Targeting FGFR alterations in cancer with BGJ398, a selective FGFR inhibitor Randi Isaacs MD Novartis Institutes for BioMedical Research Translational Clinical Oncology
2 | Cholangiocarcinoma Foundation | 06Feb15 | RIsaacs |
Targeting FGFRs - The original hypothesis ! FGF/R Genetic Alterations in Cancer:
4 FGFRs, 22 FGFs FGFR3 mutations FGF in bladder cancer Ig I
! FGFR3 Activating Mutations:
acid box
• superficial bladder cancer: 70% • invasive bladder cancer: 10%
Ig II Ig III
! GOF studies showed mutant FGFR3 transforms NIH3T3 cells
GRB2 SOS FRS2
PI3K
! LOF studies showed dependence on FGFR3 mutant
FGFR R248C S249C Ras GTP
G372C
TM Ras Y375C GDP
TK-1
SurvivalTK-2
MAPK
K652E
Proliferation
3 | Cholangiocarcinoma Foundation | 06Feb15 | RIsaacs |
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
4 | Cholangiocarcinoma Foundation | 06Feb15 | RIsaacs |
BGJ398 is a potent pan-FGFR inhibitor Cellular FGFR autophosphorylation assay
Biochemical kinase assay
IC50 µM
FGFR1
FGFR2
FGFR3
FGFR4
FGFR1
FGFR2
FGFR3
FGFR4
0.0009
0.0014
0.001
0.06
0.0065
0.0058
0.0058
0.225
BGJ398 has predominant activity against FGFR1, FGFR2 and FGFR3 5 | Cholangiocarcinoma Foundation | 06Feb15 | RIsaacs |
BGJ398 is selective against a panel of kinases Biochemical assay
BGJ398
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Kinase
IC50 nM
Kinase
IC50 nM
Kinase
IC50 nM
FGFR1 FGFR2 FGFR3 FGFR4
0.9 1.4 1 60
ABL ALK Aurora AXL BTK CAMK2 CK1 CDK1 CDK2 CDK4 COT1 CSK ERK2 EPHA4 EPHB4 FAK FLT3 FYN GSK3β HCK
2300 > 10000 > 10000 > 10000 > 10000 > 10000 > 10000 > 10000 > 10000 > 10000 > 10000 > 10000 > 10000 > 10000 > 10000 > 10000 > 10000 1900 > 10000 > 10000
HER1 HER2 HER4 IGF1R INS1R IRAK4 JAK1 JAK2 JAK3 JNK2 JNK3 KIT VEGFR2 LCK LYN MER MET MK2 MK5 MNK1 MNK2 MSTIR mTOR P38a P38g
> 10000 > 10000 > 10000 > 10000 > 10000 > 10000 > 10000 > 10000 > 10000 > 10000 > 10000 750 180 2500 300 > 10000 > 10000 > 10000 > 10000 > 10000 > 10000 > 10000 > 9000 > 10000 > 10000
PAK2 ac. PDGFRα PDK1 PI3Ka PI3Kb PI3Kd PIK4b PIM2 PKA PKBa PKCa PKCθ PKN1 PKN2 PLK1 RET ROCK2 RON SRC S6K SYK TYK2 VPS34 YES ZAP70
> 10000 > 10000 > 10000 > 10000 > 10000 > 10000 > 9000 > 10000 > 10000 > 10000 > 10000 > 10000 > 10000 > 10000 > 10000 > 10000 > 10000 > 10000 > 10000 > 10000 > 10000 > 10000 > 9000 1100 > 10000
The Cancer Cell Line Encyclopedia BGJ398 profiled in 748 cell lines
BGJ398 IC50 µM
>8
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~5%
BGJ398 cellular sensitivity is greatest among the FGFR genetically altered cell lines FGFR genet. alter.
FGFR wt
BGJ398 IC50 uM
2.5
1.5
0.5
48%
3%
8 | Cholangiocarcinoma Foundation | 06Feb15 | RIsaacs |
BGJ398 cellular sensitivity is greatest among the FGFR genetically altered cell lines
BGJ398 IC50 uM
0.25
0.20
0.15
0.1
0.05
FGFR fusion 9 | Cholangiocarcinoma Foundation | 06Feb15 | RIsaacs |
FGFR1 amp
FGFR2 amp
FGFR2 mut
FGFR3 mut
BGJ398 inhibits proliferation of bladder cancer cell lines with FGFR3 genomic alterations *
>3000 FGFR3 mutation FGFR3 fusion
BGJ398 IC50 nM
2500
FGFR3 wt 2000
*FGFR3 not expressed
1500
*
1000
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EJ198
HT1376
J82
KU1919
T24
UMUC3
VMCUB1
647-V
SW1710
BFTC805
HTB9
HT1197
TCCSUP
SW780
RT4
MGHU3
RT112
0
RT112/82
500
BGJ398 shows in vivo anti-tumor activity in the RT112 bladder cancer rat model (FGFR3 fusion)
Vehicle
BGJ398
BGJ398
5 mg/kg
10 mg/kg
Vehicle
pFRS2 pMAPK MAPK 11 | Cholangiocarcinoma Foundation | 06Feb15 | RIsaacs |
BGJ398
BGJ398
5 mg/kg
10 mg/kg
pFRS2
3h
pMAPK ß-tubulin
24h
BGJ398 Is Effective in FGFR1amp Lung Cancer Models Pharmacologic Activity of BGJ398 in Lung Cancer Cell Lines (N = 112)
Antitumor Efficacy in H1581 FGFR1amp Lung Cancer Xenografts
H1581 Tumor Volume, mm3
FGFR1 Copy Number
Vehicle qd
> 4 FGFR1 copies
NCI-H1581 DMSO
DMSO
BGJ398
pFRS2 α-actinin
BGJ398
! 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
Graus-Porta D, et al. AACR 2012 [abstract 854]; Wolf J, et al. AACR 2012 [abstract LB-122]. 12 | Cholangiocarcinoma Foundation | 06Feb15 | RIsaacs |
