Papel de los nuevos Tki:
AXITINIB
Dr. Javier Puente Vázquez
Servicio Oncología Médica
Hospital Universitario Clínico San Carlos
The challenge of treatment in mRCC
• Benefits of tyrosine kinase inhibitors (TKIs) are well established;
however, there are limitations
– There are few complete responses
– Initial partial responses are followed by progression
– In other cases there is no objective benefit
• Drug resistance remains an ongoing obstacle to successful
treatment of mRCC
– Limits the success of therapy and reduces survival rates
Motzer RJ, et al. J Clin Oncol 2009; Rini B, et al. J Clin Oncol 2010; Escudier B, et al. J Clin Oncol 2010; Escudier B, et al. N Engl J Med 2007; Hudes G, N
Engl J Med 2007
Patterns of tumor progression on VEGF or VEGFR
inhibitors
Late progressors
Change in Tumor
Measurements (%)
Group A
Early progressors
Change in Tumor
Measurements (%)
Change in Tumor
Measurements (%)
Primary refractory
Group B
Group C
Targeted therapy in mRCC: mechanisms of resistance
Group A
Group B-C
TTP > 6 months. TKI´s sensitive
Cont. VEGFr inhibitors ?
TTP < 6 months. TKI´s resistance
Switch to mTOR inhibitors ?
Inhibiting VEGF Receptors 1, 2, 3
Axitinib is an Oral, Potent, and Highly Selective Inhibitor of
VEGF Receptors 1, 2, 3
• Small molecule indazole derivative
• Orally administered: 5 mg BID
●
5 mg Film Coated Tablet
Axitinib
N
CONHMe
S
H
N
N
BID = twice daily
Hu-Lowe DD, et al. Clin Cancer Res. 2008;14:7272–7283.
Disrupting Tumour Progression
Axitinib comprehensively disrupts tumour progression by inhibiting the
VEGF receptor signalling system.
PIGF
VEGF C
VEGF A
VEGF B
Axitinib
VEGF D
VEGFR 2
VEGFR 1
Tumour Growth
via
Vascular Angiogenesis
Tumour Cell Proliferation
Ellis LM, Hicklin DJ. Nat Rev Cancer. 2008;8:579–591.
VEGFR 3
Tumour Spread
via
Metastatic Tumour Colonisation
via Lymphangiogenesis
Axitinib is a Selective Inhibitor of VEGF Receptors 1, 2, 3
Selective Inhibitor
• Low IC50 indicates higher
affinity.
• Axitinib inhibits VEGF
receptors 1, 2, and 3 at
picomolar concentrations,
suggesting potent and
highly selective activity
against these receptors.
Hu-Lowe DD, et al. Clin Can Res. 2008;14:7272–7283.
Receptors
RTK
Cellular IC50 (nM)
VEGFR-1
0.1*
VEGFR-2
0.2
VEGFR-3
0.1–0.3
PDGFR-α
5.0
PDGFR-β
1.6
KIT
1.7
CSF-1R
73
FGFR-1
231
FLT3
>1000
RET
>1000
Axitinib is More Potent Than Most VEGF Receptor Kinase Inhibitors
1,000
100
Potency: IC50
(nM)
Less
potent
More
potent
VEGFR-1
VEGFR-2
VEGFR-3
10
1
0.1
AV-951
Axitinib
Cediranib Motesanib Sunitinib
AMG-706
ABT-869
Pazopanib Sorafenib Vatalanib Vandetanib
PTK787
0.01
Figure modified using data from: Chow LQM, Eckhardt SG. J Clin Oncol. 2007;25:884–896; Eskens FALM, et al.
Proceedings of the 99th Annual Meeting of the American Association for Cancer Research. 2008. Abstract LB-201;
and Hu-Lowe DD, et al. Clin Cancer Res 2008;14:7272-7283
Decreasing VEGFR-2 in Animal Models
Axitinib Decreases VEGFR-2 in Animal Models
• Blockade of VEGFR-2 may
lead to a decrease in MVD
and blood flow.
