Transcript Slide 1

6th Advancing Cancer Care in the Elderly Conference
Taking Aim with Targeted Therapies: Are We Hitting the Right Marks?
Renal Cell Carcinoma:
A New Standard of Care
Roberto Pili M.D.
Associate Professor of Oncology and Urology
The Sydney Kimmel Comprehensive Cancer Center at
Johns Hopkins
Baltimore MD
Disclosure
• Research funding: Pfizer, Cephalon, Celgene
• Consultant: Active Biotech, Locus, Novartis, Genentech
Objectives
• To review the biological and clinical features of renal cell
carcinoma
• To summarize the clinical activity & toxicity profiles of
antiangiogenesis agents in renal cell carcinoma
• To describe the future development of anti angiogenesis
therapies for renal cell carcinoma
Renal Cell Carcinoma
• In the United States in 2008:
– 54,390 estimated new cases of RCC
– 13,010 estimated deaths
• Risk factors:
– Male sex (3:2), Cigarette smoking (2:1), Hypertension,
Obesity
– Hereditary syndromes (15-40% lifetime risk)
• Incidence:
– Increasing (median age 65 y.o.)
• For mRCC:
– Median survival: 10.9-26.4 months
– 20%-30% of patients present with mRCC
– 20%-40% of patients will develop mRCC after
nephrectomy
Staging of RCC
Cohen , NEJM 2005
Histological Classification
of Human Renal Epithelial Neoplasms
RCC
Clear cell
Papillary type 1
Papillary type 2
Chromophobe
Oncocytoma
Incidence (%)
75%
5%
10%
5%
5%
Associated
mutations
VHL
c-Met
FH
BHD
BHD
Type
BHD=Birt-Hogg-Dubé; FH=fumarate hydratase; VHL=von Hippel-Lindau.
Modified from Linehan WM et al. J Urol. 2003;170:2163-2172.
Kinase expression: Genetic Signatures
-
-
C-MET
Clear cell
Papillary
C-KIT
Chromophobe
Oncocytoma
Teh BT, 2006
KinomeExpression in Renal Tumors
Factors Predicting Prognosis in RCC
Anatomic
Histologic
Clinical
• Tumor size
• Metastasis
• Venous
involvement
• Lymph node
involvement
• Fuhrman grade
• Morphology
• Microvascular
invasion
• Tumor necrosis
• PS
• Cachexia-related
symptoms
• Thrombocytosis
PS = performance status.
Shuch BM, et al. Semin Oncol. 2006;33:563-575.
MSKCC Risk Factor Model in mRCCIFN days
0 risk factors (n=80 patients)
1 or 2 risk factors (n=269 patients)
3, 4, or 5 risk factors (n=88 patients)
1.0
Proportion Surviving
0.9
MS:
20 mo
10 mo
4 mo
0.8
Risk factors associated with worse prognosis
0.7
• KPS <80
0.6
• Low serum hemoglobin (13 g/dL/11.5 g/dL: M/F)
0.5
• High corrected calcium (10 mg/dL)
0.4
• High LDH (300 U/L)
0.3
• Time from Dx to IFN- <1 yr
0.2
0.1
0
0
6
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16
Time From Start of IFN- (years)
Motzer RJ et al. J Clin Oncol. 2002;20:289-296.
Targets in RCC
Vorinostat
Everolimus
Everolimus
LBH589
Temsirolimus
Bevacizumab
VEGF-Trap
Cell division
Cell proliferation
Angiogenesis
Axitinib
Pazopanib
Angiogenesis
Adapted from Brugarolas J NEJM 2007
Rational Targets in RCC
• IL-2
- immune response
• Sorafenib
FDA approved for RCC 1992
FDA approved for RCC 12/05
– VEGFR, PDGFR, RAF
• Sunitinib
FDA approved for RCC 1/06
– VEGFR, PDGFR
• Temsirolimus - mTor
• Everolimus - mTor
• Bevacizumab -VEGF
• VEGF-Trap -VEGF
• Erlotinib - EGFR
EGFR=epidermal growth factor receptor.
