Transcript Challenges in the Treatment of Breast Cancer: Overcoming

Advances in Treatment of
Renal Cell Carcinoma: Evolving Role
of mTOR Inhibitors
Robert J. Motzer MD
Memorial Sloan-Kettering Cancer Center
New York, NY
Renal Cell Carcinoma (RCC)
• RCC is the most common cancer of the kidney1,2
– Current analyses estimate more than 50,000 new cases and
13,000 deaths in the United States in 20073,4
• Recurrence develops in approximately 40% of
patients with localized tumors5
• Approximately 30% of patients with RCC present with
metastatic disease1
– 5-year survival rate for patients with metastatic RCC
is <10%6
1. Motzer RJ, et al. N Engl J Med. 2007;356:115-124
3. Pickle LW, et al. CA Cancer J Clin. 2007;57:30-42
5. Lam JS, et al. World J Urol. 2005;23:202-212
2. Parkin DM, et al. CA Cancer J Clin. 2005;55:74-108
4. Jemal A, et al. Ca Cancer J Clin. 2007;57:43-66
6. Motzer RJ, et al. N Engl J Med.1996;335:865-875
Treatment of Advanced/Metastatic RCC
• RCC is highly resistant to chemotherapy
• Cytokines have response rates of 5% to 20%
and median OS of 12 months but their use is
limited by toxicity1,2
• Therapies targeted to VEGF and mTOR are
the new standard of care1,3
OS = overall survival; VEGF = Vascular endothelial growth factor.
1. Motzer RJ, et al. N Engl J Med. 2007;356:115-124
2. Hutson TE, et al. Clin Genitourin Cancer Suppl.2006;5(Suppl 1):S31-S39
3. Escudier B, et al. N Engl J Med. 2007;356:125-134.
Clear Cell RCC: VHL Gene Mutation
E2
CUL2
Elongin B
VHL protein
Β-domain
Elongin C
VHL complex
disrupted
Mutant α-domain
HIFα
accumulation
VEGF
Rbx1
VHL = von Hippel-Lindau
HIF = hypoxia-inducible factor
VEGF = vascular endothelial growth factor
PDGF = Platelet-derived epithelial growth factor
Glut1
PDGF
DeVita. Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins. 2005;1826.
RCC Treatment Algorithm
Regimen
Treatment-naive
patient
Treatment-refractory
patient
(≥ second-line)
Setting
Therapy
Options
MSK risk: good or
intermediate
Sunitinib
Bevacizumab
+ IFN-α
High-dose IL-2
MSK risk: poor
Temsirolimus
Sunitinib
Cytokine refractory
Sorafenib
Sunitinib
Bevacizumab
Refractory to
VEGF/VEGFR or mTOR
inhibitors
Everolimus
Sequential TKIs
or VEGF
Inhibitor
MSK = Memorial Sloan-Kettering; mTOR = mammalian target of rapamycin.
TKI = tyrosine kinase inhibitor; VEGF = vascular endothelial growth factor.
VEGFR = vascular endothelial growth factor receptor.
Bukowski RM. Presented at: 43rd ASCO Annual Meeting. June 1-5, 2007; Chicago, IL. Adapted from M Atkins
PI3K/Akt/mTOR pathway
VEGF
RTKs
RTKs
GRB
SOS
308-
AKT
PIP3
Hypoxia
PI3K
Glucose
Amino-acids
-473
HIF-1
PI3K
RAS
HGF
PDGF
PDK
1
IRS1
“Plenty”
“Famine”
EGF
IGF
PI3K-CIII
AMPK
RTKs
LKB1
HK2
RICTOR
REDD1
eNOS
mTORC2
PTEN
GRB
SOS
mLST8
RAS
mSIN1
TSC1/2
Raf
MEK
RHEB
RAPTOR
RAD001
FKBP-12
ERK
mTORC1
mLST8
4EBP
S6K
VHL & O2
Tumor Suppressor
Protein Translation
D-cyclins, c-myc
HIF-1/2α
G1-S transition
Proliferation
Angiogenesis
Glycolysis
Autophagy
Rationale for mTOR Inhibitors in RCC
•
von Hippel–Lindau (VHL) mutations
are commonly observed (57%) in
clear-cell RCC1
•
Loss of VHL function leads to
accumulation of hypoxia-inducible
factor (HIF)-1 and HIF-2, and
overexpression of VEGF, PDGF, and
TGF2,3
•
Activation of mTOR augments
production of proangiogenic growth
factors by increasing HIF-1 activity4,5
•
Therefore, inhibiting mTOR could block
HIF-1/-2 signaling4
1. Maxwell et al. Nature 1999;399:271–5
2. Ohh et al. Nat Cell Biol 2000;2:423–7
3. Iliopoulos et al. Proc Natl Acad Sci USA 1996;93:10595–9
4. Hudson et al. Mol Cell Biol 2002;22:7004–14
5. Hopfl et al. Cancer Res 2002;62:2962–70
Rationale for mTOR Inhibition in mRCC
VHL = Von Hippel-Lindau; HIF = hypoxia-inducible factor.
