Inhibidores de Tirosin-kinasas en el Cáncer de Riñón: Sunitinib Hospital Universitario Central de...

Inhibidores de Tirosin-kinasas en el Cáncer de Riñón: Sunitinib

Hospital Universitario Central de Asturias (HUCA) Servicio de Oncología MédicaEmilio Esteban

SunitinibInhibidor multiselectivo de Receptores Tirosina kinasa

Familia erbB IR split FGFR VEGFR eph Trk Tie c-Met RET

RTK Class I II III IV V VI VII IX X XII

Clase I II III IV V VI X XII

Kinase EGFR IGF1R PDGFR c-Kit FLT-3 FGFR1 VEGFR1/2/3 Tie-2 c-Met RET

Enzyme >10,000 2,400 8 4 NA 830 2/9/17 5,520 5,310 83

Cell (nM) 8,900 3,500 10 2 10 880 2-10 NA 11,700 50

Sunitinib en segunda LíneaEstudios Fase II

*Dose reduction permitted (to 37.5 mg/day and then to 25 mg/day)**One patient was omitted from the analysis in the confirmatory study due to a change in diagnosis

Motzer R et al. J Clin Oncol. 2006;24:16-24; Motzer R et al. JAMA. 2006;295:2516-2524.

SUTENT® SUTENT®Esquema

4 semanas de tratamiento seguido de 2 semanas de descanso (4/2)

Patients with advanced disease and failure of prior cytokine therapy

Continue SUTENT® treatment unless progression or intolerability

SUTENT®

50 mg/día*

Pooled analysis of evaluable patients from both studies (n=168)**

Dos estudios Fase II independientes :

Inicial (n=63)

Confirmatorio (n=106)

Pool Estudios Fase IISunitinib en 2ª Línea tras Citokinas

44% RG

SLP: 8 mesesSG: 19 meses

JAMA. 2006;295:2516-2524.

Sunitinib contra Interferón-alfa (IFN-) como Tratamiento de Primera línea del Carcinoma Celular

Renal Metastásico

N=750

Criterios de Elegibilidad

Histología de cc

Sin tx sistémico previo

ECOG PS 0 o 1

Enfermedad medible

N=750

Criterios de Elegibilidad

Histología de cc

Sin tx sistémico previo

ECOG PS 0 o 1

Enfermedad medible

AALLEEAATTOORRIIZZAACCIIÓÓNN

AALLEEAATTOORRIIZZAACCIIÓÓNN

Sunitinib 50 mg PO QDEsquema 4/2

(n=375)(n=375)

Sunitinib 50 mg PO QDEsquema 4/2

(n=375)(n=375)

IFN-9 MU SQ TIW

(n=375)

IFN-9 MU SQ TIW

(n=375)

Objetivo Primario: Supervivencia Libre de Progresión

Objetivo secundario: Supervivencia global, Calidad de vidaMotzer RJ et al. NEJM 2007;356:115-124.

Objetivos del estudio

Supervivencia Supervivencia

Libre de ProgresiónLibre de Progresión

– 90% power to detect a 35% improvement

– Primary endpoint (EP) met at the pre-planned Interim Analysis 2

Objetivo PrimarioObjetivo PrimarioObjetivo PrimarioObjetivo Primario Objetivos SecundariosObjetivos SecundariosObjetivos SecundariosObjetivos Secundarios

Supervivencia Global

• 85% power to detect a 35.7% improvement

• 390 events required for the final analysis

Response rate, Safety, Patient-reported outcomes

QoL

Supervivencia Global

• 85% power to detect a 35.7% improvement

• 390 events required for the final analysis

Response rate, Safety, Patient-reported outcomes

QoL

Características de los Pacientes

Características Sunitinib (n=375)IFN-

(n=375)

Edad mediana, años (rango) 62 (27-87) 59 (34-85)

ECOG PS 0/1 (%) 62/38 61/39

Nefrectomía previa (%) 90 89

Sitios de participación de la enfermedad (%)Pulmón Hígado Hueso

782630

792430

Número de sitios metastásicos (%)1≥2

1981

2476

Factores de riesgo de MSKCC* (%) 0 (favorable)1-2 (intermedio)3 (pobre)

37567

34597

Supervivencia Libre Progresión

No. at Risk Sunitinib: 235 90 32 2No. at Risk IFN-: 152 42 18 0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

Time (Months)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pro

gre

ssio

n F

ree

Su

rviv

al P

rob

ab

ilit

y SunitinibMediana: 11 meses(95% CI: 10–12)

IFN- Mediana: 5,1 meses(95% CI: 4–6)

