Dose escalation study of ODM-203, a selective dual FGFR/VEGFR inhibitor, in patients with advanced solid tumours J Rodon 1 , C Garratt 2 , K Laapas 2 , H Leskinen 2 , H Björklund 2 , J Hietamäki-Zaagman 2 , K Peltola 3 , A Azaro 1 , C Massard 4 , P Bono 3 1 Vall d'Hebron University Hospital and Universitat Autonoma de Barcelona, Barcelona, Spain; 2 Orion Corporation Orion Pharma, Espoo, Finland; 3 Comprehensive Cancer Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland; 4 Institute Gustave Roussy, University of Paris Sud, Dept. of Cancer Medicine, Villejuif, France
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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
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*
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9* 13* 21*
15*
Weeks treatment
*ongoing
51*
RET
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KIDES best tumour response
11*
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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