BGJ398 45 mg/kg qd
**One-way ANOVA: Dunnett vs vehicle.
BGJ398 IC50 nM DMS 114
BGJ398 10 mg/kg qd BGJ398 20 mg/kg qd
PTX’s with FGFR2 amplification respond to BGJ398 GAM033 (Crownbio)
CHGA010
Vehicle pFGFR2
BGJ398 15mg/kg
Vehicle pErk1/2 Erk1/2
FGFR2
13 | Cholangiocarcinoma Foundation | 06Feb15 | RIsaacs |
β-tubulin
BGJ398 15mg/kg
BGJ398 FIM Phase 1 study design Dose expansion Arm 1: ~20-40 FGFR1 amplified squamous NSCLC continuous daily dosing
Dose escalation Oral, once-daily BGJ398, 28-day cycle MTD declaration 28Jun 2012 125mg QD
Dose levels Decision to dose escalate based on review of toxicity (DLT) in Cycle 1 and other clinical, PK, and laboratory data
Solid tumors FGFR1 or 2 amplified or FGFR3 mutated or other FGFR genetic alterations 14 | Cholangiocarcinoma Foundation | 06Feb15 | RIsaacs |
Arm 2: 21 FGFR ampl / mut solid tumors continuous daily dosing 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 14
Baseline patient characteristics N = 119 Median age (range), years Age ≥ 65 years, n (%) Male / female, n (%)
59 (25-86) 31 (26) 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 a
Includes urothelial cell carcinoma of any origin.
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3 Data as of September 9, 2014 cutoff
Patient disposition N = 119 Treatment ongoing, n (%) Treatment discontinued, n (%)
8 (7) 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 5-60 mg n = 19
All patients =115; n (%) 100 mg 125 mg (c) 150 mg n=6 n = 53 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)
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)
Stomatitis
17 | Cholangiocarcinoma Foundation | 06Feb15 | RIsaacs |
BGJ398 pharmacokinetics 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
Data as of September 24, 2013 cutoff. 18 | Cholangiocarcinoma Foundation | 06Feb15 | RIsaacs |
125 mg/day
1000
BGJ398 Concentration, ng/mL
! Consistent
Day 15 100
10
Day 1
1
0
0 1 2 3 4
6
8
Time, h
24
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)
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 19 | Cholangiocarcinoma Foundation | 06Feb15 | RIsaacs |
FGF23: an FGFR ligand that controls phosphate homeostasis and VitD3 metabolism Lumen
Kidney: Proximal tubule VitD3 metabolism
_
Pi re-absorption _
Basolateral membrane
FGFR1
FGF23
Bone: Osteocytes
FGF23
ɑ-KLOTHO
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 20 | Cholangiocarcinoma Foundation | 06Feb15 | RIsaacs |
Can we identify a monitorable biomarker that predicts exposures associated with pathway inhibition? Biomarker study:
! ROC Analysis:
Biomarker
AUC
Pi
0.9
Sensitivity Specificity
measures diagnostic power of a biomarker
1
0.88
! Reversibility upon treatment discontinuation? Treatment days 1 3
Pi (mg/dL)
11
7
9
15
7 5 vehicle
BGJ398 10mg/kg
BGJ398 20mg/kg
21 | Cholangiocarcinoma Foundation | 06Feb15 | RIsaacs |
vehicle
BGJ398 10mg/kg
BGJ398 20mg/kg
Hyperphosphatemia as a pharmacodynamic marker of FGFR pathway inhibition 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
1 Dienstmann R, et al. Ann Oncol. 2013;25:552-563. 22 | Cholangiocarcinoma Foundation | 06Feb15 | RIsaacs |
Individual Time Plot of Phosphate in 100-mg Dose Cohort 2.0
Change From Baseline of Phosphate, mmol/L
! Biologic rationale and
Dose delay
1.5 1.0 0.5 0.0
Dose reduction (60 mg/day)
-0.5 -1.0 Baseline
10
20
30
40
50
Study Day of Assessment
• •
Serum Pi level in cycle 1 increases after exposure to BGJ398 Dose interruption results in quick decrease of serum Pi level
60
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
160
Days to the First Dose Interruption/Reduction
140 120 100 80 60 40 20
Data as of 31JAN14 cutoff
0
23 | Cholangiocarcinoma Foundation | 06Feb15 | RIsaacs |
100 mg Continuous Dosing
125 mg Continuous Dosing
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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Best Percent Change from Baseline
BGJ398 has clinical activity across multiple tumor types with FGFR genetic alterations
25 | Cholangiocarcinoma Foundation | 06Feb15 | RIsaacs |
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 26 | Cholangiocarcinoma Foundation | 06Feb15 | RIsaacs |
Phase 2 study of BGJ398 in cholangiocarcinoma opened in July 2014 N ≈55 Advanced cholangiocarcinoma w/FGFR2 gene fusion/other FGFR genetic alteration Prior CDDP-based chemotherapy or gemcitabinecontaining therapy for pts unable to receive CDDP
BGJ398 125mg qd x 21 days (28d cycles)
Primary endpoint: - ORR Secondary endpoint: - PFS, DCR, BOR, OS - Safety - PK
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Continue until disease progression, unacceptable toxicity, withdrawal of consent or death
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
28 | Cholangiocarcinoma Foundation | 06Feb15 | RIsaacs |