Brugarolas et al. N Engl J Med. 2007;356:185-187. Copyright 2007 Massachusetts Medical Society. All rights reserved.
Gnarra et al. Nat Genet. 1994;7:85-90.
Schips et al. Am J Clin Pathol. 2004;122:931-937.
Shin Lee et al. J Surg Oncol. 2003;84:166-172. Horiguchi et al. J Urol. 2003;169:710-713.
Thomas et al. Nat Med. 2006;12:122-127.
Brugarolas. N Engl J Med. 2007;356:185-187.
Temsirolimus Mechanism of Action
Growth
factors
Nutrients, Energy,
Stress, and O2
p13 kinase
AKT
p70S6K
Temsirolimus
mTOR
4E-BP1
FKBP-12
c-myc
Ribosomal proteins
Cyclin-D1
Elongation factors
Ornithine
decarboxylase
PROLIFERATION
HIF-1 and HIF-2
VEGF and PDGF
Adapted from Adjei et al.
GROWTH,
PROLIFERATION,
and ANGIOGENESIS
Temsirolimus
mTOR Pathway Inhibitor
HO
O 43
HO
• Rapamycin derivative
O
O
• Intravenous
O
N
O
HO
O
O
O
O
OH
O
O
O
• Daily or weekly dose
– Daily IV  5: 15 (19.2) mg/day
– Weekly IV: 25-250 mg
Temsirolimus
Bjornsti. Nat Rev Cancer. 2004;4:335.
mTOR Inhibitors
• 3 Analogs of rapamycin developed as antitumor agents
– Temsirolimus
– Everolimus (RAD001)
– AP23573
O
O
OH
OH
HO
O
O
42
OMe
O
N
O
HO
OH
O
O
O
O
O
MeO
OM
e
Temsirolimus
Bjornsti. Nat Rev Cancer. 2004;4:335.
O
O
N
O
OH
O
O
OH
O
O
O
Everolimus (RAD001)
O
Randomized Phase 2 Trial of Temsirolimus:
Median Survival by Risk Group
Risk Group
n (%)
Median Survival
Months (95% CI)
Temsirolimus (second line, n = 105*)
8 (8%)
24 (18, 27)
Intermediate
48 (46%)
23 (17, 26)
Poor
49 (47%)
8.2 (7, 10)
111
15 (10, 18)
Favorable
79 (18%)
30 (21, 38)
Intermediate
271 (62%)
14 (12, 16)
Poor
87 (20%)
4.9 (4.3, 6.3)
463
13 (12, 15)
Favorable
Overall
MSKCC data (first line, n = 437†)
Overall
* Patients for whom prognostic factor data available. † IFN-based treatments.
Atkins MB, et al. J Clin Oncol. 2004;22(5):909-918. Reprinted with permission from the American Society of Clinical Oncology.
