Characterization of FGFR signaling pathway as therapeutic targets ...
Targeting FGFR alterations in cancer with BGJ398, a...
Transcript of Targeting FGFR alterations in cancer with BGJ398, a...
Randi Isaacs MD
Novartis Institutes for BioMedical Research Translational Clinical Oncology
Targeting FGFR alterations in cancer with BGJ398, a selective FGFR inhibitor
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Targeting FGFRs - The original hypothesis
! FGF/R Genetic Alterations in Cancer:
! FGFR3 Activating Mutations: • superficial bladder cancer: 70% • invasive bladder cancer: 10%
! GOF studies showed mutant FGFR3 transforms NIH3T3 cells
! LOF studies showed dependence on FGFR3 mutant
FGFR
FRS2
GRB2 SOS Ras GTP
Ras GDP
MAPK
PI3K
Proliferation
Survival
FGF
4 FGFRs, 22 FGFs
Ig I
Ig II
Ig III
acid box
TM
TK-1
TK-2
G372C
K652E
R248CS249C
FGFR3 mutations in bladder cancer
Y375C
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Targeting FGFRs - The extended hypothesis
FGF/R Genetic Alterations in Cancer: ! Activating Mutations:
• FGFR3: bladder • FGFR2: endometrial, lung • FGFR4: rhabdomyosarcoma
! Gene amplification • FGFR1: breast, lung • FGFR2: gastric, breast • FGF19: liver
! Gene rearrangements → fusions • FGFR1, FGFR2, FGFR3:
cholangio, GBM, bladder, prostate, breast, lung
YM Wo et al Cancer Discovery 2013
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Biochemical kinase assay
Cellular FGFR autophosphorylation assay
BGJ398 is a potent pan-FGFR inhibitor
BGJ398 has predominant activity against FGFR1, FGFR2 and FGFR3
FGFR1 FGFR2 FGFR3 FGFR4 IC50 µM 0.0009 0.0014 0.001 0.06
FGFR1 FGFR2 FGFR3 FGFR4
0.0065 0.0058 0.0058 0.225
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Kinase IC50 nM Kinase IC50 nM Kinase IC50 nM
FGFR1 0.9 HER1 > 10000 PAK2 ac. > 10000 FGFR2 1.4 HER2 > 10000 PDGFRα > 10000 FGFR3 1 HER4 > 10000 PDK1 > 10000 FGFR4 60 IGF1R > 10000 PI3Ka > 10000
INS1R > 10000 PI3Kb > 10000 ABL 2300 IRAK4 > 10000 PI3Kd > 10000 ALK > 10000 JAK1 > 10000 PIK4b > 9000
Aurora > 10000 JAK2 > 10000 PIM2 > 10000 AXL > 10000 JAK3 > 10000 PKA > 10000 BTK > 10000 JNK2 > 10000 PKBa > 10000
CAMK2 > 10000 JNK3 > 10000 PKCa > 10000 CK1 > 10000 KIT 750 PKCθ > 10000
CDK1 > 10000 VEGFR2 180 PKN1 > 10000 CDK2 > 10000 LCK 2500 PKN2 > 10000 CDK4 > 10000 LYN 300 PLK1 > 10000 COT1 > 10000 MER > 10000 RET > 10000 CSK > 10000 MET > 10000 ROCK2 > 10000
ERK2 > 10000 MK2 > 10000 RON > 10000 EPHA4 > 10000 MK5 > 10000 SRC > 10000 EPHB4 > 10000 MNK1 > 10000 S6K > 10000
FAK > 10000 MNK2 > 10000 SYK > 10000 FLT3 > 10000 MSTIR > 10000 TYK2 > 10000 FYN 1900 mTOR > 9000 VPS34 > 9000
GSK3β > 10000 P38a > 10000 YES 1100 HCK > 10000 P38g > 10000 ZAP70 > 10000
Biochemical assay BGJ398 is selective against a panel of kinases
BGJ398
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The Cancer Cell Line Encyclopedia BGJ398 profiled in 748 cell lines
BG
J398
IC50
µM
~5%
> 8
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BGJ398 cellular sensitivity is greatest among the FGFR genetically altered cell lines
0.5
1.5
2.5
BG
J398
IC50
uM
FGFR wt FGFR genet. alter.