Hazard Ratio = 0.415(95% CI: 0.320–0.539)P <0.000001

Supervivencia Global Final

Muerte TotalSunitinib 190IFN-a 200


0 3 6 9 12 15 18 21 24 27 30 33 36

Tiempo (meses)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pro

bab

ilid

ad d

e S

up

ervi

ven

cia

Glo

bal

Sunitinib (n=375) Mediana: 26.4 meses

(95% CI: 23.0 - 32.9)IFN- (n=375) Mediana: 21.8 meses (95% CI: 17.9 - 26.9)

Proporción de Riesgo = 0.821(95% CI: 0.673 - 1.001)p =0.051 (Rango logarítmico)

375 44 / 326 38 / 283 48 / 229 42 / 180 14 / 61 4 / 2nMuerte/nRiesgo Sunit

375 61 / 295 46 / 242 52 / 187 25 / 149 15 / 53 1 / 1nMuerte/nRiesgo IFN-



10

Overall Survival: Crossover patients censored (n=25)

0 3 6 9 12 15 18 21 24 27 30 33 36

Time (months)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Ove

rall

Su

rviv

al P

rob

abili

ty

Sunitinib (n=375) Median: 26.4 months (95% CI: 23.0 - 32.9)IFN- (n=375) Median: 20.0 months (95% CI: 17.8 - 26.9)

Hazard Ratio = 0.808(95% CI: 0.661 - 0.987)p =0.0362 (Log-rank)

SG en pacientes que no recibieron ningún tratamiento de post-estudio

*Incluye a 20 pacientes que cambiaron a sunitinib en el estudio

*

0 3 6 9 12 15 18 21 24 27 30 33 36

Tiempo (meses)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pro

bab

ilid

ad d

e S

up

erv

iven

cia

Glo

bal

Sunitinib (n=193) Mediana 28.1 meses (95% CI: 19.5 - NA)IFN- (n=162)

Mediana 14.1 meses (95% CI: 9.7 - 21.1)

Proporción de Riesgo = 0.647(95% CI: 0.483 - 0.870)p =0.0033 (Rango logarítmico)

Respuesta (RECIST)

Criterio del

InvestigadorRevisión Central

Independiente

Sunitinib(n=374)

IFN-a

(n=373)Sunitinib(n=365)

IFN-a

(n=346)

Nº de Pacientes (%)

Respuestas Objetivas* 174 (46) 45 (12) 142 (39) 29 (8)

Respuestas completas 5 (1) 4 (1) 0 0

Respuestas Parciales 169 (45) 41 (11) 142 (39) 29 (8)

Estabilizaciones 152 (41) 205 (55) 146 (40) 165 (48)

PR o no evaluables 48 (13) 123 (33) 77 (21) 152 (44)

Respuestas objetivas por RECIST

*Sunitinib vs IFN-: P<0.000001

13

Toxicidad Analítica

Sunitinib (%) IFN- (%)

Evento All grade Grade 3/4 All grade Grade 3/4

Neutropenia 72 11/1* 46 7

Anemia 71 3/<1 64 4/<1

Thrombocytopenia 65 8* 21 0

Lymphopenia 59 12 63 22*

Hypophosphatemia 36 4/<1 32 6

Hyperamylasemia 31 4/1* 28 2/<1

* P <0.05

14

Toxicidad

Evento

Sunitinib (%) IFN- (%)

All grade Grade 3/4 All grade Grade 3/4

Fatigue 51 7 51 11/<1*

Diarrhea 53 5* 13 0

Nausea 44 3 33 1

Stomatitis 25 1 2 <1

Hypertension 24 8* 1 <1

Hand-foot syndrome 20 5* 1 0

Ejection fraction decline 10 2 3 1

Pyrexia 7 1 34 0

Chills 6 1 29 0

Myalgia 5 <1 16 <1

Flu-like symptoms 1 0 8 <1* P <0.05

Functional Assessment of Cancer Therapy-General (FACT-G): Puntuación total

1º. Efecto Global del tratamiento a favor de Sunitinib2º. FACT-G basal es un factor pronóstico de mejor SLP

P <0,001

Avances en Supervivencia Libre de Progresión en CCR

Time (months)

PFS = progression-free survival

Kane RC et al. Clin Cancer Res 2006;12:7271–7278; Gore ME et al. ASCO 2008. Abstract 5039; Hudes G et al. N Engl J Med 2007;356:2271–2281; Escudier BJ et al. N Engl J Med 2007;356:125–134; Frampton JE et al. BioDrugs 2008;22:113–120; Figlin RA et al. ASCO 2008. Abstract 5024; Escudier BJ. ASCO 2008. Abstract 5025.

