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Pazopaniben el tratamiento del
Carcinoma de Células Renales
Pazopaniben la primera línea del cáncer renal avanzado
Luis LeónServicio de Oncología Médica
Santiago de Compostela
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Tumour cell membrane
VEGFR-1 PDGFR
P PP P
c-KIT
PP P P
Pazopanib bloquea moléculas clave implicadas en la angiogénesis
P P PP
VEGFR-2
PP P P
VEGFR-3
FAKPI3KRAS PLC
Proliferation MigrationSurvival
PP P P
1. Sonpavde et al. Expert Opin Investig Drugs 2008;17:253–61.
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Pazopanib
32
Sorafenib
25
Sunitinib
54
1. Kumar et al. Br J Cancer 2009;101:1717–23.Figure adapted from Karaman et al. Nat Biotechnol 2008;26:127–32.
Inhibidor multikinasa
Kinases inhibited with IC50 <1 μM
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Datos de Eficacia
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Matching placebo (n=28)
Pazopanib 800 mg once daily (n=27)
Patients with advancedor metastatic RCC
(N=225)
Randomization
Phase II study: VEG1026161
Inclusion• ECOG
performance status 0 or 1
• Treatment-naïve or one prior cytokine or bevacizumab failure
Patients received pazopanib after interim analysis
1. Hutson et al. J Clin Oncol 2010;28:475–80.2. US NIH. Available from: http://clinicaltrials.gov/ct2/show/NCT00244764?term=pazopanib+renal&rank=2 (last updated Jan 6, 2011)
Clinicaltrials.gov identifier NCT002447642
Complete/partialresponse
Stable diseaseProgressive
disease
Pazopanib 800 mg once daily (n=170)
Pazopanib 800 mg once daily for 12 weeks
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Objetivos del estudio (revisados)1
Objetivo principal% de respuestas según RECIST (PFS antes de la modificación)
Objetivos secundariosDuración de respuesta
PFS durante la fase de aleatorización
Seguridad y tolerabilidad
Análisis global PFS
1. Hutson et al. J Clin Oncol 2010;28:475–80.
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Características de los pacientes
CharacteristicPatients(N=225)
Mean age, years (range) 59.8 (32–81)
Gender, n (%)FemaleMale
69 (31)156 (69)
Prior nephrectomy, n (%) 205 (91)
Prior radiotherapy, n (%) 43 (19)
Prior systemic therapy, n (%)No prior systemic therapyPrior systemic therapy*
155 (69)70 (31)
MSKCC risk criteria, n (%)†
FavourableIntermediatePoorUnknown
97 (43)92 (41)5 (2)
31 (14)‡
*Cytokine, chemotherapy, hormonal or bevacizumab-based regimens; †For 162 patients, calcium instead of corrected-calcium was used to derive their total MSKCC risk factor; ‡31 patients were missing data on ≥1 of the 5 risk factors and, thus, did not have sufficient data to be assigned to a risk category
1. Hutson et al. J Clin Oncol 2010;28:475–80.
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9
Tasa de respuesta global1
35 3437
0
10
20
30
40
50
Overall population Cytokine-naïve Bevacizumab orcytokine pretreated
Overa
ll r
esp
on
se r
ate
(%
)
Pazopanib 800 mg once daily
1. Hutson et al. J Clin Oncol 2010;28:475–80.
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Pazopanib es superior a placebo en PFS1
La comparación de PFS por un comité independiente demostró una ventaja a favor de pazopanib
Los pacientes cruzados a pazopanib no se censuraron
Week 12 randomization
point
PazopanibPlacebo
Pro
po
rtio
n p
rog
res
sio
n-f
ree
1.0
0.8
0.6
0.4
0.2
0.0
0 10 20 30 40 50 60 70 80 90 100Weeks on study
Median: 51.7 weeks2
(95% CI: 43.9, 60.3)
6.2 months(4.6, 10.9) 11.9 months
(10.0, –)