Phase 1 Trial of Temsirolimus and IFN-α:
Results
MTD/Recommended doses:
Temsirolimus: 15 mg weekly
IFN-: 6 MU SC 3 times a week
Endpoint
Total Population
MTD Population
Response rate
11%
8%
Clinical benefit
46%
44%
9.1 months
7.6 months
Median PFS
MTD = maximum tolerated dose; PFS = progression-free survival
Motzer et al. J Clin Oncol 25:3958-3964, 2007
Phase 3 Trial:
Temsirolimus vs IFN-α in First-Line Treatment of Poor-Risk mRCC
IFN-α escalating to 18 MU SC tiw
(n = 207)
N = 626
Eligibility Criteria
 Previously untreated mRCC
 Poor prognosis (≥3 predictors of poor
risk):
– LDH >1.5 × ULN
– Hemoglobin <LLN
– Corrected calcium >10 mg/dL
– Diagnosis to first treatment <1 year
– KPS 60-70
– Multiple organ sites of metastasis




Temsirolimus 25 mg IV weekly
(n = 209)
Temsirolimus 15 mg IV weekly +
IFN- 6 MU SC tiw
(n = 210)
Randomized, international multicenter trial
All histologies included
Primary end point: OS
Treatment continued until PD, toxicity, or symptom deterioration
LLN = lower limit of normal; ULN = upper limit of normal; OS = overall survival.
Hudes G, Motzer RJ et al. N Engl J Med. 2007;356:2271-2281.
Phase 3 Study of Temsirolimus and IFN-:
Patient Baseline Characteristics
Characteristic
IFN-
(n = 207)
Temsirolimus +
IFN-
Temsirolimus
(n = 210)
(n = 209)
Median age (years)
60
58
59
Male (%)
71
66
69
Karnofsky PS (% ≤ 70)
83
80
84
Previous nephrectomy (%)
67
66
67
Clear-cell tumor histology (%)
82
81
78
< 1 year from initial diagnosis to
randomization (%)
79
83
85
≥ 3 poor prognostic features (%)
95
93
94
< 3 poor prognostic features (%)
5
7
6
Poor risk by MSKCC criteria (%)
76
69
76
≥ 2 sites of organ metastasis (%)
80
79
80
PS = performance status; MSKCC = Memorial Sloan-Kettering Cacner Center.
Hudes et al. N Engl J Med. 2007;356:2271-2281.
Phase 3 Study of Temsirolimus and IFN-:
Overall Survival
n
Median OS,
months
(95% CI)
IFN-α
207
7.3 (6.1-8.8)
Temsirolimus
209
10.9 (8.6-12.7)
Temsirolimus + IFN
210
8.4 (6.6-10.3)
Probability of survival
1.00
0.75
0.50
0.25
Temsirolimus (n = 209)
Temsirolimus + IFN-α (n = 210)
IFN-α (n = 207)
0.00
0
5
10
15
20
25
Interferon-α
207
126
80
Temsirolimus
209
159
Combination
210
135
30
42
15
3
0
110
56
19
3
0
93
50
17
7
2
Months
No. at Risk
Hudes et al. N Engl J Med. 2007;356:2271-2281. Copyright © 2007 Massachusetts Medical Society. All rights reserved.
Phase 3 Study of Temsirolimus and IFN-:
Progression-free Survival and Response
Probability of PFS
1.00
IFN-α
Temsirolimus
Temsirolimus + IFN-α
0.75
Median PFS
(months)
1.9
3.8
3.7
n
207
209
210
ORR (%)
4.8
8.6
8.1
0.50
0.25
0
0
5
10
15
20
25
30
Months
No. at Risk
Interferon-α
207
55
24
10
5
1
0
Temsirolimus
209
91
38
14
7
1
0
Combination
210
89
32
16
4
1
1
PFS, progression-free survival; ORR, objective response rate
Hudes et al. N Engl J Med. 2007;356:2271-2281. Copyright © 2007 Massachusetts Medical Society. All rights reserved.
Temsirolimus ± IFN-α
Maximum Percent Reduction in Tumor Measurement*
Change from baseline (%)
200
100
0
–100
44%
IFN
67%
TEMSR
Patients
*Investigator assessed measurements
77%
IFN + TEMSR
Temsirolimus Phase III Trial
Percent (%) of Patients with Selected Adverse Events
All Grades and Grade 3–4
IFN-α
n=203
TEMSR
n=209
TEMSR + IFN-α
n=209
Adverse Event
All
Gr 3–4
All
Gr 3–4
All
Gr 3–4
Asthenia
66
27
54
12
64
30
Nausea
43
5
37
4
42
2
Rash
5
0
37
1
16
2
Dyspnea
28
8
30
9
26
11
Diarrhea
20
2
28
1
27
5
Edema
9
0
27
0
16
2
Vomiting
29
3
21
3
31
2
Stomatitis
3
0
20
1
21
5
Hudes et al. N Engl J Med. 2007;356:2271-2281.