FDA approved for RCC 5/07
RCC: Current NCCN Treatment Paradigm
Stage I/II/III
Surgical
excision
Observation or consider adjuvant
therapy in a clinical trial
Relapse
Stage IV
(metastatic)
Nephrectomy +
metastasectomy or
CRN
(if unresectable,
proceed to first-line
systemic therapy)
First Line
Second Line
Clinical trial
Clinical trial
Sorafenib‡
Sunitinib‡
Temsirolimus§
IFN¶
High-dose IL-2¶
Low-dose IL-2 ± IFN¶
Bevacizumab¶
Best supportive care
Sunitinib*
Temsirolimus
(poor prognosis
patients)*
Bevacizumab + IFN
High-dose IL-2†
Sorafenib†
Best supportive care
*Category 1
†Selected patients
‡ Category 1 following cytokine therapy and category 2A following TKI
§ Category 2A following cytokine therapy and category 2B following TKI
¶Category 2B.
CRN = cytoreductive nephrectomy; IL-2 = interleukin-2; NCCN = National Comprehensive Cancer Network;
TKI = tyrosine kinase inhibitor.
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: kidney cancer.
V.1.2008. http://www.nccn.org/professionals/physician_gls/PDF/kidney.pdf. Accessed 01/14/2008.
Sorafenib for mRCC:
Phase III Study Design (TARGET)
Unresectable
and/or mRCC,
1 prior systemic Tx
in last 8 months,
ECOG PS 0/1
(N=903*)
Sorafenib, 400 mg bid (n=451)
Placebo (n=452)
• 1° end point: OS
• 2° end points: ORR, PFS, safety, HR-QoL
• Demographics
– MSKCC good or intermediate risk patients(57/41)
– Clear-cell carcinoma
Escudier, NEJM 2007
Sorafenib for mRCC:
Response Rate* (TARGET)
Best Response by RECIST
Complete response
Partial response
Stable disease
Sorafenib
(n=451)
n (%)
1 (<1)
43 (10)
Placebo
(n=452)
n (%)
—
8 (2)
333 (74)
239 (53)
Progressive disease
56 (12)
167 (37)
Missing
18 (4)
38 (8)
Escudier, NEJM 2007
Sorafenib for mRCC:
Progression-Free Survival* (TARGET)
Proportion of Patients
Progression Free
1.00
0.75
Median
(months)
5.5
Sorafenib (n=451)
PFS
Sorafenib
0.50
Placebo
Hazard ratio
0.25
2.8
0.51
Placebo (n=452)
0
0
2
4
6
8
10
12
14
16
Time From Randomization (months)
Escudier, NEJM 2007
18
20
Sorafenib: Phase III TARGETs—
Summary of OS Analysis
OS at
Crossover1
OS 6 Months
PostCrossover1*
OS 6 Months
PostCrossover
With Placebo
Censored2
Sorafenib med. OS
Not reached
19.3 months
19.3 months
17.8 months
Placebo median OS
14.7 months
15.9 months
14.3 months
15.2 months
Increase in OS
39%
30%
Hazard ratio
0.72
0.77
0.74
0.88
P value
0.02
0.02
0.01
0.146
0.0005
0.0094
n/a
≤0.037
O’Brien-Fleming
stopping boundary
Final OS
16 Months
PostCrossover3
13.5%
• In the final OS analysis, 62% of total patient-years of exposure to study drug in the
placebo arm corresponded to Sorafenib
*At the time of analysis, 216/452 (48%) of patients in the placebo group had crossed over to receive Sorafenib.
1. Escudier B et al. New Engl J Med. 2007;356:125-134.
2. Eisen T et al. Presented at: ASCO 2006
3. Adapted from: Escudier B et al. 2007
Proportion of Patients Progression-Free
Sorafenib vs IFN-: Randomized Phase II
PFS by Independent Review
1.00
Median PFS
Sorafenib=5.7 months
Interferon=5.6 months
0.75
Hazard ratio=0.88 (95% Cl: 0.61-1.27)
P value (log-rank test)=0.504
Sorafenib
0.50
IFN-
0.25
0
0
1
2
3
Patients at risk
Sorafenib
Interferon
4
5
6
7
8
9
10
11
12
13
14
15
Time From Randomization (months)
97
92
75
57
30
34
16
24
4
7
Adapted from Escudier B et al. Presented at: 5th Intl Symposium on TAT; March 8-10, 2007; Amsterdam, The
Netherlands.
