The KRASG12C Inhibitor, MRTX849, Provides Insight Toward ... · 10/28/2019 · MRTX849 Achieves...
Transcript of The KRASG12C Inhibitor, MRTX849, Provides Insight Toward ... · 10/28/2019 · MRTX849 Achieves...
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NASDAQ: MRTX
Targeting the genetic and immunological drivers of cancer
The KRASG12C Inhibitor, MRTX849, Provides Insight Toward Therapeutic Susceptibility of KRAS Mutant Cancer
Presented at AACR-NCI-EORTC International Conference on Molecular Targets
October 28, 2019Jamie Christensen, Ph.D.
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Targeting KRAS Has Been Historically Challenging
K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactionsJonathan M. Ostrem,1,* Ulf Peters,1,* Martin L. Sos,1 James A. Wells,2 and Kevan M. Shokat1
5 4 8 | N A T U R E | V O L 5 0 3 | 2 8 N O V E M B E R 2 0 1 3
Direct, Reversible Inhibitors
• Smooth surface
• High affinity for & high intracellular concentrations of GTP/GDP
Downstream Effector Inhibitors
Raf / MEK and PI3K / AKT / mTOR
• Inhibition of WT signaling resulting in low therapeutic index
• Incomplete inhibition of signaling downstream of KRAS mut
Covalent Inhibition of KRAS G12C • Binding in the switch II pocket of GDP KRAS• Covalent bond to cysteine 12 • Locked in the inactive conformation
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KRAS G12C Background—Reminders
• KRAS G12C mutations prevalent in (MSKCC):
– Lung adenocarcinoma: 14%
– CRC: 4%
– PDAC: 2%
– Other: gastric, uterine/endometroid, CUP. Etc
• KRAS G12C is a transversion mutation—common in smokers
• KRAS G12 mutations impair intrinsic GTPase activity and GTP hydrolysis
• Of KRAS mutations at codon 12, G12C exhibits lower intrinsic GTPase impairment and higher sensitivity to signals that modify extrinsic GTP hydrolysis
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Drug Discovery Progression Toward MRTX849
• The addition of the C2 substituent significantly improved solubility and cellular potency and demonstrated more rapid modification of the protein compared with compound 1
• The cyanomethyl substituent on the piperazine further improved potency and allowed for the elimination of the naphthyl 3-hydroxyl group improving ADME properties
• The 8-positon of the naphthyl group to filled a hydrophobic pocket and increased potency an additional 5-fold
• Warhead modification and final optimization for reactivity and bioavailability provided MRTX849
13 hour time point in H358 cells; 224 hour time point in MIA PaCa cells
N
NNHO
N
N
O
Compound 1pERK IC50 = 7.6 µM1
N
NNHO
N
N
O
ON
Compound 2pERK IC50 = 70 nM1
N
NN
N
N
O
ON
NC
Compound 3pERK IC50 = 5 nM1
N
NN
N
N
O
ON
NC
CH3
MRTX1257pERK IC50 = 900 pM1
pERK IC50 = 6 nM2
N
NN
N
N
O
ON
NC
Cl
F
MRTX849pERK IC50 = 14 nM1
pERK IC50 = 5 nM2
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MRTX849 Identified as a Potent, Selective, Orally Bioavailable Inhibitor of KRAS G12C
• MRTX849 only binds to inactive, GDP-bound KRASG12C
• Systematic adjustment of acrylamide reactivity and optimization of the naphthyl 8-substituent led to MRTX849, which shows greater stability in whole blood and hepatocytes
• Oral PK properties of MRTX849 improved with 50% oral bioavailability and >20 hour half-life projected in humans. Extensive tissue distribution observed with Vdss of > 10 L/kg projected in humans.
