1 v reunión nacional de avances en cáncer de próstata y cáncer renal everolimus en cáncer renal...

1

V Reunión Nacionalde avances en Cáncer de Próstata y Cáncer

Renal

Everolimus en Cáncer

Renal Avanzado

Dr. Daniel Castellano

Servicio de Oncología Médica

Guadalajara 18 y 19 de Junio de 2009

2

Patogenesis de CCR

3

Von Hippel-Lindau disease:

• Rare Hereditary Syndrome (DA)

• Mutation tumour suppressor gene localized in Cr 3p25-26

Latif F et al. Science. 1993

• Abnormal VHLp

RCC: Molecular Biology

↑risk of developing multiple Hemangioblastomas in

brain, spinal cord, retina as well as clear cell Renal

Cancer, endolymphatic sac tumors and cysts in

pancreas, kidney, liver, etc..,

4

Vías moleculares en carcinogenesis del RCCBrugarolas J. NEJM 2007

1

2

3

3

3

Everolimus Temsirolimus

5

mTORControls Cell Growth, Proliferation and Angiogenesis

• mTOR is a kinase in the PI3-K/Akt signaling pathway

• Integrates multiple signals

– Growth factor receptor activity

– Cellular energy, nutrients, and oxygen levels

– Signals from other cellular signaling pathways

– Estrogen receptor signaling

• Controls production of proteins regulating cell growth, cell division, and angiogenesis in response to these signalsCell growth Angiogenesis

Ras/Raf pathway and Abl kinases

Protein production

mTOR

Growth factor receptors(IGF-1R, VEGFR, ErbB)

Oxygen, energy, and nutrients

Cell division

Estrogen receptor

6

mTOR Integrates Growth Factor and Nutrient Signaling

mTOR pathway, PI3K-AKT-mTOR, is a downstream component of several growth factor signaling pathways1

mTOR senses availability of amino acids, metabolic fuel, and energy (ATP)

mTOR activation turns on the synthesis of proteins involved in cell growth2

mTOR is a critical integrator of signaling that coordinates cell growth control3

mTOR

Growth Signaling

PI3K

AktTSC2

↑Glucose

TSC1

AMPK

Amino Acids

↑ATP

↓Glucose

↓ATP

Cell Growth & Proliferation

Protein Synthesis

Angiogenesis

Bioenergetics

Targeting the mTOR pathway can impact the bioenergetics of the cell

7

m TOR: mTOR complexes• mTOR exists in 2 different multiprotein complexes:

GBL

mTORRaptor

Rapamycin-sensitivemTORc1

4E-BP1S6K

GBL

mTORRictor

Rapamycin-insensitivemTORc2

AKTRho GTPasesRapamycin

FKBP12

Raptor: Regulatory-Associated Protein of Mtor;

Rictor: Rapamycin insensitive companyon of mTOR

RaptorRictor

8

C-Myc

HIF

Cyclin D1

VEGF

mTORC1

9

Production of Transporters

mTOR

MG1

G2

S

Cancer Cell Growth

mTOR Coordinates Cancer Cell Growth

GlucoseTransporter

IncreasedNutrient Uptake

Nutrient Availability

Secretion of Angiogenic Growth Factors

Cancer Cell

Amino AcidTransporter

Mutations in Cancer

Blood Vessel

10

Deregulation of the the mTOR Pathway

• In cancer cells, mTOR is often deregulated by

– Excessive growth factor signaling

– Gain-of-function mutations in up-stream kinases, eg, PI3-K and Akt

– Loss of function of the negative regulators PTEN, TSC1/2, and LKB1

– Increased activity of kinases that stimulate the PI3-K/Akt pathway, eg, Ras/Raf, Abl, ER