Sunitinib vs IFN- for mRCC:
Phase III Study Design
Unresectable
and/or mRCC,
No prior systemic
Tx, ECOG PS 0/1
(N=750)
Sunitinib, 50 mg qd (n=375)
4 weeks on, 2 weeks off (4/2)
IFN- (n=375)
3 MU tiw, 6 MU tiw, 9 MU tiw
• 1° end point: PFS
• 2° end points: RR, OS, safety, patient reported outcomes
• Demographics
– MSKCC good or intermediate risk patients(34/47)
– Clear-cell carcinoma
Motzer et al , NEJM 2007
Treatment-Related Adverse Events
IFN- (%)
Sunitinib (%)
Event
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
Motzer, NEJM 2007
* Greater frequency, P <0.05
First-Line Sunitinib vs IFN-α: PFS
and Response Rate
Sunitinib (n = 375)
Median: 11.0 months
(95% CI: 10.0-12.0)
IFN-α (n = 375)
Median: 5.0 months
(95% CI: 4.0-6.0)
0.9
0.8
Sunitinib
0.7
PFS
0.6
0.5
IFN-α
0.4
0.3
0.2
0.1
Hazard Ratio = 0.42; 95% CI (0.32–0.54);
0.0 P<0.001
0 1 2
Patients at Risk (n)
Sunitinib
375
IFN-α
375
IFN-α (n = 375)
35
Objective Response Rate (%)
1.0
Sunitinib (n = 375)
31%
30
25
20
P<0.001
15
10
6%
5
0
3
4
5
6
7
8
9 10 11 12 13 14
Months
235
152
90
42
Sunitinib
Treatment
32
18
2
0
PFS = progression-free survival.
Motzer RJ, et al. N Engl J Med. 2007;356:115-124.
Motzer RJ, et al. 2007 ASCO Annual Meeting; Abstract 5024.
IFN-α
Sunitinib vs IFN-: Final Overall Survival
Overall Survival Probability
1.0
Sunitinib (n = 375)
Median: 26.4 months
(95% CI: 23.0 - 32.9)
IFN- (n = 375)
Median: 21.8 months
(95% CI: 17.9 - 26.9)
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
Total Death
Sunitinib 190
IFN-
200
Hazard Ratio = 0.821
(95% CI: 0.673 - 1.001)
P = 0.051 (Log-rank)
0.1
0
0
3
6
9
12
15
18
21
Time (months)
Figlin RA, et al. 2008 ASCO Annual Meeting; Abstract 5024.
24
27
30
33
36
Figlin RA, et al. 2008 ASCO Annual Meeting; Abstract 5024.
Temsirolimus (TEMSR, CCI-779) for mRCC:
Phase III Study Design
Advanced RCC
No prior therapy
KPS ≥60
(N=626)
IFN-
escalating to 18 MU SC tiw
TEMSR
25 mg IV qw
TEMSR
15 mg IV qw + IFN- 6 MU tiw
• 1° end point: OS
• 2° end points: PFS, TTF, OR, and clinical benefit
• Demographics
– MSKCC poor (~70%) or intermediate risk patients
– Predominately clear-cell carcinoma
Hudes G et al. Presented at: ASCO; June 2-6, 2006; Atlanta, GA.
Hudes G et al. NEJM 2007
Temsirolimus vs IFN-:
Selected Adverse Events
IFN-
Adverse Event
All Grades
Temsirolimus
Grade 3/4
All Grades
Grade 3/4
Patients (%)
P = 0.02
Any Grade 3/4
NA
78
NA
67
Asthenia
64
26
51
11
Nausea
41
4
37
2
Rash
6
0
47
4
Dyspnea
24
6
28
9
Diarrhea
20
2
27
1
Stomatitis
4
0
20
1
Anemia
42
22
45
20
Hyperlipidemia
14
1
27
3
Hyperglycemia
11
2
26
11
Creatinine Increase
10
1
14
3
Neutropenia
12
7
7
3
Hudes G et al. N Engl J Med. 2007;356:2271-2281.