Log-rank, p=0.01282
1. Hutson et al. J Clin Oncol 2010;28:475–80.
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Matching placebo (n=145)Pazopanib 800 mg once daily (n=290)
Patients with advanced/metastatic RCC
(N=435)
Randomization2:1
Phase III study: VEG1051921
Stratification• ECOG performance status
0 versus 1• Prior nephrectomy• Treatment-naïve (n=233)
versus one cytokine failure (n=202)
1. Sternberg et al. J Clin Oncol 2010;28:1061-1068
Option to receive pazopanib via an open-label study at
progressionClinicaltrials.gov identifier NCT00334282
VEG107769 open-label study71 patients enrolled*
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Objetivos del estudio1
Objetivo principalPFS
Objetivos secundariosOS
ORR
Duración de respuesta
Seguridad y tolerabilidad
Análisis global PFS
Otros: calidad de vida
1. Sternberg et al. J Clin Oncol 2010;28:1061-1068
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Característica basales1
Characteristic Pazopanib(n=290)
Placebo(n=145)
Median age, year (range) 59 (28–85) 60 (25–81)
Gender, % male 68 75
Most common metastatic sites, %LungLymph nodeBoneLiver
74542826
73592622
Number of organs involved, %1 and 2≥3
4555
4852
ECOG performance status, %01
4258
4159
MSKCC risk category, %FavourableIntermediatePoor Unknown*
395533
395334
*Missing results for one or more of the five risk criteria
1. Sternberg et al. J Clin Oncol 2010;28:1061-1068
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Porcentaje de respuestas
3032
29
3 4 3
0
5
10
15
20
25
30
35
Overallpopulation
(n=435)
Treatment-naïve(n=155)
Cytokinepretreated (n=78)
Ov
era
ll re
sp
on
se
ra
te (
%)
p<0.001
Pazopanib
Placebo
1. Sternberg et al. J Clin Oncol 2010;28:1061-1068
15
6292
7614
15938
290145
Number at risk, nPazopanib
Placebo
1.0
0.8
0.6
0.4
0.2
0.0
Pro
port
ion
pro
gre
ssio
n-f
ree
Placebo 4.2Pazopanib 9.2Hazard ratio (95% CI) 0.46 (0.34, 0.62)p value (1-sided) <0.0001
Median PFS (months)
In the overall study population, PFS was significantly greater in pazopanib- versus placebo-treated patients (p<0.0001)
Time (month)
Pazopanib
Placebo
0 5 15 2010
Supervivencia libre de progresión en toda la población1
1. Sternberg et al. J Clin Oncol 2010;28:1061-1068
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Supervivencia libre de progresión en los pacientes no pretratados1,2
1.0
0.8
0.6
0.4
0.2
0.0
0 5 15 2010
Pazopanib
Placebo
Placebo 2.8Pazopanib 11.1Hazard ratio (95% CI) 0.40 (0.27, 0.60)p value (1-sided)
Median PFS (months)
In the treatment-naïve subpopulation, PFS was significantly greater in pazopanib- versus placebo-treated patients (p<0.0001)
1112
397
8422
15578
Number at risk, nPazopanib
Placebo
Time (month)
<0.0001
Pro
port
ion
pro
gre
ssio
n-f
ree
1. Sternberg et al. J Clin Oncol 2010;28:1061-1068
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Supervivencia libre de progresión en los pacientes tratados con citoquinas1,2