• mTOR inhibition counters many common defects in cancer cells

Akt/PKB

PI3-K

PTENOxygen, energy, and nutrients

TSC2 TSC1

Growth factorsIGF-1, VEGF, ErbB, etc

Protein production

4E-BP1

S6

S6K1

elF-4E

mTORRas/Raf pathway kinases

Ras/Raf,

Abl, ER

Cell growth AngiogenesisCell division

RAD001

XX XX XX

11

mTOR

MG1

G2

S

Cancer Cell Growth

mTOR Inhibition May Disrupt Cancer Cell Growth by Various Ways

GlucoseTransporter

Secretion of Angiogenic Growth Factors

Cancer Cell

Amino AcidTransporter

Blood Vessel

DECREASED

Nutrient Availability

DECREASED

12

mTOR Inhibition Molecular Rationale for Selected Cancers

Characteristic Molecular Defects

Tumor IGF-1EGFR/ HER2

ER/ PR pAKT PI3K PTEN

TSC 1/2

VHL/ HIF

Angio- genesis

Ras/ Raf

Pre-clin

NET +++ + + +++ +++

RCC ++ + ++ ++ +++ +++

Lung +++ +++ +++ +++ + +++

CRC ++ +++ +++ +++ +++ ++ ++

Breast ++ +++ +++ ++ ++ +++

+++ Closely associated with pathogenesis in a high proportion of cancers ++ Contributes to the pathogenesis of many cancers+ Contributes to pathogenesis in some cancers, or contribution is not apparent

13

RAD001An Oral mTOR Pathway Inhibitor

• Active rapamycin derivative, not a prodrug

• Oral bioavailability

• T1/2 ≈ 30 hours

• CYP3A4 metabolism

• Broad antitumor activity in preclinical & phase 1 studies

• Inhibits cell growth and angiogenesis

• Enhances activity of chemotherapy, radiation, and molecular therapeutics

RAD001(everolimus)

O O O H

OOO

N

OO

O O

O

O H

O

OH

14

RAD001Preclinical Summary

• Potent inhibition of tumor & endothelial cell proliferation

• In vivo activity vs many tumor types, including lung, colon, pancreatic, and epidermoid cancers and melanoma

• Inhibition of tumor cell VEGF production in vitro & in vivo

• Antiangiogenic effects in vivo

• Enhances apoptosis induced by DNA damaging agents

• Additive/synergistic in combination with cisplatin, gemcitabine, doxorubicin, paclitaxel, PTK/ZK, AEE788, and letrozole

• p-Akt may indicate higher PI3-K pathway activation and increased sensitivity to RAD001

• PTEN status may predict antitumor response in certain tumor types (eg, glioblastoma multiforme [GBM])

15

RAD001(everolimus)

Phase I Monotherapy Studies

16

RAD001Dose-Limiting Toxicity

Weekly Daily

Study 2101/2 5-30 mg 50 mg 70 mg 5 mg 10 mg

N = 92 0/16 1/6 Gr 3

stomatitis

0/7 0/6 1/6 Gr 3

stomatitis, Gr 3

neutropenia

Study 2107* 20 mg 50 mg 70 mg 5 mg 10 mg

N = 55 0/6 0/6 4/7

Gr 3 neutropenia,

Gr 3 stomatitis (n = 2), Gr 3

hyperglycemia

0/6 1/6 Gr 3

stomatitis

• DLTs of RAD001 are stomatitis and neutropenia*Study 2107: Phase 1 safety study in 55 patients with advanced cancer.

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• Adverse events (AEs) generally mild to moderate

– Most common: rash/erythema (~ 46%), stomatitis/ mucositis (~ 40%)

– Other common: fatigue (32%), nausea (25%), anorexia (24%), vomiting (16%), headache (14%), pruritus, infections, constipation (~ 10% each)

• Stomatitis the most common serious toxicity

• Toxicity profile nonoverlapping with many commonly used anticancer agents—no serious neuropathy, cardiotoxicity, edema, or alopecia has been seen

• Long-term (≥ 3 years) safety and tolerability in more than 1,000 patients in transplantation applications using dosages similar to those used in oncology

Data on file, Novartis.

RAD001 Safety and Tolerability: Phase 1 Monotherapy

18

RAD001Studies 2101/2 and 2107: Response*

Weekly Dose, mg Daily Dose, mg

Response

≤ 30

(n = 30)50

(n = 18)

70

(n = 38)

5

(n = 16)

10

(n = 45)

Partial NSCLC

Colon

RCC GE Rectal

Progression-free

≥ 6 mo

NSCLC

Colon

Breast

RCC RCC (n=3),

NSCLC, Breast,

Adenocystic,

Melanoma

GE RCC (n = 2)

Rectal

Mesothelioma

Progression-free

4 mo, <6 mo

NSCLC

Colon

HCC

Fibro-

sarcoma

Melanoma NSCLC

Melanoma

Adenocystic

Colon

Melanoma

*Conventional imaging using RECIST criteria.GE = gastroesophageal.

