BLU-945, a highly potent and selective 4th-generation EGFR ...

th

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) ¡À SEM

Mean tumor volume (mm3) ¡À 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¨C750)

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 ¡ú 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

¨C 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 ¡ú 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) ¡À 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

¨C 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

¨C 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) ¡À 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) ¡À 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¨C50; 2. Lazzari C et al. J Thorac Dis. 2020;12:2851¨C2858; 3. Leonetti A et al. Br J Cancer. 2019;121:725¨C737;

4. Mok, TS et al. N Engl J Med. 2017;376:629¨C640.

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¨C18, 2020, Virtual Format. Please contact medinfo@ for permission to reprint and/or distribute

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