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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.

8

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

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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

29

(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