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RAD001Conclusions: Phase 1 Single-Agent Trials

• DLTs are stomatitis, neutropenia, and hyperglycemia

• Favorable PK profile

– Oral bioavailability

– t1/2 ~ 30 hours

– Dose proportionality

– Interpatient variability ~ 50%

• Most common AEs are rash and stomatitis in ≥ 40%

– Grade 3 in < 1% and 5%, respectively

• PD and safety support recommended doses

– 10 mg/d or 50–70 mg/wk

• Tumor responses and prolonged disease stabilizations

20

RAD001Single Agent Activity in Renal Cell Cancer

25 patients with disease progression after cytokine or cytotoxic therapy

21 evaluable : 18 pts are progression-free at 3 mos

Median duration of RAD therapy is 8+ months (range 1+ to 9+)

ASCO 2006: Dr Amato, Methodist Hospital – Houston (IIT)

Phase 3 Study in 2nd/3rd Line Advanced RCC after VEGFr Inhibitor failure, RECORD-1

22 patients with disease progression after tyrosine kinase inhibitors

22 evaluable : 3 PR (16%) and 14 pts (74%) are progression-free at 3 mos

Median PFS of RAD therapy is 5.5 + months (range 1+ to 8+)

ASCO 2008: Dr J. Jac, Amato, Methodist Hospital – Houston (IIT)

2121

RAD001 (Everolimus) Plus Best Supportive Care (BSC) vs BSC Plus Placebo in Patients With Metastatic Renal Cell Carcinoma (RCC), After

Progression on VEGFr-TKI Therapy

R. Motzer, B. Escudier, S. Oudard, C. Porta, T. Hutson, S. Bracarda, R. Figlin, J. Thompson, V. Grünwald, N. Hollaender, G. Urbanowitz, A.

Kay, A. Ravaud, for the RECORD-1 Study Group

Supported by Novartis Pharmaceuticals

22

Objectives

• Phase III randomized trial of everolimus vs placebo

– 2:1 double-blind

• Primary end point: progression-free survival

– 33% risk reduction (hazard ratio = 0.67)

– 290 events to achieve 90% power

– Assessment by independent central review

• Secondary end points: safety, response, patient-reported outcomes and overall survival

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Key Eligibility Criteria

•Metastatic RCC with clear cell component

•Measurable disease

•Progressive disease on or within 6 mos of treatment with sunitinib, sorafenib, or both

•Prior bevacizumab and cytokines permitted

•Adequate performance status, blood counts and serum chemistry

24

Study Design

Final analysis

Target N = 362

Stratification

• Prior VEGFrTKI: 1 or 2

• MSKCC risk group1: favorable, intermediate, or poor

Target N = 362

Stratification

• Prior VEGFrTKI: 1 or 2

• MSKCC risk group1: favorable, intermediate, or poor

Everolimus + BSC

Placebo + BSC

Upon Disease Progression

Interim analysis

Interim analysis

• Interim analyses planned after ≈ 30% and 60% of targeted 290 events

RRAANNDDOOMMIIZZAATTIIOONN

2:12:1

1. Motzer et al. J Clin Oncol. 2004;22:454-463.

25

Study Conduct

410 patients randomized between September 2006 and October 2007 Second interim analysis cut-off: October 15, 2007, based on 191 PFS events Independent Data Monitoring Committee recommended termination of study

RRAANNDDOOMMIIZZAATTIIOONN

2:12:1

Placebo + BSC(n = 138)(n = 138)

Upon Disease Progression

Interim analysis

Interim analysis

N = 410

Stratification

• Prior VEGFrTKI: 1 or 2

• MSKCC risk group: favorable, intermediate, or poor

N = 410

Stratification

• Prior VEGFrTKI: 1 or 2

• MSKCC risk group: favorable, intermediate, or poor

=Finalanalysis

Everolimus + BSC(n = 272)(n = 272)

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Study Treatment

•Repeated 28-day cycles

•Response and safety assessments

•Dose reduction for toxicity

•Treatment continued unless progression or intolerance

Arm B: matching placebopo dailyvsvs

Arm A: everolimus10 mg po daily

27

Baseline Characteristics

Characteristic Everolimus Placebo

No. of patients 272 138

Median age, years (range) 61 (27-85) 60 (29-79)