48% 3% | Cholangiocarcinoma Foundation | 06Feb15 | RIsaacs | 8
BGJ398 cellular sensitivity is greatest among the FGFR genetically altered cell lines
0.05
0.1
0.15
0.20
0.25
BG
J398
IC50
uM
FGFR fusion FGFR1 amp FGFR2 amp
FGFR2 mut
FGFR3 mut | Cholangiocarcinoma Foundation | 06Feb15 | RIsaacs | 9
BGJ398 inhibits proliferation of bladder cancer cell lines with FGFR3 genomic alterations
>3000
2500
2000
1500
1000
500
0
RT1
12/8
2
RT1
12
MG
HU
3
RT4
SW78
0
TCC
SUP
HT1
197
HTB
9
SW17
10
647-
V VM
CU
B1
UM
UC
3
T24
KU
1919
J82
BFT
C80
5
HT1
376
EJ19
8
FGFR3 mutation
FGFR3 fusion
FGFR3 wt
*
*
*FGFR3 not expressed
BG
J398
IC50
nM
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BGJ398 shows in vivo anti-tumor activity in the RT112 bladder cancer rat model (FGFR3 fusion)
BGJ398
Vehicle 5 mg/kg 10 mg/kg
pFRS2
pMAPK
MAPK
3h
BGJ398
pFRS2
pMAPK 24h
ß-tubulin
BGJ398
Vehicle 5 mg/kg 10 mg/kg
BGJ398
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BGJ398 Is Effective in FGFR1amp Lung Cancer Models
BGJ398 IC50 nM
FGFR
1 C
opy
Num
ber
Pharmacologic Activity of BGJ398 in Lung Cancer Cell Lines (N = 112)
Antitumor Efficacy in H1581 FGFR1amp Lung Cancer Xenografts
α-actinin
DM
SO
DMS 114 NCI-H1581
pFRS2
> 4 FGFR1 copies
Graus-Porta D, et al. AACR 2012 [abstract 854]; Wolf J, et al. AACR 2012 [abstract LB-122].
! BGJ398 is effective in DMS 114 and NCI-H1581 lung cancer models • Pharmacologic activity, with IC50 < 0.04 nM • Reduced FGFR signaling, as determined by a
decrease in phosphorylated FRS2 • Antitumor activity in xenografts
BGJ398
DM
SO
BGJ398
H15
81 T
umor
Vol
ume,
mm
3
Vehicle qd BGJ398 10 mg/kg qd BGJ398 20 mg/kg qd BGJ398 45 mg/kg qd
**One-way ANOVA: Dunnett vs vehicle.
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PTX’s with FGFR2 amplification respond to BGJ398
CHGA010
Vehicle BGJ398 15mg/kg
pFGFR2
FGFR2
pErk1/2
Erk1/2
β-tubulin
GAM033 (Crownbio)
Vehicle BGJ398 15mg/kg
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BGJ398 FIM Phase 1 study design
Arm 1: ~20-40 FGFR1 amplified squamous NSCLC continuous daily dosing
Arm 2: 21 FGFR ampl / mut solid tumors continuous daily dosing
Oral, once-daily BGJ398, 28-day cycle
Dose escalation
Decision to dose escalate based on review of toxicity (DLT) in Cycle 1 and other clinical, PK, and laboratory data
Dose levels
Solid tumors FGFR1 or 2 amplified
or FGFR3 mutated or other FGFR genetic alterations
MTD declaration 28Jun 2012 125mg QD
Dose expansion
Arm 3: ≥ 10 solid tumors with FGFR genetic alterations 3 weeks on/1 week off dosing
Arm 4: Up to 80 bladder cancer with FGFR3 mut/ fusion 3 weeks on/1 week off dosing
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Baseline patient characteristics
N = 119 Median age (range), years 59 (25-86)
Age ≥ 65 years, n (%) 31 (26)
Male / female, n (%) 52 (44) / 67 (56)
WHO performance status, n (%)
0 / 1 / 2 61 (52) / 54 (46) / 3 (3)
Primary tumor type, n (%)
Breast 42 (35)
Lung 42 (35)
Bladdera 11 (10)
Other 24 (20)
Median prior lines of therapy, n 3 Data as of September 9, 2014 cutoff a Includes urothelial cell carcinoma of any origin.