Temsirolimus Phase III Trial
Percent Patients with Laboratory Abnormalities
All Grades and Grade 3–4
IFN-α
n=203
TEMSR
n=209
TEMSR + IFN-α
n=209
Abnormality
All
Gr 3–4
All
Gr 3–4
All
Gr 3–4
Anemia
43
24
50
21
66
39
Hyperlipidemia
16
1
28
7
39
2
Hyperglycemia
11
1
26
10
16
4
Hypercholesteremia
5
0
24
1
27
0
Creatinine increase
12
1
16
4
22
2
Thrombocytopenia
8
0
13
1
37
9
Neutropenia
12
8
7
3
25
14
Hudes et al. N Engl J Med. 2007;356:2271-2281.
Phase III Trial Temsirolimus vs IFN-α
Subset Analyses
Median survival
IFN-α
TEMSR
HR
Intermediate Risk1
17.7 (n=51)
13.0 (n=64)
1.17
Poor Risk1
6.0 (n=156)
10.2 (n=145)
0.76
Clear Cell
8.2 (n=170)
10.6 (n=169)
0.85
Other
4.3 (n=36)
11.6 (n=37)
0.55
HR : hazard ratio
1. MSK prognostic groups
Dutcher et al. ASCO, 2007.
Subset Analysis:
Effect of Prior Nephrectomy
No Nephrectomy
Number of
patients
OS
Nephrectomy
IFN-α
Temsirolimus
IFN-α
Temsirolimus
68
70
139
139
6.2 mo
11.5 mo
7.8 mo
10.4 mo
OS HR**
0.61
PFS
2.0 mo
PFS HR**
5.7 mo
0.62
0.84
3.5 mo
5.3 mo
0.72
P
Value*
0.20
0.47
OS and PFS are prolonged in patients receiving
temsirolimus vs IFN-α regardless of nephrectomy status
*Test of interaction between nephrectomy and treatment status based on unstratified Cox proportional hazard model.
**Temsirolimus:IFN-α.
OS = overall survival; PFS = progression-free survival.
Logan. ASCO. 2008 (abstract 5050).
RAD001
An Oral mTOR Pathway Inhibitor
• Rapamycin derivative
HO
O
• Oral
O
• Daily or weekly dose
O
N
O
O
OH
O
O
O
O
O
– Daily: 10 mg
OH
O
– Weekly: 50-70 mg
• Inhibits cell growth,
angiogenesis, and
bioenergetics
• Phase 2 trial shows activity
RAD001
Bjornsti. Nat Rev Cancer. 2004;4:335.
• Phase 3 trial under way
• New unmet medical need for
patients after VEGFr-TKI
therapy (sunitinib or
sorafenib)
• Phase II trial of everolimus
treatment shows activity in
previously treated
RCC patients1
• Everolimus, as an oral
mTOR inhibitor, has
a mechanism distinct
from that of VEGFr TKIs2
TKIs = tyrosine kinase inhibitors.
