Transcript Slide 1

V Reunión Nacional
de avances en Cáncer de Próstata y Cáncer
Renal
Everolimus en Cáncer
Renal Avanzado
Guadalajara 18 y 19
de Junio de 2009
Dr. Daniel Castellano
Servicio de Oncología Médica
1
Patogenesis de CCR
2
RCC: Molecular Biology
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
↑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..,
3
Everolimus
Temsirolimus
3
3
2
3
1
Vías moleculares en carcinogenesis del RCC
Brugarolas J. NEJM 2007
4
mTOR
Controls Cell Growth, Proliferation and Angiogenesis
•
Growth factor receptors
(IGF-1R, VEGFR, ErbB)
Oxygen, energy,
and nutrients
Ras/Raf
pathway and
Abl kinases
mTOR
•
mTOR is a kinase in the PI3-K/Akt
signaling pathway
Integrates multiple signals
–
–
Estrogen
receptor
–
–
•
Protein production
Cell growth
Cell division
Angiogenesis
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 signals
5
mTOR Integrates Growth Factor and Nutrient
Signaling
↓Glucose
mTOR pathway, PI3K-AKT↑Glucose
mTOR, is a downstream
component of several growth
factor signaling pathways1
↓ATP
PI3K
AMPK
TSC1
↑ATP
TSC2
Akt
Growth
Signaling
Amino
Acids
mTOR senses availability of
amino acids, metabolic fuel, and
energy (ATP)
mTOR activation turns on the
synthesis of proteins involved in
cell growth2
mTOR
mTOR is a critical integrator of
Protein Synthesis
Cell Growth
& Proliferation
signaling that coordinates cell
growth control3
Bioenergetics
Angiogenesis
Targeting the mTOR pathway can impact the bioenergetics of the cell
6
m TOR: mTOR complexes
• mTOR exists in 2 different multiprotein complexes:
Rapamycin-sensitive
mTORc1
FKBP12
Rapamycin-insensitive
mTORc2
mTOR
GBL
S6K
mTOR
Raptor
Raptor
4E-BP1
GBL
Rapamycin
AKT
Rictor
Rictor
Rho GTPases
Raptor: Regulatory-Associated Protein of Mtor;
Rictor: Rapamycin insensitive companyon of mTOR
7
mTORC1
Cyclin D1
HIF
C-Myc
VEGF
8
mTOR Coordinates Cancer Cell Growth
Blood Vessel
Nutrient Availability
Glucose
Transporter
Production
Increased of
Transporters
Nutrient Uptake
mTOR
Secretion of Angiogenic
Growth Factors
Mutations in
Cancer
Amino Acid
Transporter
M
G1
G2
Cancer Cell Growth
S
Cancer Cell
9
Growth factors
IGF-1, VEGF, ErbB, etc
Deregulation of the
the mTOR Pathway
•
PI3-K
PTEN
Oxygen, energy,
and nutrients
–
Ras/Raf,
Akt/PKB
In cancer cells, mTOR is often
deregulated by
Abl, ER
–
TSC2 TSC1
Ras/Raf
pathway
kinases
–
RAD001
mTOR
–
S6K1
4E-BP1
S6
Protein production
X
Cell growth
X
Cell division
elF-4E
X
•
Angiogenesis
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
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mTOR Inhibition May Disrupt
Cancer Cell Growth by Various Ways
Blood Vessel
Nutrient Availability
DECREASED
Secretion of Angiogenic
Growth Factors
Glucose
Transporter
mTOR
DECREASED
Amino Acid
Transporter
M
G1
G2
Cancer Cell Growth
S
Cancer Cell
11
mTOR Inhibition
Molecular Rationale for Selected Cancers
Characteristic Molecular Defects
Tumor
IGF-1
NET
+++
RCC
++
EGFR/
HER2
ER/
PR
pAKT
PI3K
PTEN
+
TSC
1/2
VHL/
HIF
Angiogenesis
+
+++
+++
+++
+++
Ras/
Raf
Preclin
+
++
++
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
12
RAD001
An Oral mTOR Pathway Inhibitor
• Active rapamycin derivative,
HO
not a prodrug
O
O
O
N
O
O
OH
O
O
O
O
OH
O
O
• Oral bioavailability
• T1/2 ≈ 30 hours
• CYP3A4 metabolism
• Broad antitumor activity in
preclinical & phase 1 studies
• Inhibits cell growth and
RAD001
(everolimus)
angiogenesis
• Enhances activity of
chemotherapy, radiation, and
molecular therapeutics
13
RAD001
Preclinical 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])
14
RAD001
(everolimus)
Phase I Monotherapy Studies
15
RAD001
Dose-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
0/6
1/6
Gr 3
stomatitis
Gr 3
neutropenia,
Gr 3 stomatitis
(n = 2), Gr 3
hyperglycemia
• DLTs of RAD001 are stomatitis and neutropenia
*Study 2107: Phase 1 safety study in 55 patients with advanced cancer.