% KPS, ≥ 90/≤ 80 64/36 67/33

% MSKCC risk1

Favorable/intermediate/poor 29/56/15 28/57/15

Sites of metastases, %

Lung 73 81

Bone 37 31

Liver 35 36

No. of metastatic sites

1 10 10

≥ 2 90 90

1. Motzer et al. J Clin Oncol. 2004;22:454-463.

28

Prior Therapies

Prior TreatmentEverolimus

(n = 272)%

Placebo (n = 138)

%

Nephrectomy 96 95

Radiotherapy 31 28

VEGFr-TKI therapy

Sunitinib 46 44

Sorafenib 28 30

Both 26 26

Other systemic therapy

Interferon 50 50

Interleukin 2 22 24

Chemotherapy 13 16

Bevacizumab 9 10

29

Patient Disposition and Treatment Administered

Everolimus(n = 272)

Placebo(n = 138)

Treatment ongoing, % 51 (n = 140) 22 (n = 30)

Patient discontinuation, %

Progressive disease 31 73

Adverse events 10 1

Death 3 2

Withdrawal of consent 3 1

Other reasons 2 1

Median duration of treatment

Days 95 57

Range 12-315 21-237

30

Progression-Free Survival by Treatment Central Radiology Review

Patients at Risk Everolimus 272 132 47 8 2 0 0 Placebo 138 32 4 1 0 0 0

100

80

60

40

20

0

0 2 4 6 8 10 12

Pro

bab

ility

, %

Hazard ratio = 0.30 95% CI [0.22, 0.40]

Median PFSEverolimus: 4.0 moPlacebo: 1.9 mo

Log rank P value < 0.001 Everolimus (n = 272) Placebo (n = 138)

Months

31

0

20

40

60

80

100

0 2 4 6 8 10 12 14

Months

Pro

bab

ilit

y, %

Everolimus (n = 277)Placebo (n = 139)

Hazard ratio = 0.3395 % CI [0.25, 0.43]

Median PFSEverolimus: 4.90 moPlacebo: 1.87 mo

Log rank P value = <0.001

Patients at riskEverolimusPlacebo

277 192 115 51 26 10 1 0139 47 15 6 2 0 0

Progression-Free Survival by Treatment Central Radiology Review

> 25 %

32

Progression-Free Survival by Treatment Prior Sunitinib

0

20

40

60

80

100

0 2 4 6 8 10 12 14

Months

Pro

bab

ilit

y, %

Everolimus (n = 124)Placebo (n = 60)

Log rank P value <0.001

Hazard Ratio = 0.3495 % CI [0.23, 0.51]

Median PFSEverolimus: 3.88 moPlacebo: 1.84 mo

Patients at riskEverolimusPlacebo

124 80 44 20 7 1 0 060 15 8 2 0 0 0 0

Central Radiology Review

33

Progression-Free Survival by Treatment Prior Sorafenib

0

20

40

60

80

100

0 2 4 6 8 10 12 14

Months

Pro

bab

ilit

y, %

Everolimus (n = 81)Placebo (n = 43)

Log rank P value <0.001

Hazard Ratio = 0.2595 % CI [0.16, 0.42]

Median PFSEverolimus: 5.88 moPlacebo: 2.83 mo

Patients at riskEverolimusPlacebo

81 63 43 23 15 7 1 043 23 6 3 2 0 0 0

Central Radiology Review

34

Subgroup Analysis of Progression-Free Survival

Central Radiology Review

HR N28Feb08 cut-offCentral Review 0.33 416Investigator Review 0.32 416MSKCC Risk Favorable 0.31 120 Intermediate 0.32 235 Poor 0.44 6115Oct08 cut-offCentral Review 0.30 410Investigator Review 0.31 410MSKCC Risk Favorable 0.35 118 Intermediate 0.25 231 Poor 0.39 61

0 0.4 1.0 1.4

Hazard Ratio

Everolimus benefit Placebo benefit

1.20.80.60.2

35

Subgroup Analysis of Progression-Free Survival

Central Radiology Review

1. Motzer et al. J Clin Oncol. 2004;22:454-463.

HR NCentral Review 0.30 410Investigator Review 0.31 410MSKCC RiskFavorable 0.35 118Intermediate 0.25 231Poor 0.39 61Prior TxSorafenib Only 0.29 119Sunitinib Only 0.30 184Both 0.28 107Age< 65 yrs 0.32 259≥ 65 yrs 0.29 151SexMale 0.29 317Female 0.36 93RegionU.S. & Canada 0.24 130Europe 0.37 251Japan & Australia 0.10 29

