Dose escalation study of ODM-203, a selective dual FGFR/VEGFR inhibitor, in patients with advanced solid tumours

J Rodon1, C Garratt2, K Laapas2, H Leskinen2, H Björklund2, J Hietamäki-Zaagman2, K Peltola3, A Azaro1, C Massard4, P Bono3

1Vall d'Hebron University Hospital and Universitat Autonoma de Barcelona, Barcelona, Spain; 2Orion Corporation Orion Pharma, Espoo, Finland; 3Comprehensive Cancer Center, Helsinki University

Hospital and University of Helsinki, Helsinki, Finland; 4Institute Gustave Roussy, University of Paris Sud, Dept. of Cancer Medicine, Villejuif, France

Constitutively active FGFRs are oncogenic in non-clinical studies

FGFR amplifications have an impact on patient survival in studied cancer types (breast, lung, and gastric)

VEGFR expression correlates with survival or progression in tumor types with high incidence of FGFR alterations (bladder, breast, lung, gastric)

Both VEGFR and FGFRs are drivers for angiogenesis, a hallmark of tumorigenesis

FGFR signalling is a known escape mechanism for anti-VEGFR treatments

Both FGFRs and VEGFRs have same direct target and adaptor proteins, such as Frs2

TAT Washington 21-23 March 2016

Rationale for combining FGFR and VEGFR

inhibition

IC50 (nM) ODM-203 Lucitanib AZD4547

FGFR1 11 58 0.3

FGFR2 16 186 0.2

FGFR3 6 253 1

FGFR4 35 > 1000 7

VEGFR1 26 162 87

VEGFR2 9 9 55

VEGFR3 5 34 35

Ratio

FGFR1/VEGFR2 1:1 1:5 200:1

ODM-203 is a balanced selective dual FGFR/VEGFR

inhibitor

In vitro kinase activity*

• In addition to its primary targets ODM-203 only suppresses 9 kinases out of 317 by more than 70% at 1 uM

In vitro kinase selectivity* Number of kinase inhibited to > 70% at 1 uM out of 317

0

20

40

60

80

100

Nu

mb

er

of

kin

ase

s In

hib

ited

> 7

0%

Holmström T., et al. Cancer Res 2015;75(15 Suppl) TAT Washington 21-23 March 2016

ODM-203 shows similar potency in suppressing FGFR and VEGFR cellular signalling

Effect of ODM-203 on FGFR phosphorylation

in a FGFR dependent cell line (SNU16)

Effect of ODM-203 on VEGFR phosphorylation in HUVEC cells

pFGFR

total FGFR

ODM-203

0 1 10 100 1000 nM

pVEGFR2

total VEGFR2

0 0 1 10 100 1000

- + + + + + VEGF

nM ODM-203

Cell based activity (proliferation)

Cell line (receptor) /

IC50 nM ODM-203 Lucitanib AZD4547

H1581 (FGFR1) 104 160 6

SNU 16 (FGFR2) 132 65 5

RT4 (FGFR3) 192 130 21

Angiogenesis (tube

formation) 33 1 260

Ratio

FGFR/Angiogenesis 1:4 1:120 25:1

• ODM-203 is 60-90 times less potent inhibitor of cell proliferation in FGFR independent cell lines

Holmström T., et al. Cancer Res 2015;75(15 Suppl) TAT Washington 21-23 March 2016

ODM-203 dose escalation design (KIDES study)

Total 31 patients treated with ODM-203 so far 1 DLT

Ongoing

100mg qd (N=1)

200mg qd (N=3)

400mg qd (N=7)

600mg qd (N=6)

800mg qd (N=7)

600mg qd (N=7)

Overall AE burden

Adults with advanced solid tumours (not FGFR selected) Safety: AE’s (CTCAE), labs, ECHO Target effects: phosphate, BP, FGFR/VEGFR blood markers Tumour response: RECIST 1.1 every 8 weeks

N (%)

Age, median (range) years 54 (28-80)

Gender Male 11 (35.5)

Female 20 (64.5)

Race Caucasian 29 (94.5)