MW / clogP / tPSA 604/5.8/87
Kinact/KI 35 +/-0.3mM-1s-1
Cellular Potency (24h, MIA PaCa) 5 nM
5 min/3 µM Protein Modification 66%
Hepatocyte ER% (m/h) 61 / 50
Plasma Protein Binding % (m/h) 99.0 / 98.3
F% (m/h) 63 / 50*
* Human projected F% from PBPK modeling
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MRTX849 Achieves Near Complete KRAS Modification and Inhibition In Tumors In Vivo
Normalized pERK and pS6 Inhibition6 h post administration/single dose
pERK Veh pERK 100 mpk pS6 Veh pS6 100 mpk
• Near complete inhibition of KRAS observed in tumor cells between 30 & 100 mg/kg—based on IHC
• No additional activity at higher doses• Unmodifiable pool of KRAS G12C and stromal cell
signaling impact magnitude of PD effect
KRAS G12C Protein Modification after a single dose
Veh0.5
hr2h
r6h
rVeh
0.5hr
2hr6h
rVeh
0.5hr
2hr6h
r-20
0
20
40
60
80
100
0.01
0.1
1
10
Plasma C
oncentration (ug/mL)
KR
AS
Enga
gem
ent (
% m
odifi
ed)
**10mg/kg 30mg/kg 100mg/kg
**Veh 10 30 100
0
1
2
3
Nor
mal
ized
Exp
ress
ion
MRTX849 (mg/kg)Veh 10 30 100
0.0
0.5
1.0
1.5
Nor
mal
ized
Exp
ress
ion
MRTX849 (mg/kg)
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MRTX849 Dose-dependent Anti-Tumor EfficacyMaximally Effective Dose Confirmed Between 30-100 mg/kg
• The maximally effective dose of MRTX849 was identified as 100 mg/kg QD• Doses of 200 mg/kg or greater were well-tolerated and did not improve antitumor activity• Near complete target modification/inhibition correlates with maximal antitumor activity
0 10 20 30 40 50 60 70 800
200
400
600
800
1000
1200
Study Day
Tum
or v
olum
e (m
m3 ) 3 mg/kg
10 mg/kg30 mg/kg100 mg/kg
1 mg/kgVehicle
MIA PaCa-2 Xenograft Model
0 5 10 15 20 25 30 35 40 450
200
400
600
800
1000
1200
Day
Tum
or V
olum
e (m
m3 )
Vehicle1 mg/kg3 mg/kg10 mg/kg30 mg/kg100 mg/kg
H358 Xenograft Model
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• AUC and Cave most closely correlated with antitumor activity based on schedule dependence and infusion studies
• AUC0-24 and Cave at 30 & 100 mg/kg, which demonstrated maximum antitumor activity in sensitive & partially sensitive models; respectively, were used for human efficacious exposure projections
• Free-fraction adjusted target AUCs0-24 were calculated as 14.3 ug*h/mL and 37.1 ug*h/mL
• PBPK Link modeling approaches (PK-SimTM or GastroPlus 9.5TM) were applied to project a human efficacious target dose and exposure dose and fit human data well
Derivation of Target Plasma Levels for MRTX849 Clinical Trials
Model Dose (mg/kg)
AUC0-24 (ug*h/mL)
FF adj AUC0-24 (ug*h/mL)
% Regression (day)
Projected Efficacious Total/FF adj AUC (human, ug*h/mL)
Projected Efficacious Total/FF adj Cave (human, ng/ml)
MIA PaCa-2 10 7 0.07 -52% (13)MIA PaCa-2 30 24 0.24 -96% (13) 14.3 600
HCC-44 100 63 0.63 -61% (13) 37.1 1450
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MRTX849 Anti-Tumor Efficacy Across Models Studies Designed to Identify Response/Resistance Correlates
• A panel of in vivo tumor models was utilized for response correlations (obviate in vitro disconnect)• 100 mg/kg (max efficacious dose)• No significant activity in non-G12C models
• >30% tumor regression observed in ~65% of all models (17/26) suggesting potential for single agent development
• A 75% ORR In NSCLC, while CRC models were moderately responsive (BRAFi in CRC?)
