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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.
17
• 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.
19
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
23
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)
26
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