ECOG 0 15 (48.4)

1 16 (51.6)

Primary tumour

Colorectal 8 (25.8)

Cholangiocarcinoma 6 (19.4)

Breast 4 (12.9)

Lung 3 (9.7)

RCC 2 (6.5)

Other 8 (25.8)

Baseline characteristics

TAT Washington 21-23 March 2016

ODM-203 Pharmacokinetics

1) Angiogenesis-dependent kidney cancer cell line Renca, orthotopic syngeneic mouse xenograft. 2) FGFR2-dependent gastric cancer cell line SNU-16, subcutaneous mouse xenograft; FGFR3-dependent multiple myeloma cell line KMS11, subcutaneous mouse xenograft. 3) FGFR3-dependent bladder cancer cell line RT4, subcutaneous mouse xenograft. 4) FGFR1-dependent lung cancer cell line H1581, subcutaneous mouse xenograft. TGI: Tumour growth inhibition

100

1000

10000

Free

OD

M-2

03

AU

C 0

-24

h (

h*n

g/m

L)

ODM-203 Day 1 Mean Concentrations ODM-203 exposure in patients vs. mouse xenograft models

Exposure increased with dose but was highly variable

ODM-203 absorption was slow and prolonged

Potentially therapeutic exposures achieved at 400mg qd and upwards

TAT Washington 21-23 March 2016

ODM-203 Common adverse events (>10% patients) Total 200 MG 400 MG 600 MG 800 MG

(N=31) (N=3) (N=7) (N=13) (N=7)

Preferred Term* n (%) n (%) n (%) n (%) n (%)

Bilirubin increased 19 (61.3) 5 (71.4) 7 (53.8) 7 (100)

Diarrhoea 11 (35.5 3 (42.9) 4 (30.8) 4 (57.1)

Alopecia 9 (29.0) 1 (14.3) 3 (23.1) 5 (71.4)

Increased phosphate 8 (25.8) 2 (28.6) 3 (23.1) 3 (42.9)

Jaundice 8 (25.8) 2 (28.6) 2 (15.4) 4 (57.1)

Epistaxis 7 (22.6) 1 (33.3) 1 (14.3) 2 (15.4) 3 (42.9)

Stomatitis 7 (22.6) 1 (14.3) 2 (15.4) 4 (57.1)

Fatigue 6 (19.4) 1 (14.3) 2 (15.4) 3 (42.9)

Decreased appetite 6 (19.4) 2 (28.6) 2 (15.4) 2 (28.6)

Arthralgia 6 (19.4) 2 (28.6) 4 (57.1)

Asthenia 5 (16.1) 1 (33.3) 2 (28.6) 1 ( 7.7) 1 (14.3)

Dysgeusia 5 (16.1) 2 (28.6) 2 (15.4) 1 (14.3)

Palmar-plantar erythrodysaesthesia 4 (12.9) 1 (14.3) 2 (15.4) 1 (14.3)

Headache 4 (12.9) 1 (14.3) 1 ( 7.7) 2 (28.6) *some clinically similar terms are combined

One related SAE: Diarrhoea (grade 3) at 800 mg qd One dose limiting toxicity: Corneal punctate keratitis at 800 mg qd

TAT Washington 21-23 March 2016

Dose dependent increase in unconjugated bilirubin

TAT Washington 21-23 March 2016

Scr D 1 D 4 D 8 D 15 D 22 D 29 W 6 W 80

10

20

30

40

50

60

70

80

200 MG

600 MG

800 MG

400 MG

Visit

S-B

ilir

ub

in t

ota

l (u

mo

l/l)

MRP3

Significant dose-dependent inhibition (≥50%) of UGT1A1 by ODM-203 at 0.1 µM (cf Gilbert’s sy)

No associated increase in transaminases

Bilirubin increases resulted in

temporary discontinuation or dose reduction, especially at high dose

Scr D 1 D 4 D 8 D 15 D 22 D 29 W 6 W 80

10

20

30

40

50

60

400 MG

600 MG

800 MG

200 MG

Visit

S-A

LT

(U

/l)