16
RAD001
Safety and Tolerability: Phase 1 Monotherapy
• 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.
17
RAD001
Studies 2101/2 and 2107: Response*
Weekly Dose, mg
Response
≤ 30
(n = 30)
50
(n = 18)
70
(n = 38)
5
(n = 16)
10
(n = 45)
RCC
GE
Rectal
GE
RCC (n = 2)
Rectal
Mesothelioma
Partial
NSCLC
Colon
Progression-free
≥ 6 mo
NSCLC
Colon
Breast
RCC
RCC (n=3),
NSCLC, Breast,
Adenocystic,
Melanoma
Progression-free
4 mo, <6 mo
NSCLC
Colon
HCC
Fibrosarcoma
Melanoma
NSCLC
Melanoma
*Conventional imaging using RECIST criteria.
GE = gastroesophageal.
Daily Dose, mg
Adenocystic
Colon
Melanoma
18
RAD001
Conclusions: 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
19
RAD001
Single Agent Activity in Renal Cell Cancer
ASCO 2006: Dr Amato, Methodist Hospital – Houston (IIT)
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 2008: Dr J. Jac, Amato, Methodist Hospital – Houston (IIT)
22 patients with disease progression after tyrosine kinase
inhibitors
 22 evaluable : 3 PR (16%) and 14 pts (74%) are progressionfree at 3 mos
 Median PFS of RAD therapy is 5.5 + months (range 1+ to 8+)
Phase 3 Study in 2nd/3rd Line Advanced RCC
after VEGFr Inhibitor failure, RECORD-1
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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
21
21
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
22
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
23
Study Design
Target N = 362
Stratification
• Prior VEGFr
TKI: 1 or 2
• MSKCC risk
group1: favorable,
intermediate,
or poor
R
A
N
D
O
M
I
Z
A
T
I
O
N
2:1
Everolimus + BSC
Upon
Disease
Progression
Placebo + BSC
Interim
analysis
Interim
analysis
Final
analysis
• Interim analyses planned after ≈ 30% and 60% of targeted 290 events
1. Motzer et al. J Clin Oncol. 2004;22:454-463.
24
Study Conduct
N = 410
Stratification
• Prior VEGFr
TKI: 1 or 2
• MSKCC risk
group: favorable,
intermediate,
or poor
R
A
N
D
O
M
I
Z
A
T
I
O
N
2:1
Everolimus + BSC
(n = 272)
Upon
Disease
Progression
Placebo + BSC
(n = 138)
Interim
analysis
Final
Interim
=
analysis
analysis
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
25
Study Treatment
Arm A: everolimus
10 mg po daily
vs
Arm B: matching placebo
po daily
• Repeated 28-day cycles
• Response and safety assessments
• Dose reduction for toxicity
• Treatment continued unless progression or
intolerance
26
Baseline Characteristics
Characteristic
Everolimus
Placebo
No. of patients
272
138
61 (27-85)
60 (29-79)
64/36
67/33
29/56/15
28/57/15
Lung
73
81
Bone
37
31
Liver
35
36
1
10
10
≥2
90
90
Median age, years (range)
% KPS, ≥ 90/≤ 80
% MSKCC risk1
Favorable/intermediate/poor
Sites of metastases, %
No. of metastatic sites
1. Motzer et al. J Clin Oncol. 2004;22:454-463.
27
Prior Therapies
Everolimus
(n = 272)
%
Placebo
(n = 138)
%
Nephrectomy
96
95
Radiotherapy
31
28
Sunitinib
46
44
Sorafenib
28
30
Both
26
26
Interferon
50
50
Interleukin 2
22
24
Chemotherapy
13
16
9
10
Prior Treatment
VEGFr-TKI therapy
Other systemic therapy
Bevacizumab
28
Patient Disposition and
Treatment Administered
Everolimus
(n = 272)
Placebo
(n = 138)
51 (n = 140)
22 (n = 30)
Progressive disease
31
73
Adverse events
10
1
Death
3
2
Withdrawal of consent
3
1
Other reasons
2
1
95
57
12-315
21-237
Treatment ongoing, %
Patient discontinuation, %
Median duration of treatment
Days
Range
29
Progression-Free Survival by Treatment
Central Radiology Review
100
Hazard ratio = 0.30
95% CI [0.22, 0.40]
Probability, %
80
Median PFS
Everolimus: 4.0 mo
Placebo: 1.9 mo
60
Log rank P value < 0.001
Everolimus (n = 272)
Placebo (n = 138)