0 0.4 1.0 1.4

Hazard Ratio

Everolimus benefit Placebo benefit

1.20.80.60.2

1

36

−100%

−75%

−50%

−25%

0%

25%

50%

75%

100%

Best Response n (%)

PR 5 (2) Stable 185 (67) PD 57 (21) NE 30 (11)

Best Response n (%)

PR 0 Stable 45 (32) PD 74 (53) NE 20 (14)

Maximum % Change in Target Lesions and Objective Response Rate*

Everolimus Placebo

NE = not evaluable

* Central Radiology Review

37

Laboratory Abnormalities*

Everolimus%, (n = 269)

Placebo%, (n = 135)

All Grades Grade 3/4 All Grades Grade 3/4

Hematology

Anemia 91 9 / < 1 76 5

Lymphopenia† 42 14 / 1 29 5

Thrombocytopenia 20 < 1 2 0 / < 1

Neutropenia 11 0 3 0

Chemistry

Hypercholesterolemia† 76 3 32 0

Hypertriglyceridemia 71 < 1 30 0

Hyperglycemia† 50 12 23 1

Elevated creatinine 46 < 1 33 0

Hypophosphatemia† 32 4 7 0

Elevated AST 21 < 1 7 0

Elevated ALT 18 < 1 4 0

*≥ 10% of everolimus patients†Significant difference between sum of grade 3/4 events for everolimus and placebo groups (P < 0.05)

38

Treatment-Related Adverse Events*

Everolimus%, (n = 269)

Placebo%, (n = 135)

All Grades Grade 3 All Grades Grade 3

Stomatitis† 40 3 8 0

Asthenia / fatigue 37 3 24 1

Rash 25 < 1 4 0

Diarrhea 17 1 3 0

Anorexia 16 < 1 6 0

Nausea 15 0 8 0

Mucosal inflammation 14 1 2 0

Vomiting 12 0 4 0

Cough 12 0 4 0

Edema peripheral 10 0 3 0

Infections† 10 3 2 0

Pneumonitis† 8 3 0 0

Dyspnea 8 1 2 0

*≥ 10% of everolimus patients and additional selected AEs.†Significant difference between sum of grade 3/4 events for everolimus and placebo groups (P < .05) .

39

Baseline

Month 12

Month 5

Month 11

Pneumonitis with Everolimus Therapy

40

Overall Survival by Treatment

0

20

40

60

80

100

0 2 4 6 8 10 12 14 16Months

Pro

bab

ilit

y, %

Everolimus (n = 277)Placebo (n = 139)*

Hazard Ratio = 0.8295 % CI [0.57, 1.17]

MedianEverolimus: NA monthsPlacebo: 13.01 months

Log rank P value = 0.137

Patients at RiskEverolimusPlacebo

277 267 236 191 108 52 11 1 0139 131 114 91 53 19 6 1 0

41

Standards for RCC Therapy by Phase III Trial ASCO 2007

Setting Phase III

Treatment- naïve

Good or intermediate risk*

Sunitinib

Bevacizumab + IFN-

Poor risk* TemsirolimusSunitinib

Previously treated

Prior cytokine Sorafenib

Prior VEGFr-TKI

Prior mTOR inhibitor

*MSKCC risk status.

42

Standards for RCC Therapy by Phase III Trial ASCO 2008

Setting Phase III

Treatment- naive

Good or intermediate risk*

Sunitinib

Bevacizumab + IFN-

Poor risk* TemsirolimusSunitinib

Previously treated

Prior cytokine Sorafenib

Prior VEGFr-TKI Everolimus

Prior mTOR inhibitor

*MSKCC risk status.