Scr D 1 D 4 D 8 D 15 D 22 D 29 W 6 W 80

10

20

30

40

50

60

70

80

90

100

400 MG

600 MG

800 MG

200 MG

Visit

S-A

ST

(U

/l)

Serum total bilirubin vs. ODM-203 concentration

Tota

l bili

rub

in (µ

mo

l/l)

ODM-203 (ng/ml)

Biomarkers of FGFR and VEGFR pathways

• Changes in soluble markers of FGFR/VEGFR activity are very variable

• Few hypertension AE’s although increases in mean BP

PD effects may be affected by temporary discontinuations due to adverse events, particularly at higher doses

VEGF

Day 1

Day 4

Day 8

Day 1

5

Day 2

2

Day 2

9

Week 6

Week 8

ODM-203 exposure (max pre-dose)

Day 1

Day 4

Day 8

Day 1

5

Day 2

2

Day 2

9

Week 6

Week 8

Serum phosphate

Systolic blood pressure change from baseline by visit

TAT Washington 21-23 March 2016

FGF23

• Increased phosphate reflects renal FGFR inhibition

• 3 patients at 800mg qd received sevelamer

• No discontinuations due to phosphate

Mean p

hosphate

(m

mo

l/L)

-100

-80

-60

-40

-20

0

20

40

60

80

100

Ch

ange

in t

um

ou

r si

ze (

%)

ODM-203 best tumour response

800 mg

600 mg

400 mg

ODM-203 dose

Patients at 100/200mg excluded for low exposure. Evaluable patients with at least baseline and follow up assessments.

Best response at 8 weeks (RECIST)

Progressive disease 7

Stable disease 13

Partial response 2

Complete response 0

TAT Washington 21-23 March 2016

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10 8 4 40 8 16 24 18 7 8 29* 26*

12*

9* 13* 21*

15*

Weeks treatment

*ongoing

51*

RET

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1 a

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FGFR

1 a

mp

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KIDES best tumour response

11*

FGFR

2 f

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on

Response in a patient with colangiocarcinoma patient harbouring FGFR2 fusion

Long-standing disease with unequivocal progressive disease at time of starting ODM-203 • 40 weeks ODM-203 treatment • Best response -19% at 24 weeks • FGFR2 fusion (G3BP2) found • Dose 400mg qd

PRE

8 wks

Target lesion 1 Target lesion 2

PRE

8 wks

AE’s: fatigue, taste disorder, stomatitis, increased bilirubin,

epistaxis, alopecia, ↓ ejection fraction

TAT Washington 21-23 March 2016

Response in a patient with myoepithelial carcinoma with FGFR2 mutation (p.C382R)

• 62 yr old male

• Diagnosed 2008

• Radiotherapy after primary surgery

• Previous cisplatin, vinorelbine

• Initial ODM-203 dose 600mg qd: ongoing at 300mg qd after 12 weeks

• Tumour reduction 36.3% at 8 weeks

8 weeks ODM-203

Pre-treatment

TAT Washington 21-23 March 2016

• ODM-203 is a small molecule with balanced FGFR1-4 and VEGFR 1-3 inhibition that is

relatively selective.

• Exposure increased with dose up to 800mg qd, achieving anticipated therapeutic dose,

and was somewhat variable.

• One DLT (Keratitis) was reported at 800mg qd (MAD).

• UGT1A1 inhibition caused dose dependent bilirubin increases, resulting in early dose

reduction, especially at 800mg qd.

• Diarrhoea and mucocutaneous events occurred commonly after several weeks

treatment, and responded to temporary discontinuation or dose reduction of ODM-203.

• Exposure-related mean changes in phosphate, soluble markers and modest blood

pressure increases suggest on-target activity and may be limited by early dose

reductions due to increased bilirubin.

• Significant clinical responses were observed in patients with RCC and FGFR aberrant

cholangio and myoepithelial carcinoma.

• Study expansion and evaluation of dosing schedule is ongoing.

Conclusions

TAT Washington 21-23 March 2016