1.0
0.8
0.6
0.4
0.2
0.0
0 5 15 2010
Placebo 4.2Pazopanib 7.4Hazard ratio (95% CI) 0.54 (0.35, 0.84)p value (1-sided) <0.001
Median PFS (months)
In the cytokine-pretreated subpopulation, PFS was significantly greater in pazopanib- versus placebo-treated patients (p<0.001)
518377
7516
13567
Number at risk, nPazopanib
Placebo
Time (month)
Pazopanib
Placebo
Pro
port
ion
pro
gre
ssio
n-f
ree
1. Sternberg et al. J Clin Oncol 2010;28:1061-1068
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Beneficio en todos los subgrupos
PFS was significantly improved with pazopanib across all sub-groups: Age, gender, PS and MSKCC risk status
Favours pazopanib Favours placebop<0.001 by log-rank test for all
Baseline factor
0.2 0.4 0.8 1.00.6
Hazard ratio (95% CI)
1.2
Primary analysis
MSKCC risk: favourable
MSKCC risk: intermediate
Female
Male
Age <65 years
Age ≥65 years
ECOG performance status 0
ECOG performance status 1
1. Sternberg et al. J Clin Oncol 2010;28:1061-1068
Objetivo principal: OSP
rop
ort
ion
su
rviv
ing
0.0
0
0.2
0.4
0.6
0.8
1.0
10 20 30 40
290145
PazopanibPlacebo
Patients at risk
21393
14771
9553
259
Time of crossover
PazopanibPlacebo
Hazard ratio=0.9195% CI (0.71–1.16)p=0.224
Median OSPazopanib: 22.9 monthsPlacebo: 20.5 months
54% of placebo patients crossed over
Sternberg et al. Annals Oncol 2010; 21(Suppl 8): Abstract LBA22 and oral presentation
Time (months)
20
Toxicidad
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Efectos de clase en ensayo fase III (VEG105192)1
Pazopanib(n=290)
Placebo(n=145)
Adverse event All grades, % All grades, %
Proteinuria 9 0
Hypothyroidism 7 (3)2 0
Hand–foot syndrome 6 <1
Mucositis/stomatitis 4/4 <1/0
Arterial thromboembolic 3* 0
*2% of arterial thromboembolic events were Grade 3 or worse in severity
1. Sternberg et al. J Clin Oncol 2010;28:1061-1068; 2. Wolter ASCO 2011
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Adverse event
VEG1026161 VEG1051922
Pazopanib (n=225), % Pazopanib (n=290), % Placebo (n=145), %
All grade
Grade 3 Grade 4All
gradeGrade 3 Grade 4
All grade*
Grade 3 Grade 4
Diarrhoea 63 4 0 52 3 <1 9 <1 0
Hypertension 41 9 0 40 4 0 10 <1 0
Hair colour changes 43 0 0 38 <1 0 3 0 0
Nausea 42 <1 0 26 <1 0 9 0 0
Anorexia 24 <1 0 22 2 0 10 <1 0
Vomiting 20 <1 0 21 2 <1 8 2 0
Fatigue 46 5 0 19 2 0 8 1 1
Asthenia – – – 14 3 0 8 0 0
Abdominal pain 16 3 0 11 2 0 1 0 0
Headache 20 0 0 10 0 0 5 0 0
*In study VEG105192, 4 and 3% of patients in the pazopanib and placebo arms, respectively, had Grade 5 adverse events
1. Hutson et al. J Clin Oncol 2010;28:475–80.2. .
*presentes en ≥10% of pacientes
Efectos adversos de Pazopanib en ensayos fase II y III
Sternberg et al. J Clin Oncol 2010;28:1061-1068
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Pazopanib: elevación de transaminasas y Br
Proportion of subjects, %
Pazopanib (n=290)
Placebo (n=145)