43

Conclusions

•Everolimus prolongs progression-free survival in RCC patients after progression on VEGFr-TKI therapies

•Everolimus is the first and only agent with established clinical benefit for the treatment of patients with RCC after VEGFr-TKI therapy

•Everolimus should be standard-of-care in this setting

•FDA approved March 2009

44

Phase II study RAD001/Bevacizumab in Advanced RCC (Asco 2008)

• 59 mClear-cell RCC patients (Aug 2006 - Nov 2007)

– No previous targeted agents: 30 patients

– Previous targeted agents: 29 patients

• Sunitinib 15, Sorafenib 10, Sorafenib and sunitinib 2, IL-2 and sorafenib 2

• ECOG 0-1

• Maximum of 1 previous immunotherapy or chemotherapy regimen

• No previous bevacizumab or M-TOR inhibitors

• Motzer prognostic score:

– Low: 12 (20%)

– Intermediate: 45 (76%)

– High:2 (4%)

• Bevacizumab 10mg/kg IV infusion, every 2 weeks

• RAD001 10mg PO daily

4545

RAD001/Bevacizumab in Advanced RCC Treatment Received, Activity, Discontinuation

Prev Untreated (N=30)

Prev Treated (N=29)

Treatment duration (median, months) 6

Currently on treatment 14 (24%)

Response

PR 7 (23%) 5 (17%)

SD 16 (53%) 17 (59%)

PD 2 (7%) 4 (14%)

NE 5 (17%) 3 (10%)

PFS (months) 12 11

OS (months) 17 12

• 13 of 15 patients previously treated with sunitinib had DCR: PR 4, SD 9

• Reasons for discontinuing treatment (N=45)

– Progression: 24

– Toxicity: 9 (proteinuria, embolus, stomatitis, diarrhea)

– Other: 12 (intercurrent illness, MD decision, Pt refusal)

4646

RAD001/Bevacizumab in Advanced RCC Toxicity (N=59)

Number of Patients (%)

Toxicity Grade 1/2 3 4

Hematologic

Neutropenia 10 (23%) 1 (2%) 0

Thrombocytopenia 25 (57%) 1 (2%) 0

Anemia 41 (93%) 0 0

Non-Hematologic

Fatigue 35 (59%) 4 (7%) 1 (2%)

Skin toxicity (rash, pruritus) 53 (90%) 0 0

Hypertension 14 (24%) 1 (2%) 0

Proteinuria 9 (15%) 10 (17%) 2 (3%)

Mucositis/Stomatitis 28 (47%) 4 (7%) 0

Diarrhea 16 (27%) 5 (8%) 0

Hyperlipidemia 39 (66%) 2 (3%) 0

Nausea/vomiting 18 (31%) 0 0

Epistaxis 6 (10%) 0 0

4747

RECORD-2Phase II Trial of RAD001 Plus Bevacizumab

• First-line treatment of patients with metastatic clear-cell carcinoma of the kidney

• Primary endpoint: Progression-free survival

• Secondary endpoint: Overall survival

SC = Subcutaneous; IFN- = Interferon alfa.

RAD001 10 mg/day

plus Bevacizumab 10 mg/kg q 2 wk IVS

CREEN

IFN- dose escalation SC plus

Bevacizumab 10 mg/kg q 2 wk IV

N = 360

Randomized 1 : 1

FPFV:4Q08

4848

RECORD-3 Randomized Phase II Crossover Design

• First-line treatment of patients with previously untreated mRCC

• Stratified by MSKCC risk criteria

• Primary endpoint: Progression-free survival

• Secondary endpoint: Overall survival, safety, efficacy, QoL

MSKCC = Memorial Sloan-Kettering Cancer Center; QoL = Quality of life.

RAD001 10 mg/day S

CREEN

Sunitinib 50 mg/day,

4 wk on/2 wk off

Randomized 1 : 1

Sunitinib 50 mg/day,

4 wk on/2 wk off

RAD001 10 mg/day

Disease progression

4949

RAPTOR RAD001 as Monotherapy in the Treatment of Advanced Papillary Renal Cell Tumors

• Phase II, multicenter, international study of RAD001 as first-line treatment for patients with metastatic papillary RCC

Study start date is January 2009.ECOG PS = Eastern Cooperative Oncology Group performance status.

Type I/II metastatic papillary RCC

N = 60

Inclusion criteria:•≥ 1 measurable lesion•ECOG PS 0 or 1•Adequate bone marrow,

liver, and renal function•Adequate lipid profile•No prior systemic therapy

RAD001 10 mg/day

5050

Estudio multicéntrico, abierto, de acceso expandido de RAD001, en pacientes

con carcinoma renal metastásico que han progresado a pesar de la terapia con  inhibidor de tirosina quinasas del receptor del factor de crecimiento endotelial

vascular

30 centros en España abiertos para tratamiento