• No significant correlation with co-occurring genetic alterations
• HER family score & cell cycle defects show trend
• Incomplete modification of KRAS in selected models potentially due to differences in extrinsic modulation of GTP hydrolysis
A549
HCT
116
H12
99
KYSE
-410
LU11
693
LU64
05SW
1573
CR62
56H
2122
LU25
12H
2030
PA13
83CR
6243
LU11
692
SW83
7SW
756
LU11
47LU
1155
4LU
99H
CC44
LU51
91LU
5212
H35
8Ca
lu-1
LU52
45H
1373
LU65
LU25
29M
iaPa
ca-2
-100
-50
0
50
100
non-G12C G12C
EsophagusLung PDX Colon PDXCervixPancreasLung Colon
Pancreas PDX
CDX X X X X X X X X X X X X X
PDX X X X X X X X X X X X X X
KRAS G12C MAF (%) 39 56 97 100 36 100 63 100 55 62 70 57 NA 54 45 54 100 100 100 67 84 93 99 92 100 98
KRAS CNV 3 NA 13 2 2 2 5 2 4 3 NA 2 NA 3 NA 5 2 NA NA 3 4 6 3 6 4 3
STK11 mut N Y N N N Y N Y N N N N Y Y N N N N Y N N N N Y N N
KEAP1 mut N Y N N N Y N Y N N N N N N Y N Y Y Y N N N N N N N
HER family Y N Y N Y Y Y N Y Y Y Y NA Y N N N N Y Y N Y Y N N NCDKN2A homodel N Y Y Y N Y N N Y N N* N NA N Y Y N N N N N N N N N Y
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MIA PaCa-2 H1373
Veh QD x 1 QD x 524 6 24 246
Veh
6 24 6 24QD x 1 QD x 5
24Veh
6 24 6 24QD x 1 QD x 5
24
Complete Response
Veh6 24 6 24QD x 1 QD x 7
24Veh
6 24 6 24QD x 1 QD x 7
24Veh
6 24 6 24QD x 1 QD x 7
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H358 H2122Partial response/Refractory
Mechanisms of Response and Resistance to MRTX849Durable Inhibition of ERK (but not S6) tracks with tumor response
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Mechanisms of Intrinsic Resistance to MRTX849Feedback Signaling and Bypass Pathways---NCI-H358
VehiclepS6
30m
pk Q
D x
130
mpk
QD
x 3
30m
pk Q
D x
3
Vehicle
pERK6hr 48hr24hr
30m
pk Q
D x
1
2 0 2 5 3 0 3 5 4 0 4 5 5 00
2 5 0
5 0 0
7 5 0
1 0 0 0
D a y
Tum
or V
olum
e (m
m3 )
V e h ic le 1 m g /k g 3 m g /k g 1 0 m g /k g 3 0 m g /k g
1 0 0 m g /k g
Dose–dependent Anti-Tumor Efficacy in H358
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Pharmacogenomic Screens to Identify Combination Targets and Resistance Mechanisms
• Screened ~90 agents in combination with MRTX849 across 8 lung cell lines in vitro that were partially MRTX849-resistant in vivo.
• MRTX849-anchored CRISPR screens: ~1,000 genes, 4 KRASG12C cell lines, in vitro/in vivo
• Top combination targets: EGFR family, FGFR1, SOS1, SHP2, mTOR, CDK4/6.
• Top resistance genes: CDKN2A, KEAP1, RB1, PTEN, NRAS.
GTP-KRASG12C
RSK
MEK
ERK
cRAF
PTEN
AKT
PI3K
mTOR
S6
S6K1
SOSSHP2
EGFR
MYC
CCND1
CDK4/6 RB1 E2F
Grb2
GDP-KRASG12C
NF1RAS GAPs
RTKs FGFR1
KEAP1NRAS
Class HER CDK mTOR/PI3K SRCMRTX KRAS
G12CiCalu-1H1373H1792H2030H2122
HCC1171HCC44
LU99SW1573
SW837
Small Mol Combo Screen MRTX849 Combination Targets and Resistance Gene Map
KRASMYC
mTORSHP2 CDK6
NRASKEAP1
RB
CCND1
Log FC Veh D14 / plasmid
Log
FC 8
49 D
14 /
plas
mid
SOS1CRAF
PTEN
S6
LOF Confers Resistance
MRTX849 Combination
Targets
CRISPR Screens
H2122 in vivo
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Conclusions
• MRTX849 is a novel small molecule KRASG12C inhibitor in clinical trials
• Maximal and durable inhibition of KRAS liked to defined PK parameters maximizes response
• Tumors harboring KRAS G12C are broadly dependent on KRAS for growth and survival…….
• ……However, complex signaling circuitry in some KRAS-dependent tumors can result in partial bypass of dependence
• Mechanisms are heterogeneous and relate to feedback or bypass signaling, enhanced nucleotide cycling, and KRAS-independent cell cycle transition
• Rational combination approaches provide a practical solution to address heterogeneity
• Target plasma derivation and corelative science will aid in rational development of MRTX849
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AcknowledgmentsMirati Tx Array CollaboratorsMatt Marx J. Brad Fell Channing Der (UNC)Jill Hallin John Fischer Adrienne Cox (UNC)Peter Olson Brian Baer Piro Lito (MSK)Ruth Aranda Nick Saccamano Pasi Janne (DFCI)Jeff Winkelman Mike Burkard Chip Petricoin (GMU)Andrew Calinisan Dylan HartleyLars Engstrom James BlakeDavid Briere Josh BallardHarrah Chiang Larry BurgessLauren Hargis Mark ChicarelliNiranjan Sudhakar John J. GaudinoVickie Bowcut Lauren Hanson
Tony TangPavel Savechenkov
Monceros Biosystems Guy VigersAdam Pavlicek Karyn BouhanaJulio Fernandez-Banet Ron HinklinSole Gatto Eric Hicken