Mediana (meses)

Escudier ASCO 2008

Figlin ASCO 2008

Multiple studies

Torisel PI

Gore ASCO 2008

Kane 2006

Time (Months)

Nexavar PI

CALGB 90206

BSC

INF-α+ IL-2+5-FU

Temsirolimus

Sunitinib

Bevacizumab + INF-α

Sorafenib

Bevacizumab + INF-α

INF-α alone

20

04

-20

08

1Kane RC et al. Clin Cancer Res 2006;12:7271–7278; 2Hudes G et al. N Engl J Med 2007;356:2271–2281; 3Escudier BJ et al. N Engl J Med 2007;356:125–134; 4Gore ME et al. ASCO 2008. Abstract 5039; 5Escudier BJ. ASCO 2008. Abstract 5025; 6Escudier BJ et al. Lancet 2007;370:2103; 7Figlin RA et al. ASCO 2008. Abstract 5024.

21,8

21

18,5

15,2

7,3

7-9

Mediana (meses)

IFN

Figlin ASCO 2008

IFN

Placebo

Gore ASCO 2008

Kane 2006

Nexavar

IFN

Torisel

IFN

Bevacizumab + IFN

20

04

-20

09

Time (months)

BSC

Temsirolimus

Sunitinib

Avastin+IFNα

TARGETs

INF-α+ IL-2+5-FU

Avances en Supervivencia Global CCR avanzado

18-2318-23

2626

SUNITINIB 1ª línea de CCR avanzado: USO EXPANDIDO

● 4.564 pacientes con Cáncer Renal avanzado se reclutaron entre Junio 2005 a Diciembre 2007

● 52 países

● Criterios de Inclusión: >18ª, confirmación histológica de RCC y no disponibilidad del fármaco

● Objetivo Principal: Asegurar el acceso a sunitinib de aquellos pacientes donde no se contaba con la aprobación de las agencias reguladoras

● Pacientes del “mundo real”: Metástasis cerebrales, PS>2, Ancianos e histologías distintas a células claras

Gore M, et al. Lancet in press


All patients

Patient subgroups

Brain metastases

ECOG PS ≥2Non-clear

cell histologyAge ≥65

years

No. of evaluable patients 4,349 320 582* 588 1,414

Months (95% CI)

Median progression-free survival

10.9(10.3–11.2)

5.6(5.2–6.1)

5.1(4.2–5.5)

7.8(6.3–8.3)

11.3(10.7–12.3)

Median overall survival18.4

(17.4–19.2)9.2

(7.8–10.9)6.7

(6.0–7.9)13.4

(10.7–14.9)18.2

(16.6–19.8)



Favourable 744 ptsIntermediate 889 ptsPoor 249 pts

Median = 4.8 months* (95% CI: 3.9–5.6)

Pro

gre

ssio

n-f

ree

surv

ival

p

rob

abil

ity

Time (months)

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.00 3 6 9 12 15 18 21

Median = 8.4 months* (95% CI: 8.1–9.7)

Median = 13.5 months* (95% CI: 11.8–15.0)



Preferred term, % Grade 1-2 Grade 3-4

Diarrhea 27.8 3.2

Nausea 23.8 1.6

Fatigue 20.3 5.8

Mucosal inflammation 18.3 1.8

Dysgeusia 17.0 0.6

Stomatitis 17.0 1.7

Vomiting 16.3 1.7

Anorexia 15.5 1.7

Hand–foot syndrome 11.1 4.0

Dyspepsia 10.8 0.2

Asthenia 10.3 4.2

Hypertension 10.2 3.7

Rash 9.7 0.4

Constipation 9.2 0.2

Epistaxis 9.0 0.4

Headache 7.7 0.4

Hypothyroidism 2.0 0.2

Cardiac failure 0.0 0.1

Cardiac failure congestive 0.0 0.2



Fatigue

0

2

4

6

8

10

12

All Brain mets PS ≥2 Non-clear cellRCC

Age ≥65 years

Patie

nts

(%)

Thrombocytopenia

0

2

4

6

8

10

12


Age ≥65 years

Patie

nts

(%)

Hand-foot Syndrome

0

2

4

6

8

10

12


Age ≥65 years

Patie

nts

(%)

Asthenia

0

2

4

6

8

10

12


Age ≥65 years

Patie

nts

(%)

Neutropenia

0

2

4

6

8

10

12


Age ≥65 years

Patie

nts

(%)

Hypertension

0

2

4

6

8

10

12


Age ≥65 years

Patie

nts

(%)

Diarrhoea

0

2

4

6

8

10

12


Age ≥65 years

Patie

nts

(%)

0

2

4

6

8

10

12

All Brain mets PS ? 2 Non-clear cellRCC

Age ?65 years



Fatigue

0

2

4

6

8

10

12


Age ≥65 years

Patie

nts

(%)