1. Jac et al. J Clin Oncol. 2008;26 [Abstract 5113].
2. Lane et al. Clin Cancer Res 2009;15:1612–22.
Progression free survival (%)
Rationale for RECORD-1 Phase III trial:
Renal Cell cancer treatment with Oral RAD001 given Daily
Progression-free survival
100
75
n = 37
50
25
Median = 11.17+ (1.66 35.77+) months
0
0
10
20
Time (months)
30
40
RECORD-1:
Study Summary
• Multicenter, Phase III, randomized trial of everolimus
vs placebo
• Primary endpoint: progression-free survival (PFS)
– 33% risk reduction (hazard ratio = 0.67)
– 290 events to achieve 90% power
• Key eligibility criteria
– mRCC with clear-cell component
– Progressive disease on or within 6 months of
treatment with sunitinib, sorafenib, or both
– Prior bevacizumab and cytokines permitted
RECORD-1: Study Design and Conduct
N=416
Stratification by:
Prior VEGFr-TKI:
1 or 2
MSKCC risk group 1:
favorable,
intermediate,
or poor
R
A
N
D
O
M
I
Z
A
T
I
O
N
2:1
Everolimus 10 mg/day + BSC
(n=277)
Upon
disease
progression
Study
unblinded
Placebo + BSC
(n=139)
Safety interim
analysis
2nd interim
analysis data
cut-off: 15-Oct-07,
n=410
End of doubleblind analysis
data cut-off:
28-Feb-08
Survival
follow-up:
15-Nov-08
● 416 patients randomized between Dec-06 and Nov-07
● Analysis cut-off: 28-Feb-08, based on 266 PFS events
● Second interim analysis cut-off: 15-Oct-07, efficacy boundary crossed with 410 patients / 191 PFS events
BSC = best supportive care; MSKCC = Memorial Sloan-Kettering Cancer Center.
Motzer et al. Lancet 2008;372:449–456; complete study unblinded on 28-Feb-08.
RECORD-1:
Baseline Patient Characteristics (N=416)
Characteristic
Everolimus
Placebo
277
139
61 (27–85)
60 (29–79)
29/56/14
28/57/15
Sunitinib
46
44
Sorafenib
28
30
Both
26
26
Interferon
50
50
Interleukin-2
22
24
Chemotherapy
13
16
Bevacizumab
9
10
No. of patients, n
Median age, years (range)
MSKCC risk*, %
Favorable/intermediate/poor
Prior VEGFR-TKI therapy, %
Other systemic therapy, %
*Motzer et al. J Clin Oncol 2004;22:454–63.
Escudier et al. Ann Oncol 2008;19:viii45 [Abstract 720].
RECORD-1:
PFS by Treatment; End of Double-blind
Central radiology review1
Hazard ratio = 0.33
95% CI [0.25, 0.43]
80
Median PFS
Everolimus: 4.90 months
Placebo: 1.87 months
60
Log rank P value <0.001
Everolimus (n=277)
Placebo (n=139)
40
Hazard ratio = 0.32
95% CI [0.25, 0.41]
100
Median PFS
Everolimus: 5.49 months
Placebo: 1.87 months
80
Probability (%)
100
Probability (%)
Investigator assessment2
20
Log rank P value <0.001
60
Everolimus (n=277)
Placebo (n=139)
40
20
0
0
0
2
4
6
8
10
12
14
0
2
4
6
Time (months)
8
10
12
14
Time (months)
Number of patients at risk, n
Number of patients at risk, n
Everolimus
277
192
115
51
26
10
1
0
Everolimus
277
210
149
76
33
11
2
0
Placebo
139
47
15
6
2
0
0
0
Placebo
139
62
25
8
5
0
0
0
PFS = progression-free survival
Analysis on Feb 2008 data cut-off.
1. Escudier B et al. Ann Oncol 2008;19:viii45 [Abstract 720]; 2. Kay et al. Presented at ASCO-GU 2009 [Abstract 278] by Motzer.
RECORD-1:
PFS by Investigator
106 Placebo Patients Crossed Over to Receive Everolimus
100
Everolimus (# events/106 treated = 45/106)
Probability (%)
80
Kaplan–Meier median
Everolimus: 5.09 mo 95% CI [3.71,7.56]
60
40
20
0
0
1
2
3
4
106
91
6
7
8
9
10
11
12
3
2
1
1
0
Time (months)
Number of patients at risk, n
Everolimus
5
69
61
30
27
Analysis on Feb 2008 data cut-off.
Kay et al. Presented at ASCO-GU 2009 [Abstract 278] by Motzer.
15
9
RECORD-1:
Maximum % Change in Target Lesions and Objective Response Rate*
Everolimus
Placebo
100%
100%
75%
75%
50%
50%
25%
25%
0%
0%
−25%
−25%
−50%
−75%
−100%
Best response
n (%)
PR
5 (2)
Stable
185 (67)
PD
57 (21)
NE
30 (11)
NE = not evaluable; * Central radiology review.
Escudier et al. Ann Oncol 2008;19:viii45 [Abstract 720].