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Patient disposition
N = 119 Treatment ongoing, n (%) 8 (7)
Treatment discontinued, n (%) 111 (93)
Primary reason for discontinuation, n (%)
Disease progression 78 (66)
Withdrew consent 14 (12)
Adverse event 12 (10)
Death 5 (4)
Other 2 (2)
• Most frequent AEs leading to discontinuation were eye disorders (n = 4)
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Treatment emergent adverse events (all grades) regardless of study drug relationship
All patients =115; n (%) 5-60 mg n = 19
100 mg n = 6
125 mg (c) n = 53
150 mg n = 6
125 mg (i) n = 31
Hyperphosphatemia 5 (26) 6 (100) 43 (81) 5 (83) 23 (74)
Constipation 1 (5) 3 (50) 28 (53) 0 15 (48)
Stomatitis 0 4 (67) 23 (43) 2 (33) 12 (39)
Decreased appetite 3 (16) 3 (50) 24 (45) 3 (50) 13 (42)
Diarrhea 7 (37) 5 (83) 15 (28) 1 (17) 11 (36)
Fatigue 7 (37) 0 16 (30) 1 (17) 11 (36)
Nausea 6 (32) 4 (67) 14 (26) 3 (50) 9 (29)
Asthenia 1 (5) 2 (33) 11 (21) 1 (17) 6 (19)
Blood creatinine increased 1 (5) 2 (33) 12 (23) 1 (17) 7 (23)
ALT increased 2 (10) 1 (17) 9 (17) 1 (17) 3 (10)
AST increased 2 (10) 1 (17) 11 (21) 1 (17) 3 (10) | Cholangiocarcinoma Foundation | 06Feb15 | RIsaacs | 17
BGJ398 pharmacokinetics ! Consistent
accumulation upon multiple dosing at doses ≥ 60 mg
! Accumulation in the range of 4- to 8-fold on day 15 (≥ 60 mg) likely due to autoinhibition of Cyp3A4 clearance pathways
125 mg/day, mean (CV%) Day 1 (n = 40) Day 15 (n = 31)
Cmax, ng/mL 102 (73) 253 (51)
AUClast, h⋅ng/mL 890 (101) 3614 (57) Data as of September 24, 2013 cutoff.
Time, h 0
1
10
100
1000
0 1 2 3 4 6 24
125 mg/day
BG
J398
Con
cent
ratio
n, n
g/m
L
Day 15
Day 1
8
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BGJ398 treatment causes soft tissue mineralization in preclinical tox species
! Linked to elevated systemic levels of Pi, VitD3
! Preceded the onset of tissue mineralization
! Inactive analogue of BGJ398 did not alter Pi, VitD3
Alveolar Mineralization
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FGF23: an FGFR ligand that controls phosphate homeostasis and VitD3 metabolism
Kidney: Proximal tubule
FGFR1
ɑ-KLOTHO
FGF23
Lumen Basolateral membrane
_
Bone: Osteocytes
FGF23 VitD3 metabolism
Pi re-absorption _ FGF23
Pi ↑ VitD3 ↑
• FGF23 and ɑ-klotho ko mice develop tissue mineralization and hyperphosphatemia
• Patients with familial tumoral calcinosis (LOF mutations in FGF23) suffer from hyperphosphatemia and ectopic calcifications
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Can we identify a monitorable biomarker that predicts exposures associated with pathway inhibition?
Biomarker study:
! Reversibility upon treatment discontinuation?