TEMSR for mRCC:
Response Rates
IFN-
(n=207)
n (%)
TEMSR
(n=209)
n (%)
TEMSR + IFN (n=210)
n (%)
Objective response
(CR + PR)
15 (7)
19 (9)
24 (11)
Clinical benefit
(CR + PR [SD ≥16
wks])
60 (29)
96 (46)
86 (41)
Best response
Hudes G et al. Presented at: ASCO; June 2-6, 2006; Atlanta, GA.
Hudes G et al. NEJM 2007
Temsirolimus vs IFN-:
OS by Treatment Arm
P = 0.008; IFN-α vs temsirolimus
1.00
Probability of Survival
P = 0.70; IFN-α vs IFN-α + temsirolimus
0.75
Arm 2: Temsirolimus (n = 209)
0.50
Arm 1: IFN-α (n = 207)
0.25
Arm 3: Temsirolimus + IFN-α
(n = 210)
0.00
0
Patients at Risk (n)
IFN-α
Temsirolimus
5
10
15
20
25
30
35
Time From Randomization (months)
207
209
126
159
80
110
42
56
15
19
3
3
0
0
Hudes G, et al. N Engl J Med. 2007;356:2271-2281. Copyright © 2007 Massachusetts Medical Society. All rights reserved.
Temsirolimus vs IFN-α, Poor-Risk
mRCC: Correlation With Survival
Subgroup
N
Histology
Clear cell
Other
339
73
Age
<65 Years
≥65 Years
287
129
Prognostic Risk
Intermediate
Poor
115
301
0.0
HR (95% CI)
0.5
Temsirolimus Better
Dutcher JP, et al. 2007 ASCO Annual Meeting; Abstract 5033.
1.0
1.5
IFN-α Better
2.0
AVOREN for mRCC:
Phase III Study Design
Advanced RCC
No prior therapy
KPS ≥60
(N=649)
Bevacizumab +
IFN-α2a (n=327)
1:1
IFN-α2a + placebo (n=322)
•
Bevacizumab/placebo 10mg/kg i.v. q2w until progression
•
IFN-2a 9MIU s.c. three times/week (maximum of 52 weeks)
(dose reduction allowed)
•
Multinational ex-US study: 101 study sites in 18 countries
•
Stratification factors: country and Motzer score
PD = progression of disease; i.v. = intravenous; s.c. = subcutaneous
Escudier, ASCO 2007
Escudier, Lancet 2007
AVOREN: Selected grade 3/4
adverse events*
Adverse event
Number of patients (%)
IFN +
Bevacizumab +
placebo
IFN
(n=304)
(n=337)
Any grade 3/4 adverse event
137 (45)
203 (60)
Fatigue/asthenia/malaise
46 (15)
76 (23)
Proteinuria
0 (0)
22 (6.5)
Hypertension
2 (0.7)
13 (3.9)
Hemorrhage
1 (0.3)
11 (3.3)
Venous thromboembolism
Gastrointestinal perforation
2 (0.7)
6 (1.8)
0 (0)
5 (1.5)
Arterial ischemia
1 (0.3)
4 (1.2)
*Based on safety population
AVOREN: Tumor response
Response
Overall response rate (%)*
Complete response
Partial response
IFN + placebo
(n=289)
Bevacizumab + IFN
(n=306)
13
2
11
31
1
30
p<0.0001
Median duration of response
(months)
Median duration of stable
disease (months)
*Patients with measurable disease only
11
13
7
10
AVOREN: Investigator-Assessed
PFS
1.0
Probability of Being
Progression Free
0.9
Median PFS
0.8
Bevacizumab + IFN- 2a = 10.2 mo
IFN- 2a + placebo = 5.4 mo
HR = 0.63, P<0.0001
0.7
0.6
0.5
0.4
0.3
0.2
0.1
5.4
0
0
10.2
6
Escudier B, et al. Lancet. 2007;370:2103-2111.
12
Time (months)
18
24
AVOREN: PFS Is Maintained With
Bevacizumab + Lower-Dose IFN
1.0
Median PFS
Bevacizumab + lower-dose IFN = 13.6 months
All bevacizumab + IFN patients = 13.5 months
0.9
Probability of Being
Progression Free
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0
3
6
9
12
15
Time (months)
Melichar B, et al. Ann Oncol. 2008 April. [Epub ahead of print.]
