Pazopanib
en la primera línea del
cáncer renal avanzado
Pazopanib
en el tratamiento del
Carcinoma de Células Renales
Luis León
Servicio de Oncología Médica
Santiago de Compostela 1
Pazopanib bloquea moléculas clave implicadas en la
angiogénesis
PDGFR
VEGFR-1
VEGFR-2
VEGFR-3
c-KIT
Tumour cell
membrane
P
P
P
P
RAS
P
P
P
P
P
P
P
P
PI3K
Proliferation
P
P
P
P
FAK
Survival
1. Sonpavde et al. Expert Opin Investig Drugs 2008;17:253–61.
P
P
P
P
PLC
Migration
2
Inhibidor multikinasa
Kinases inhibited
with IC50 <1 μM
Pazopanib
Sunitinib
Sorafenib
32
54
25
1. Kumar et al. Br J Cancer 2009;101:1717–23.
Figure adapted from Karaman et al. Nat Biotechnol 2008;26:127–32.
3
Datos de Eficacia
4
Phase II study: VEG1026161
Inclusion
• ECOG
performance
status 0 or 1
• Treatment-naïve or
one prior cytokine
or bevacizumab
failure
Patients with advanced
or metastatic RCC
(N=225)
Pazopanib 800 mg once daily
for 12 weeks
Complete/partial
response
Progressive
disease
Stable disease
Randomization
Pazopanib 800 mg
once daily (n=170)
Pazopanib 800 mg
once daily (n=27)
Clinicaltrials.gov identifier NCT002447642
Matching placebo
(n=28)
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)
5
Objetivos del estudio (revisados)1
Objetivo principal
% de respuestas según RECIST (PFS antes de la
modificación)
Objetivos secundarios
Duración 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.
6
Características de los pacientes
Characteristic
Mean age, years (range)
Patients
(N=225)
59.8 (32–81)
Gender, n (%)
Female
Male
69 (31)
156 (69)
Prior nephrectomy, n (%)
205 (91)
Prior radiotherapy, n (%)
43 (19)
Prior systemic therapy, n (%)
No prior systemic therapy
Prior systemic therapy*
155 (69)
70 (31)
MSKCC risk criteria, n (%)†
Favourable
Intermediate
Poor
Unknown
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.
7
8
Tasa de respuesta global1
Overall response rate (%)
50
40
Pazopanib 800 mg once daily
35
34
Overall population
Cytokine-naïve
37
30
20
10
0
1. Hutson et al. J Clin Oncol 2010;28:475–80.
Bevacizumab or
cytokine pretreated
9
Pazopanib es superior a placebo en PFS1
Proportion progression-free
1.0
0.8
Median: 51.7 weeks2
(95% CI: 43.9, 60.3)
Week 12
randomization
point
0.6
6.2 months
(4.6, 10.9)
Log-rank, p=0.01282
11.9 months
(10.0, –)
0.4
0.2
Pazopanib
Placebo
0.0
0
10
20
30
40
50
60
Weeks on study
70
80
90
100
La comparación de PFS por un comité independiente demostró una ventaja
a favor de pazopanib
Los pacientes cruzados a pazopanib no se censuraron
1. Hutson et al. J Clin Oncol 2010;28:475–80.
10
Phase III study: VEG1051921
Patients with advanced/
metastatic RCC
(N=435)
Stratification
• ECOG performance status
0 versus 1
• Prior nephrectomy
• Treatment-naïve (n=233)
versus
one cytokine failure
(n=202)
Randomization
2:1
Pazopanib 800 mg
once daily (n=290)
Matching placebo (n=145)
Option to receive pazopanib
via an open-label study at
progression
Clinicaltrials.gov identifier NCT00334282
VEG107769 open-label study
71 patients enrolled*
1. Sternberg et al. J Clin Oncol 2010;28:1061-1068
11
Objetivos del estudio1
Objetivo principal
PFS
Objetivos secundarios
OS
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
12
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, %
Lung
Lymph node
Bone
Liver
74
54
28
26
73
59
26
22
Number of organs involved, %
1 and 2
≥3
45
55
48
52
ECOG performance status, %
0
1
42
58
41
59
MSKCC risk category, %
Favourable
Intermediate
Poor
Unknown*
39
55
3
3
39
53
3
4
*Missing results for one or more of the five risk criteria
1. Sternberg et al. J Clin Oncol 2010;28:1061-1068
13
Porcentaje de respuestas
Pazopanib
Placebo
Overall response rate (%)
p<0.001
35
32
30
29
30
25
20
15
10
5
3
4
3
0
Overall
population
(n=435)
1. Sternberg et al. J Clin Oncol 2010;28:1061-1068
Treatment-naïve
Cytokine
(n=155)
pretreated (n=78)
14
Supervivencia libre de progresión en toda la
población1
Proportion progression-free
1.0
Median PFS (months)
Placebo
Pazopanib
Hazard ratio (95% CI)
p value (1-sided)
0.8
4.2
9.2
0.46 (0.34, 0.62)
<0.0001
0.6
0.4
0.2
Pazopanib
Placebo
0.0
Number at risk, n
Pazopanib
Placebo
0
5
10
Time (month)
15
20
290
145
159
38
76
14
29
2
6
In the overall study population, PFS was significantly greater in pazopanib- versus placebo-treated
patients (p<0.0001)
1. Sternberg et al. J Clin Oncol 2010;28:1061-1068
15
Supervivencia libre de progresión en los pacientes no
pretratados1,2
Proportion progression-free
1.0
Median PFS (months)
Placebo
Pazopanib
Hazard ratio (95% CI)
p value (1-sided)
0.8
2.8
11.1
0.40 (0.27, 0.60)
<0.0001
0.6
0.4
0.2
Pazopanib
Placebo
0.0
Number at risk, n
Pazopanib
Placebo
0
5
10
Time (month)
15
20
155
78
84
22
39
7
11
2
1
