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

| Cholangiocarcinoma Foundation | 06Feb15 | RIsaacs | 2

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


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


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


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


The Cancer Cell Line Encyclopedia BGJ398 profiled in 748 cell lines

BG

J398

IC50

µM

~5%

> 8


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


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


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.


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


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

14 | Cholangiocarcinoma Foundation | 06Feb15 | RIsaacs | 14

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.


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)


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


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


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


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


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)


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)


BGJ398 has clinical activity across multiple tumor types with FGFR genetic alterations

Bes

t Per

cent

Cha

nge

from

Bas

elin

e


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


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


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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