Best response
−50%
−75%
−100%
PR
n (%)
0
Stable
45 (32)
PD
74 (53)
NE
20 (14)
RECORD-1:
Selected Treatment-related Adverse Events; End of Double-blind
Everolimus
%, (n = 274)
All grades
Placebo
%, (n = 137)
Grade 3/4
All grades
Grade 3/4
Stomatitis
42
3/0
8
0/0
Asthenia
22
2/0
9
<1/0
Fatigue
23
3/0
17
<1/0
Rash
28
1/0
5
0/0
Diarrhea
21
1/0
4
0/0
Nausea
18
<1/0
8
0/0
Mucosal inflammation
17
1/0
1
0/0
Edema peripheral
13
<1/0
4
0/0
Infections (total)
13
2/2
2
0/0
Dyspnea
10
2/0
3
0/0
Pneumonitis
14
4/0
0
0/0
Hypercholesterolemia
18
3/0
2
0/0
Hypertriglyceridemia
15
1/0
2
0/0
8
4/0
<1
<1/0
Laboratory Abnormalities
Hyperglycemia
● Four treatment-related deaths: one each of candidal sepsis/ARDS, sepsis, acute respiratory failure, and recurrent
bronchopulmonary aspergillosis
Analysis on Feb 2008 data cut-off.
Kay et al. Presented at ASCO-GU 2009 [Abstract 278] by Motzer.
Temsirolimus: Predictors of Response
• 20 specimens from patients with advanced RCC who had been
treated with temsirolimus
• Expression levels of pS6 and pAkt correlated with patient
response to temsirolimus
Number of Objective Responses
(Minor Response or PR)/Total Number of Patients With Composite Expression
Low pS6
Intermediate pS6
High pS6
Low pAkt
0/3
0/1
0/1
Intermediate pAkt
0/1
0/3
2/6
High pAkt
0/0
1/1
1/3
High tumor pS6 or pAkt expression may predict response to temsirolimus
(4/10 vs 0/9 [low expression of pS6 or pAkt]; P=0.02)
pAkt = phosphorylated Akt gene; PR = partial response.
Cho. Clin Genitourinary Cancer. 2007;5:379.
Combination Therapies:
Targeting VEGF at Multiple Levels
Vertical blockade
mTOR
Temsirolimus
HIF
O2
VEGF
VEGFR
Bevacizumab
Sorafenib, sunitinib
Adapted with permission from Kaelin. Clin Cancer Res. 2004;10:6290s; Atkins. ASCO 2006 Plenary session; Pantuck. Cancer. 2007;109:2257.
Combination Drug Therapy
Selected Adverse Events with Agents
Rash or
Gastro-intestinal
Hand-foot
Reaction
Hypertension
Cytopenia
Sunitinib
Yes
Yes
Yes
Sorafenib
Yes
Yes
Bevacizumab
Temsirolimus
Mucosal
Yes
Yes
Yes
Yes
Proteinuria
Yes
Yes
Yes
Phase I Trial of Sunitinib + Temsirolimus
Dose Level
Temsirolimus (mg)
Sunitinib (mg)
-1
10
25
0
15
25
1
25
25
2
25
37.5
3
25
50
(starting dose)
DLT as defined in protocol
• Grade 4 neutropenia > 7 days; febrile neutropenia
• Persistent grade 3 nonhematologic toxicity > 7days
• Grade 4 HTN, hemorrhage
• Any thromboembolic event
Two of 3 patients in 1st cohort developed DLT: rash (1 pt), cellulitis + thrombocytopenia (1 pt)
DLT = dose-limiting toxicity
Fischer P, Motzer et al; JCO 26, 672s, Abst 16020
Phase 2 Trial of Bevacizumab plus Everolimus:
Adverse Events
AEs
Grade 3
Grade 4
Fatigue
4 (7%)
1 (2%)
Hypertension
1 (2%)
0
10 (17%)
2 (3%)
Mucositis/stomatitis
4 (7%)
0
Diarrhea
5 (8%)
0
Hyperlipidemia
2 (3%)
0
Neutropenia
1 (2%)
0
Thrombocytopenia
1 (2%)
0
Anemia
1 (2%)
1 (2%)
Nonhematologic
Proteinuria
Hematologic
Whorf et al. ASCO, 2008. Abstract 5010.