In the treatment-naïve subpopulation, PFS was significantly greater in pazopanib- versus placebotreated patients (p<0.0001)
1. Sternberg et al. J Clin Oncol 2010;28:1061-1068
16
Supervivencia libre de progresión en los pacientes
tratados con citoquinas1,2
Proportion progression-free
1.0
Median PFS (months)
Placebo
Pazopanib
Hazard ratio (95% CI)
p value (1-sided)
0.8
4.2
7.4
0.54 (0.35, 0.84)
<0.001
0.6
0.4
0.2
Pazopanib
Placebo
0.0
Number at risk, n
Pazopanib
Placebo
0
5
10
Time (month)
15
20
135
67
75
16
37
7
18
5
In the cytokine-pretreated subpopulation, PFS was significantly greater in pazopanib- versus
placebo-treated patients (p<0.001)
1. Sternberg et al. J Clin Oncol 2010;28:1061-1068
17
Beneficio en todos los subgrupos
Hazard ratio (95% CI)
Baseline factor
Primary analysis
MSKCC risk: favourable
MSKCC risk: intermediate
Female
Male
Age <65 years
Age ≥65 years
ECOG performance status 0
ECOG performance status 1
0.2
p<0.001 by log-rank test for all
0.4
0.6
0.8
1.0
1.2
Favours pazopanib Favours placebo
PFS was significantly improved with pazopanib across all sub-groups:
Age, gender, PS and MSKCC risk status
1. Sternberg et al. J Clin Oncol 2010;28:1061-1068
18
Objetivo principal: OS
1.0
Hazard ratio=0.91
95% CI (0.71–1.16)
p=0.224
Proportion surviving
0.8
Median OS
Pazopanib: 22.9 months
Placebo: 20.5 months
0.6
0.4
Pazopanib
Placebo
0.2
54% of placebo patients crossed over
Time of crossover
0.0
0
10
20
30
40
290
145
213
93
147
71
95
53
25
9
Patients at risk
Pazopanib
Placebo
Sternberg et al. Annals Oncol 2010; 21(Suppl 8): Abstract LBA22 and oral presentation
Time (months)
Toxicidad
20
Efectos de clase en ensayo fase III (VEG105192)1
Pazopanib
(n=290)
Placebo
(n=145)
All grades, %
All grades, %
9
0
7 (3)2
0
Hand–foot syndrome
6
<1
Mucositis/stomatitis
4/4
<1/0
Arterial thromboembolic
3*
0
Adverse event
Proteinuria
Hypothyroidism
*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
21
22
Efectos adversos de Pazopanib en ensayos fase II y III
*presentes en ≥10% of pacientes
VEG1026161
Adverse event
VEG1051922
Pazopanib (n=225), %
Pazopanib (n=290), %
Placebo (n=145), %
All
grade
Grade 3
Grade 4
All
grade
Grade 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.
et al. J Clin Oncol 2010;28:1061-1068
2. Sternberg
.
23
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
• 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
1. US FDA. Available from:
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM186338.pdf
2. Kapadia, ASCO 2011.
24
La elevación de ALT asociada a Pazopanib se produce
de forma temprana1
Cumulative incidence
0.16
0.14
0.12
0.10
0.08
0.06
0.04
ALT >5X ULN (N=586)
0.02
0.0
0
6 12
24
32
48
64
80
96
112
Weeks
Elevations in ALT levels were detected in the first 18 weeks of
pazopanib treatment in the vast majority of subjects who
developed such abnormalities
1. US FDA. Available from:
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM
186338.pdf
25
Modificación o retraso de dosis debidos a efectos
secundarios
VEG1026161
VEG1051922,3
Pazopanib
(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†
Treatment modification
*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;28:1061-1068
3. GlaxoSmithKline. Data on file.
26
Comparison of 20% QoL Deterioration Rates
for Pazopanib-Treated and Placebo Patients,
EORTC QLQ-C30
Treatment-Naive Patients
Pazopanib
Placebo
0
56
112
168
224
280
336
392
448
Event Rates (%)
Event Rates (%)
All Patients
100
90
80
70
60
50
40
30
20
10
0
504
100
90
80
70
60
50
40
30
20
10
0
Pazopanib
Placebo
0
56
112
168
Event Rates (%)
Cytokine-Pretreated Patients
100
90
80
70
60
50
40
30
20
10
0
Pazopanib
Placebo
0
56
224
280
336
392
Number of Days Until Event
Number of Days Until Event
112
168
224
280
336
Number of Days Until Event
ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
392
448
504
EORTC QLQ-C30 Global
Health Status/QOL Scale
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Pazopanib
Placebo
0
10 20 30 40 50 60 70 80 90 100
Cumulative Distribution
Function
Cumulative Distribution
Function
HRQoL Deterioration
Cumulative Distribution
Function
HRQoL Deterioration From Baseline
EQ-5D Utility Index
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Pazopanib
Placebo
0
10 20 30 40 50 60 70 80 90 100
HRQoL Deterioration From Baseline
EQ-5D VAS Score
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Pazopanib
Placebo
0
10 20 30 40 50 60 70 80 90 100
HRQoL Deterioration From Baseline
ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
(A) IL8 2767AT
(rs1126647)
(B) IL8 251TA
(rs4073)
(A)HIF1A
IL8 2767AT
(C)
(rs1126647); (B)
1790GA
IL8 251TA
(rs11549467)
(rs4073); (C)
HIF1A 1790GA
(rs11549467).
29
CONCLUSIONES
- 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
30
¿Cuál
es el
camino?
31
Gracias
32