Biomarker AUC Sensitivity Specificity
Pi 0.9 1 0.88
! ROC Analysis: measures diagnostic power of a biomarker
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vehicle BGJ398 10mg/kg
BGJ398 20mg/kg
5
7
9
11
Pi (
mg/
dL)
vehicle BGJ398 10mg/kg
BGJ398 20mg/kg
Treatment days
1 3 7 15
Hyperphosphatemia as a pharmacodynamic marker of FGFR pathway inhibition ! Biologic rationale and
mechanism of action1
! The FGF23/FGFR pathway normally mediates phosphate secretion from renal tubules
! Dose- and exposure-related hyperphosphatemia seen in majority of patients at doses ≥ 100 mg daily ! Not seen with less potent FGFR
inhibitors (multi-TKIs)
! Managed through dietary restrictions, phosphate-lowering therapy, and drug interruptions
• Serum Pi level in cycle 1 increases after exposure to BGJ398
• Dose interruption results in quick decrease of serum Pi level
Individual Time Plot of Phosphate in 100-mg Dose Cohort
1 Dienstmann R, et al. Ann Oncol. 2013;25:552-563.
Study Day of Assessment
-1.0
-0.5
0.0
1.0
1.5
2.0
Baseline 10 20 30 40 50 60
Cha
nge
From
Bas
elin
e
of P
hosp
hate
, mm
ol/L
0.5
Dose delay
Dose reduction (60 mg/day)
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Hyperphosphatemia leads to predictable dose interruptions and empiric selection of alternate dosing schedule
100 mg/day continuous
n = 6
125 mg/day continuous
n = 43 Median time to first dose interruption or reduction, days 23.5 22
Median duration of first dose interruption, days 4.5 7
100 mg Continuous Dosing 0
20
40
60
80
100
160
Day
s to
the
Firs
t Dos
e In
terr
uptio
n/R
educ
tion
120
140
125 mg Continuous Dosing Data as of 31JAN14 cutoff | Cholangiocarcinoma Foundation | 06Feb15 | RIsaacs | 23
Intermittent dosing schedule demonstrates greater tolerability and compliance
125 mg/day Continuous n = 53, n (%)
125 mg/day 3 Weeks On/1 Week Off
n = 31, n (%)
Cycle 1 dose interruptions 24 (45) 5 (16)
Cycle 1 dose reductions 13 (24) 2 (6)
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BGJ398 has clinical activity across multiple tumor types with FGFR genetic alterations
Bes
t Per
cent
Cha
nge
from
Bas
elin
e
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62-year-old male with metastatic cholangiocarcinoma to liver with FGFR2-BICC1 gene fusion Baseline and 8-week follow-up CT scans
Patient history and course High throughput NGS demonstrated FGFR2 gene fusion and 27 mutations, including TP53 (MI-ONCOSEQ) Received 6 cycles 5-FU/Gem/CDDP with best response SD BGJ398 125 mg qd administered for 3 cycles, dose reduced to 100 mg for hyperphosphatemia/grade 1 elevated creatinine Disease progression at end of cycle 3
Wu et al Cancer Discovery 2013
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Phase 2 study of BGJ398 in cholangiocarcinoma opened in July 2014
BGJ398 125mg qd x 21 days (28d cycles)
N ≈55 Advanced cholangiocarcinoma w/FGFR2 gene fusion/other FGFR genetic alteration
Prior CDDP-based chemotherapy or gemcitabine-containing therapy for pts unable to receive CDDP
Continue until disease progression, unacceptable toxicity, withdrawal of consent or death
Primary endpoint: - ORR Secondary endpoint: - PFS, DCR, BOR, OS - Safety - PK
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Conclusions ! The 125-mg once-daily dose was identified as the MTD ! BGJ398 has a tolerable safety profile, with
hyperphosphatemia an on-target and manageable AE ! The 3-weeks-on/1-week-off intermittent schedule
demonstrates greater compliance and tolerability vs continuous dosing
! Clinical activity has been observed in multiple tumor types, patients with FGFR3-mutated bladder cancer may be especially sensitive to BGJ398 ! Refinement of molecular profile for Identification of sensitive
subpopulations of patients with other tumors is ongoing
! Clinical trials in bladder cancer, cholangiocarcinoma, glioblastoma, squamous NSCLC, and endometrial cancer are open or planned
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