RECORD-2
Phase II First-line in RCC: RAD001 + Bevacizumab
• Patients with previously untreated metastatic RCC
• RAD001 + bevacizumab vs. interferon-α + bevacizumab
• Open label, randomized, group sequential design
S
C
R
E
E
N
Randomize
RAD001 10 mg/d + Bevacizumab
10 mg/kg IV q 2 wks
Prim Endpoint:
• PFS
Sec Endpoints:
• Response
1:1
Interferon-α dose escalation SQ +
Bevacizumab 10 mg/kg IV q 2 wks
• Survival
• Safety
• QoL
Phase II Trial: ECOG BeST
Bevacizumab 10 mg/kg IV every 2 weeks
(days 1 and 15)
Advanced RCC
Stratified by:
Prior therapy
(cytokine/vaccine vs
no cytokine)
Motzer risk category
(low, intermediate, or high)
(N=360*)
Bevacizumab 10 mg/kg IV every 2 weeks
(days 1 and 15) +
Temsirolimus 25 mg IV weekly
(days 1, 8, 15, and 22)
Bevacizumab 10 mg/kg IV every 2 weeks
(days 1 and 15) +
Sorafenib 400 mg bid
Sorafenib bid +
Temsirolimus IV weekly
(days 1, 8, 15, and 22)†
• Primary endpoint: PFS
• Secondary endpoints: ORR, OS, and correlates (dynamic contrast-enhanced MRI, biomarkers)
*Accrual goal.
†Arm to be added when phase II doses are available from ongoing phase I trials.
ECOG = Eastern Cooperative Oncology Group; BeST = Bevacizumab-Sorafenib-Temsirolimus;
PFS = progression-free survival; ORR = overall response rate; OS = overall survival
Randomized Phase II Crossover Design
(RECORD-3)
• First-line treatment of patients with previously untreated mRCC
• Primary end point: Progression-free survival (part I)
• Secondary end points: Progression-free survival at the end of
part II, overall survival, safety, quality of life
S
C
R
E
E
N
Sunitinib
50 mg/day,
4 wk on/2 wk off
Everolimus
10 mg/day
Disease
progression
Randomized
1:1
Sunitinib
50 mg/day,
4 wk on/2 wk off
Part I
ClinicalTrials.gov. NCT00903175.
Everolimus
10 mg/day
Part II
Temsirolimus vs Sorafenib in Advanced Renal Cell
Carcinoma as Second-Line Therapy in Patients Who
Have Failed First-Line Sunitinib Therapy
Study Design: International, Prospective, Randomized, Open-label, Outpatient, Multicenter Study
Patients with advanced RCC, PD by
RECIST criteria while receiving 1st-line
sunitinib therapy, at least 1
measureable lesion, at least 2 wks
since prior treatment with sunitinib,
palliative radiation therapy, and/or
surgery, and resolution of all toxic
effects of prior therapy, age ≥18
R
A
N
D
O
M
I
Z
A
T
I
O
N
Temsirolimus 25 mg IV q week
n = 220
Sorafenib 400 mg PO BID
n = 220
Primary endpoints: PFS, safety, and tolerability
Secondary endpoints: RR (CR & PR), OS, SD at 12, 24, 36 wks, clinical benefit (CR+PR+SD at > 24 wks),
duration of response and best tumor shrinkage
PD = pre-determined; RECIST = Response Evaluation Criteria In Solid Tumors; PFS = progression-free survival;
PR = partial response; CR = complete response; OS = overall survival; SD = standard deviation.
ClinicalTrials.gov. NCT00474786.
mTOR Inhibitors in mRCC
Conclusions
• Phase 3 trial in patients with poor prognosis shows
survival benefit for temsirolimus over IFN-
• Phase 3 trial of everolimus in TKI-refractory shows
improvement in progression-free survival
• mTOR is an important therapeutic target
• Studies of tumor biology, combination programs,
and novel mTOR inhibitors are of high priority
Advances in Treatment of
Renal Cell Carcinoma: Evolving Role
of mTOR Inhibitors
Robert J. Motzer MD
Memorial Sloan-Kettering Cancer Center
New York, NY