18
21
24
Renal Cell Cancer-Targeted Rx
Drug
N
Phase I/II
line
Regimen
PR/ORR
PFS
(months)
Sunitinib
750 III
169 II
I
2
vs.IFN
37/84
41/67
11 vs. 5
8.2
Sorafenib
189 II
903 III
1
2
vs. placebo 10/82
5.7
5.5 vs. 2.8
Temsirolimus
(poor risk)
626 III
I
vs. IFN
9/54
3.7 vs. 1.9
Bevacizumab
649 III
116 II
1
2
vs. IFN
31/70
10/
10.2 vs.5.4
4.8
Efficacy of Sequencing Antiangiogenic
Agents in Resistant RCC
Sorafenib
(Phase III;
IFNResistant) 1
(n=451)
Sunitinib (Ph II:
Bevacizumab Resistant)
(n=61) 2
Axitinib (Phase
II: IFNResistant)
(n=52) 3
Axitinib (Phase II;
Soraf-/SunitResistant)
(n=62) 4
5.5
23.6*
NR
7.4/6.1
(n=62/14**)
NR
10
16
46
21
26/30
(n=154/71)
53
61
40
34
45/48
(n=154/71)
Median
PFS,
months
ORR, %
Stable
Disease, %
*TTP
**Patients received both sorafenib and sunitinib
N Engl J Med 2007; 356:125 -34
2. Rini BI, et al. ASCO 2006; # 4522
3. Rini BI, et al. ASCO 2005; #4509
4. Rini BI, et al. ASCO 2007; # 5032
5. Hutson TE, et al.
ASCO 2007; abstract 5031
1. Escudier B, et al.
Pazopanib
(Phase II; First Line/Interferon Resistant)
(n=225 )5
Everolimus After Progression on
VEGFR-TKI: Study Design
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 + best
supportive care
(n = 272)
Upon
Disease
Progression
Placebo + best
supportive care
(n = 138)
Interim
Analysis
Final
Interim
=
Analysis
Analysis
• 410 patients randomized between September 2006 and October 2007
• Second interim analysis cutoff: October 15, 2007, based on 191 PFS events
• Independent Data Monitoring Committee recommended termination of study
Motzer RJ, et al. 2008 ASCO; Motzer RJ, Lancet 2008
Everolimus After Progression on
VEGFR-TKI: Prior Therapies
Everolimus
(n = 272)
%
Placebo
(n = 138)
%
Nephrectomy
96
95
Radiotherapy
31
28
Sunitinib
46
44
Sorafenib
28
30
Sunitinib and sorafenib
26
26
Interferon
50
50
Interleukin 2
22
24
Chemotherapy
13
16
Bevacizumab
9
10
Prior Treatment
VEGFR-TKI therapy
Other systemic therapy
Motzer RJ, et al. 2008 ASCO ; Motzer RJ, Lancet 2008
Treatment-Related Adverse Events*
Everolimus
%, (n = 269)
Stomatitis†
Asthenia / fatigue
Rash
Diarrhea
Anorexia
Nausea
Mucosal inflammation
Vomiting
Cough
Edema peripheral
Infections†
Pneumonitis†
Dyspnea
All Grades
40
37
25
17
16
15
14
12
12
10
10
8
8
Grade 3
3
3
<1
1
<1
0
1
0
0
0
3
3
1
Placebo
%, (n = 135)
All Grades
8
24
4
3
6
8
2
4
4
3
2
0
2
Grade 3
0
1
0
0
0
0
0
0
0
0
0
0
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) .
Motzer R et al. ASCO 2008
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 (%)
3 (1)
171 (63)
53 (20)
45 (16)
NE = not evaluable
* Central Radiology Review
Best Response
PR
Stable
PD
NE
n (%)
0
44 (32)
63 (46)
31 (22)
100
Everolimus vs Placebo:
PFS by Central Radiology
Review
Everolimus (n = 272)
PFS Probability (%)
Placebo (n = 138)
80
Hazard ratio = 0.30
95% CI (0.22, 0.40)
Log-rank P<0.001
60
Median PFS
Everolimus: 4.0 mo
Placebo: 1.9 mo
40
20
0
0
2
4
Motzer RJ, et al. 2008 ASCO Annual Meeting; Abstract LBA5026.