• Significant reductions in
intensity of VEGFR-2 and
VEGFR-3 of
RIP-Tag2† tumour vessels
after 7 days of axitinib
treatment
Axitinib
7 days
Vehicle
Axitinib 7 days
*Different from corresponding vehicle (P< 0.05)
†The RIP-Tag2 animal model is of pancreatic islet cell cancer.
MVD = microvessel density
Inai T, McDonald D. J Am Pathol. 2004;165:35–52. Olsson AK, et al. Molec Cell Biol. 2006;7:359–371.
Reduces Tumour Blood Vessels
Axitinib Reduces the Number of Tumour Blood Vessels
• Axitinib reduced MVD and normalised tumour vasculature in 7 days
– Withdrawal resulted in regrowth of vessels.
CD31
Untreated
Axitinib 7 days
RIP-Tag2
Mancuso MR, et al. J Clin Invest. 2006;116:2610–2621.
Withdrawal 2 days
Withdrawal 7 days
Decreasing Tumour Blood Flow
Axitinib Decreases Tumour Blood Flow
• Axitinib rapidly decreases tumour blood vessel patency,
blood flow, and vessel number within 24 hours of exposure.
Vehicle
Reduction
of Flow
Reduction of
Angiogenic
Vessels
Overlay
Inai T, McDonald D. J Am Pathol. 2004;165:35–52
Axitinib 1 Day
Axitinib Blocks Vascular Sprouting in Animal Models
Vascular Sprouting
Untreated
• Vascular sprouting is
one of the initial
processes associated
with angiogenesis.
Axitinib 7 days
•
Axitinib effectively
blocks vascular
sprouting.
Tammela T, et al. Nature. 2008;454:656–660; Inai T, McDonald D. J Am Pathol. 2004;165:35–52.
Axitinib Reduces Tumour Growth
Reduction in Vascular Permeability
• Axitinib decreased vascular permeability after 7 days.
KPS (mL/100 g/min)
Color 1
maps of Kps
values 2
in the central
tumour1slice
Control
Control
Axitinib
Axitinib 2
0.100
0.075
0.050
0.025
0.010
Baseline
7 days post-treatment
MRI = magnetic resonance imaging; Kps = tumour endothelial transfer coefficient
Wilmes LJ, et al. Magn Reson Imaging. 2007;25:319–327.
Axitinib Reduces Tumour Growth
Reduction in Tumour Volume
•
Axitinib reduced tumour volume in mice.
400
300
(mm3)
MRI enhanced tumour
measurements showed
significant decreases in
tumour volume for the
axitinib vs. control
group.
Mean volume change after 7 days
+ 213 mm3
Control
Axitinib
200
100
- 160 mm3
0
–100
–200
MRI = magnetic resonance imaging; Kps = tumour endothelial transfer coefficient
Wilmes LJ, et al. Magn Reson Imaging. 2007;25:319–327.
-RR: 44.2%
-TTP: 15.7 meses
-SG: 29.9 meses
Motzer, et al. ASCO 2011
Motzer, et al. ASCO 2011
Reflexiones
ASPECTOS POSITIVOS
• Estudio Fase III
randomizado.
• Estudio PURO de 2ª línea.
• Mediana PFS: 6.7 meses
• TR: 19%
• Tolerancia similar Tki
• Baja tasa de discontinuación
ASPECTOS ????
• 45% de los pacientes no
recibieron sunitinib.
• En pre-Sunit, PFS: 4.8 meses
• ¿Porqué tanta discrepancia
entre IRC e investigadores?
• ¿Porqué dar la opción de
incrementar la dosis?
Conclusiones
- Axitinib es un nuevo inhibidor de tirosina quinasa de alto poder
inhibitorio
sobre
VEGFR
1,
2
y
3.
- En el contexto de la segunda línea, y en comparación con
sorafenib, prolonga la SLP de forma significativa.
- Axitinib presenta un perfil de tolerabilidad semejante a otros Tki
(hipertensión, hipotiroidismo) pero, en comparación con
sorafenib,
presenta
menos
SMP,
rash
y
alopecia.
- Axitinib se postula como una alterantiva terapéutica en el
contexto
de
la
segunda
línea
del
CCRm.