40
20
0
Patients at Risk
Everolimus
Placebo
0
2
4
6
Months
8
10
12
272
138
132
32
47
4
8
1
2
0
0
0
0
0
30
Progression-Free Survival by Treatment
Central Radiology Review
> 25 %
31
Progression-Free Survival by Treatment
Prior Sunitinib
Central Radiology Review
32
Progression-Free Survival by Treatment
Prior Sorafenib
Central Radiology Review
33
Subgroup Analysis of Progression-Free
Survival
Central Radiology Review
34
Subgroup Analysis of Progression-Free
Survival
Central Radiology Review
1
1. Motzer et al. J Clin Oncol. 2004;22:454-463.
35
Maximum % Change in Target Lesions
and Objective Response Rate*
100%
Everolimus
Placebo
75%
50%
25%
0%
−25%
Best Response
−50%
−75%
−100%
PR
Stable
PD
NE
n (%)
5 (2)
185 (67)
57 (21)
30 (11)
Best Response
PR
Stable
PD
NE
n (%)
0
45 (32)
74 (53)
20 (14)
NE = not evaluable
* Central Radiology Review
36
Laboratory Abnormalities*
Everolimus
%, (n = 269)
All Grades
Grade 3/4
Hematology
Anemia
Lymphopenia†
Thrombocytopenia
Neutropenia
Chemistry
Hypercholesterolemia†
Hypertriglyceridemia
Hyperglycemia†
Elevated creatinine
Hypophosphatemia†
Elevated AST
Elevated ALT
Placebo
%, (n = 135)
All Grades Grade 3/4
91
42
20
11
9/<1
14 / 1
<1
0
76
29
2
3
5
5
0/<1
0
76
71
50
46
32
21
18
3
<1
12
<1
4
<1
<1
32
30
23
33
7
7
4
0
0
1
0
0
0
0
*≥ 10% of everolimus patients
37
†Significant difference between sum of grade 3/4 events for everolimus and placebo groups (P < 0.05)
Treatment-Related Adverse Events*
Stomatitis†
Asthenia / fatigue
Rash
Diarrhea
Anorexia
Nausea
Mucosal inflammation
Vomiting
Cough
Edema peripheral
Infections†
Pneumonitis†
Dyspnea
Everolimus
%, (n = 269)
All Grades
Grade 3
40
3
37
3
25
<1
17
1
16
<1
15
0
14
1
12
0
12
0
10
0
10
3
8
3
8
1
Placebo
%, (n = 135)
All Grades
Grade 3
8
0
24
1
4
0
3
0
6
0
8
0
2
0
4
0
4
0
3
0
2
0
0
0
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)
38 .
Pneumonitis with Everolimus Therapy
Baseline
Month 11
Month 5
Month 12
39
Overall Survival by Treatment
40
Standards for RCC Therapy by Phase III Trial
ASCO 2007
Setting
Treatmentnaïve
Previously
treated
Phase III
Sunitinib
Good or intermediate
risk*
Bevacizumab + IFN-
Poor risk*
Temsirolimus
Prior cytokine
Sorafenib
Sunitinib
Prior VEGFr-TKI
Prior mTOR inhibitor
*MSKCC risk status.
41
Standards for RCC Therapy by Phase III Trial
ASCO 2008
Setting
Treatmentnaive
Previously
treated
Phase III
Sunitinib
Good or intermediate
risk*
Bevacizumab + IFN-
Poor risk*
Temsirolimus
Prior cytokine
Sorafenib
Prior VEGFr-TKI
Everolimus
Sunitinib
Prior mTOR inhibitor
*MSKCC risk status.
42
Conclusions
• Everolimus prolongs progression-free survival
in RCC patients after progression on VEGFrTKI 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
43
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
44
RAD001/Bevacizumab in Advanced RCC
Treatment Received, Activity, Discontinuation
Prev Untreated
(N=30)
•
•
Prev Treated
(N=29)
Treatment duration (median, months)
Currently on treatment
Response
PR
6
14 (24%)
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)
45
45
RAD001/Bevacizumab in Advanced RCC
Toxicity (N=59)
Number of Patients (%)
Toxicity
Grade
1/2
3
4
Neutropenia
10 (23%)
1 (2%)
0
Thrombocytopenia
25 (57%)
1 (2%)
0
Anemia
41 (93%)
0
0
Fatigue
35 (59%)
4 (7%)
1 (2%)
Skin toxicity (rash, pruritus)
53 (90%)
0
0
Hypertension
14 (24%)
1 (2%)
0
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
6 (10%)
0
46 0
Hematologic
Non-Hematologic
Proteinuria
Epistaxis
46
RECORD-2
Phase 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
S
C
R
E
E
N
N = 360
RAD001 10 mg/day
plus
Bevacizumab 10 mg/kg q 2 wk IV
Randomized
1:1
IFN- dose escalation SC
plus
Bevacizumab 10 mg/kg q 2 wk IV
SC = Subcutaneous; IFN- = Interferon alfa.
47
FPFV:
4Q08
47
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
S
C
R
E
E
N
RAD001
10 mg/day
Disease
progression
Randomized
1:1
Sunitinib
50 mg/day,
4 wk on/2 wk off
MSKCC = Memorial Sloan-Kettering Cancer Center; QoL = Quality of life.
Sunitinib
50 mg/day,
4 wk on/2 wk off
RAD001
10 mg/day
48
48
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
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
Study start date is January 2009.
ECOG PS = Eastern Cooperative Oncology Group performance status.
RAD001 10 mg/day
49
49
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
50
50