6
Months
8
10
12
Prospective Trials of Sequential
Targeted Agents
Agent
Population
N
OR/TS
(%)
PFS
Sunitinib1
Phase 2: Bevacizumab-refractory
62
23/75
7.1 months
Axitinib2
Phase 2: Sorafenib-refractory
62
23/55
7.4 months
Sorafenib3
Phase 2: Bevacizumab-or
sunitinib-refractory
26 each
3/38
3.8 months
RAD0014
Phase 3: RAD001 vs placebo in
TKI-refractory
410
1/50
4.0 months
Temsirolimus
Phase 3: Temsirolimus vs
sorafenib in patients previously
treated with sunitinib
480
Axitinib
Phase 3: Axitinib vs sorafenib in
previously treated patients
540
OR = overall response; TS = tumor shrinkage.
1. Rini, et al. J Clin Oncol (in press); 2. Rini, et al. 2007 ASCO Annual Meeting; 3. Sheppard, et al. 2008
ASCO Annual Meeting; 4. Motzer, et al. 2008 ASCO Annual Meeting.
RCC Therapies 2008
Setting
Treatmentnaive
Previously
treated
*MSKCC risk status.
Treatment
Good or
intermediate risk*
Clinical trial
Sunitinib
IL-2 (selected pts)
Bevacizumab +/- IFN-
Poor risk*
Temsirolimus
Prior cytokine
Sorafenib/Sunitinib
Prior VEGFr-TKI
Clinical trial
(Everolimus)
Prior mTOR
inhibitor
Clinical trial
Adapted from Atkins M ASCO 2006
Issues in Sequencing Anti-Angiogenesis
Agents in RCC
Why do we still observe responses after
sequencing anti VEGF agents?
- Do some drugs have better PK profile?
Interpatient PK variability?
- Is it due to OFF VEGF target
mechanisms?
- Is the target VEGF always inhibited?
Does the sequence affect toxicity?
What are the mechanisms of resistance to anti
VEGF therapies?

Potential Mechanism of Resistance
to VEGF Inhibitors
SDF1
CAFs
Osteopontin
PDGF
BMDCs
SDF1
MMP9
Bone marrow derived cells (i.e myeliod suppressive cells)
Cancer associated fibroblasts
Adapted from Casanovas O Cancer Cell 2005
1Oromi
A et al Cell 2005 3Du R Cancer Cell 2008
2Ebos JM et al PNAS 2007
RCC Microenvironment is Responsible
1000.00
800.00
600.00
400.00
Sunitinib 40mg/kg
200.00
0.00
0
20
40
60
80
100
Days post implantation of tumor piece
In vitro proliferation (% of control)
Ave Tumor Volume (mm3)
Sunitinib resistant disease
Tumor volume
for Tumor Response/Resistance to RTKIs
Sorafenib
30mg/kg
100
75
Vehicle
CTL
50
25
0
0
62.5
125
250
500
Sunitinib (nM)
Hammers H et al AACR 2008
Combination Strategies: Sequential Approach
VEGF
dependence
7
6
Tumor Size
5
4
3
2
1
0
Month
0
2
RTKI
RTK = receptor tyrosine kinase
4
6
8
10
12
Anti-VEGF w/wo HIF-1 Inhibitor
Sequential Approach: Phase II Study of
VEGF Trap in Metastatic RCC (ECOG 4805)
Eligibility Criteria
• Confirmed clear cell RCC
• Measurable metastatic
disease
• Prior TKI treatment
Stratification
• Low vs intermediate vs high
risk (Motzer criteria)
• Prior cytokine : yes vs no
• Prior nephrectomy: yes vs no
(N=120*)
R
A
N
D
O
M
I
Z
A
T
I
O
N
VEGF Trap 4 mg
IV d1-15
Crossover allowed
VEGF Trap 1 mg
IV d1-15
Primary end points: PFS
Secondary end points: ORR,SD,
duration of response, , safety
Combination Strategies: Concomitant Approach
VEGF
dependence
HIF-1
dependence
7
6
Tumor Size
5
4
3
Delay TTP
2
1
0
Month
0
2
4
6
RTKI
RTKI + HIF-1 Inhibitor
8
10
12
Phase II Study of Bevacizumab,
Sorafenib, and Temsirolimus in mRCC
(ECOG 2804 “BeST” Trial): Study Design
Eligibility Criteria
• Confirmed clear cell RCC
• Measurable metastatic disease
• <25% of any other histology
(papillary, chromophobe, or
oncocytic)
• Primary or metastatic lesion
• Not curable by standard
radiotherapy or surgery
• Prior nephrectomy
*Expected enrollment.