Thrombocytopenia

0

2

4

6

8

10

12


Age ≥65 years

Patie

nts

(%)

Hand-foot Syndrome

0

2

4

6

8

10

12


Age ≥65 years

Patie

nts

(%)

Asthenia

0

2

4

6

8

10

12


Age ≥65 years

Patie

nts

(%)

Neutropenia

0

2

4

6

8

10

12


Age ≥65 years

Patie

nts

(%)

Hypertension

0

2

4

6

8

10

12


Age ≥65 yearsPa

tient

s (%

)

Diarrhoea

0

2

4

6

8

10

12


Age ≥65 years

Patie

nts

(%)

Anaemia

0

2

4

6

8

10

12

All Brain mets PS ? 2 Non-clear cellRCC

Age ?65 years

Patie

nts

(%)


Agente Tratamiento

previoNº Pts Pronostico

Buen/Inter (%)

RO/EE (%) SLP(meses)

Everolimus SU/SO/BEV 272 29/56 1/63 4

SU (Rini) 1 BEV 32 - 6/81

SO (Knox)2 BEV 197 - 3/78

SO (Shepard)3 BEVSU

1824

28/2825/58

0/330/41

2,93,8

SUSO (Sablin)4

SOSU

6822

43/3541/45

15/519/55

6,24,2

SUSO (Dham)5

SOSU

2314

35/5250/43

17/497/50

82

SU (Eichelberg)6

SO 30 - 26/23 10

1-ASCO 2006, (4522);2- ASCO 2007 (5096); 3- ASCO 2008 (5123); 4- ASCO 2007 (5038); 5- ASCO 2007 (5106); 6- E Ass Urol 2008, in press

SU: sunitinib; SO:sorafenib; BEV: bevacizumab; Pts: Pacientes; RO: respuestas objetivasEE: enfermedad estable; SLP: supervivencia libre progresión

Clinical Guidelines: European Association of Urology

Treatment of mRCC: NCCN Guidelines 1

Setting Category 1 Evidence2 Category 2 Evidence3

First-line therapy

First-line treatment of patients with relapsed or medically unresectable

Stage IV renal cancer

Sunitinib Clear cell histology

Sunitinib 2A (non-clear cell histology)

Temsirolimus 2A

Bevacizumab + IFN 2A Sorafenib 2A (selected patients)

Poor prognosis patients

only

Temsirolimus (clear and non-clear cell histology)

Second-line therapy

Prior cytokine Sorafenib

Sunitinib

All 2B IFN, High Dose

IL-2, Low Dose IL-2 +/-

IFN, Bevacizumab

Prior VEGFR inhibitor

Sunitinib 2A, Sorafenib 2A,

All 2B IFN, High Dose IL-2, Low Dose IL-2 +/- IFN, Bevacizumab

1Kidney Cancer, NCCN 2007 Clinical Practice Guidelines in Oncology; 2Unform NCCN consensus, based on high-level evidence, that the recommendation is appropriate; 32A Uniform NCCN consensus, based on lower level evidence including clinical experience, that the recommendation is appropriate 2B Non-uniform NCCN consensus (but no major disagreement), based on lower lever evidence including clinical experience, that the recommendation is appropriate

Metastatic Renal Cell Carcinoma Treatment: EORTC guidelines

● Metastatic RCC responds, albeit at a low rate, to cytokines. – For those with intermediate or poor-risk disease, cytokines confer no benefit.

● On the evidence phase III trials availables:

– Sunitinib should be first line therapy in patients with good or intermediate risk metastatic disease.

– An alternative would be Bevacizumab plus IFN-alpha. – In patients ineligible for sunitinib, Sorafenib is an option.

– In patients with poor prognosis (as defined in the pivotal trial), Temsirolimus is recommended. In

this group, Sunitinib could be an alternative. – For a small number of first line patients with good PS, high dose IL-2 may be recommended.

– The role of targeted agents in the treatment of patients with RCC of non-clear cell histologies remains to be established.

– Nephrectomy is an important component of the multimodality treatment of mRCC. However, it is not yet known whether this benefit is also seen in patients treated with targeted agents

Algoritmo de tratamiento en pacientes con CCR avanzado

Setting Phase III Phase II or Sub-analysis

First-line therapy

Good or intermediate risk*

SunitinibHD IL-2

Bevacizumab + IFN- Sorafenib

Poor risk* Temsirolimus Sunitinib

Second-line therapy

Prior cytokine Sorafenib Sunitinib

Prior VEGFR inhibitor Everolimus Sunitinib or sorafenib

Prior mTOR inhibitor No data available

*MSKCC risk status.

Muchas gracias

Inhibidores de Tirosin-kinasas en el Cáncer de Riñón: Sunitinib Hospital Universitario Central de...

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