All grades Grade 3 Grade 4 All grades Grade 3 Grade 4
ALT increase 53 10 2 22 1 0
AST increase 53 7 <1 19 <1 0
Br increase 36 3 <1 10 1 <1
Alkaline phosphatase
27 1 <1 35 2 0
1. US FDA. Available from: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM186338.pdf
2. Kapadia, ASCO 2011.
• Liver enzyme elevations were largely reversible following dose modification, interruption or cessation1
• Many subjects were able to continue on pazopanib and adapted
• Fatal hepatic events were reviewed across the entire safety database (N=1830)Out of 1830 subjects there were two fatal cases, which were possibly attributable to pazopanib. This is equivalent to 0.1% (95% CI: 0.03, 0.4)1
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La elevación de ALT asociada a Pazopanib se produce de forma temprana1
Elevations in ALT levels were detected in the first 18 weeks of pazopanib treatment in the vast majority of subjects who developed such abnormalities
Cu
mu
lati
ve i
nci
de
nce
0.0
0.02
0.04
0.06
0.08
0.10
0 6 12 24 32 48 64 80 96 112
Weeks
0.12
0.14
0.16
ALT >5X ULN (N=586)
1. US FDA. Available from: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM186338.pdf
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Modificación o retraso de dosis debidos a efectos secundarios
VEG1026161 VEG1051922,3
Treatment modificationPazopanib
(n=225)Pazopanib
(n=290)Placebo (n=145)
Dose reduction due to adverse events, % 31* 243 33
Treatment discontinuation due to adverse events, % 15 14† 3†
*Subsequent re-escalations in approximately 50% of patients who reduced their dose of pazopanib; †Not including three patients who, in addition to adverse events, had concurrent other reasons at the time they discontinued participation in the study
1. Hutson et al. J Clin Oncol 2010;28:475–80.2. Sternberg et al. J Clin Oncol 2010;28:1061-10683. GlaxoSmithKline. Data on file.
Comparison of 20% QoL Deterioration Rates for Pazopanib-Treated and Placebo Patients, EORTC QLQ-C30
ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
0 56 168 280 336 3920
3040
60
90100
Ev
en
t R
ate
s (
%)
Number of Days Until Event504
7080
50
1020
112 224 448
All Patients
PazopanibPlacebo
0 56 168 280 336 3920
3040
60
90100
Ev
en
t R
ate
s (
%)
Number of Days Until Event504
7080
50
1020
112 224 448
Treatment-Naive Patients
PazopanibPlacebo
0 56 168 280 336 3920
3040
60
90100
Ev
en
t R
ate
s (
%)
Number of Days Until Event
7080
50
1020
112 224
Cytokine-Pretreated Patients
PazopanibPlacebo
HRQoL Deterioration
ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
0 10 50 80 90 1000
0.30.4
0.6
0.91.0
Cu
mu
lati
ve
Dis
trib
uti
on
Fu
nc
tio
n
HRQoL Deterioration From Baseline
0.70.8
0.5
0.10.2
30 60
EORTC QLQ-C30 GlobalHealth Status/QOL Scale
PazopanibPlacebo
704020 0 10 50 80 90 1000
0.30.4
0.6
0.91.0
Cu
mu
lati
ve
Dis
trib
uti
on
Fu
nc
tio
n
HRQoL Deterioration From Baseline
0.70.8
0.5
0.10.2
30 60
EQ-5D Utility Index
PazopanibPlacebo
704020
0 10 50 80 90 1000
0.30.4
0.6
0.91.0
Cu
mu
lati
ve
Dis
trib
uti
on
Fu
nc
tio
n
HRQoL Deterioration From Baseline
0.70.8
0.5
0.10.2
30 60
EQ-5D VAS Score
PazopanibPlacebo
704020
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(A) IL8 2767AT (rs1126647); (B) IL8 251TA(rs4073); (C) HIF1A 1790GA (rs11549467).
(B) IL8 251TA(rs4073)
(A) IL8 2767AT (rs1126647)
(C) HIF1A 1790GA (rs11549467)
CONCLUSIONES
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- Pazopanib es superior a placebo (PFS) en primera línea de cáncer renal metastásico
- Pazopanib obtiene un porcentaje de respuestas del 30% en esta población
- La tolerancia a pazopanib es buena, y las toxicidades manejables
- Debe prestarse especial atención a las alteraciones en la función hepática
- Pazopanib no produce un deterioro en la calidad de vida
- Necesitamos marcadores predictivos de respuesta
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¿Cuál es el camino?
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Gracias