ SEM
BLU-945 inhibits EGFR+/T790M/C797S driven pathway activation
0
1Blueprint
0
10
20
30
40
Days post treatment initiation
50
Single agent BLU-945 was sufficient for tumor stasis in this model
Co-dosing BLU-945 with either osimertinib or gefitinib led to significant tumor regression
Single agent and combination doses were well tolerated in the animal model
Data suggest that BLU-945 can be combined with other EGFR TKIs to address
allelic EGFR heterogeneity
1. Ramalingam SS et al. N Engl J Med. 2020;382:41每50; 2. Lazzari C et al. J Thorac Dis. 2020;12:2851每2858; 3. Leonetti A et al. Br J Cancer. 2019;121:725每737;
4. Mok, TS et al. N Engl J Med. 2017;376:629每640.
Acknowledgments
Some of the cell assays and in vivo experiments were conducted at Pharmaron Beijing Co., Ltd (China), Shangai LIDE Biotech Co., Ltd (China), WuXi AppTec Co., Ltd
(China). Medical writing support was provided by Cristina Tomas, PhD, and editorial support was provided by Michelle Seddon, Dip Biotech Co., Psych, all of Paragon,
Knutsford, UK, supported by Blueprint Medicines Corporation, Cambridge, MA, according to Good Publication Practice guidelines.
Disclosures
Study sponsored by Blueprint Medicines Corporation. BW, CS, CU, DW, FS, JC, JH, KH, KW, MD, ME, RW, SS, TD, TG, and ZZ are employees of Blueprint Medicines
Corporation, or were at the time the work presented was developed, and own stock. BCC received research funding from Abbvie, AstraZeneca, Bayer, Blueprint Medicines
Corporation, Champions Oncology, Dizal Pharma, Dong-A ST, Eli Lilly, GIInnovation, Janssen, Medpacto, MOGAM Institute, MSD, Novartis, Ono, Yuhan; consulted for
AstraZeneca, Blueprint Medicines Corporation, BMS, Boehringer-Ingelheim, Eli Lilly, Janssen, Medpacto, MSD, Novartis, Ono, Pfizer, Roche, Takeda, Yuhan; owns stock in
Bridgebio therapeutics, Gencurix Inc, KANAPH Therapeutic Inc., TheraCanVac Inc.; participated in scientific advisory board for KANAPH Therapeutic Inc; reports royalties
from Champions Oncology; and is the founder of Daan biotherapeutics. C-WP and SML and have no disclosures.
Presented at ESMO 2020, September 14每18, 2020, Virtual Format. Please contact medinfo@ for permission to reprint and/or distribute
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