At: http://www.clinicaltrials.gov.
(N=360*)
R
A
N
D
O
M
I
Z
A
T
I
O
N
Bevacizumab
IV over 30-90 min d1-15
Temsirolimus
IV over 30 min
d1, d8, d15, d22
Bevacizumab
IV over
+
30-90
min d1-15
Sorafenib
bid PO, d1-28
Bevacizumab
IV over
+
30-90
min d1-15
Temsirolimus
IV over 30 min
d1, d8, d15, d22
+ PO bid, d1-28
Sorafenib
Primary end point: PFS
Toxicities in RCC Patients Receiving
RTKIs
• Most common:
– Fatigue
– Hypertension
– Hand-foot syndrome
– Diarrhea
• Rarer but potentially mores serious:
– Cardiac events
– Hypothyroidism
– Thromboembolic events
– Bleeding
• To date no validated predictors
• No clear linear association with pharmacokinetics
• Limiting factor in combination strategies
Kinase Dendrogram
VATALANIB
SORAFENIB
SUNITINIB
KINASE
INHIBITION
CLINICAL
EFFICACY ?
TOXICITY ?
Adapted from Fabian et al, Nature Biotech 2006
Predictors of Toxicity with RTKIs
• Pharmacogenomics: Single nucleotide
polymorphism (SNPs) may correlate with sunitinib
treatment-related toxicity *- larger study needed
• Some SNPs may be associated with tissue
restricted toxicity (i.e. creatine kinase and cardiac
toxicity)
• Correlation of SNPs, toxicity and pharmacokinetcs
to be assessed
• Awaiting for analysis from E2805 adjuvant study
• Is age a predictor factor?
* Faber PW et al ASCO 2008 abstract #5009
Probability of Severe Toxicity
from Sunitinib in Older Adults
van der Veldt AAM British Journal of Cancer (2008) 99(2), 259 – 265
Clinical Development of
Antiangiogenesis in RCC
1
For advanced disease
Neoadjuvant therapy
Adjuvant therapy
VEGF inhibitor
mTOR inhibitor
2
Optimizing dose and schedule
to overcome resistance?
Targeted agents
1) VEGF inhibitors
2) mTOR inhibitors
3) Others (ie, HDAC inhibitors)
3
Combination strategies
IL-2, IFN-α
Other immunotherapy strategies
Chemotherapy?
1) Capecitabine
2) Gemcitabine
3) Others
HDAC = histone deacetylase.
RCC: Role for Palliative Nephrectomy
IFN
Two randomized trials:
Nx + IFN
1) EORTC:
Nx + IFN
IFN
N
42
43
CR
12
2
PR
7
6
Survival (mo)
17
7 p=0.03
N
120
121
CR
0
0
PR
3
3
Survival (mo)
11.1
8.1 p=0.05
2) SWOG:
Nx + IFN
IFN
1 Mickisch,
Lancet 358, 2001; 2 Flanigan, NEJM 345, 2001.
ASSURE Trial (ECOG 2805)
Eligibility Criteria
• pT1b, G3-4; pT2-4; N+
disease, no metastatic
disease
• Confirmed clear cell or
non–clear cell RCC
• Intermediate high–risk or
very high–risk disease
• Prior radical or partial
nephrectomy
R
A n=444
N
D
O
N=1332* M n=444
I
Z
A
T
I n=444
O
N
Treatment repeats every 6
weeks for up to 9 courses
in the absence of disease
progression or unacceptable
toxicity
Sunitinib 50 mg PO qd for 4 of 6 wk
+
Sorafenib placebo for 6 wk
Sorafenib 400 mg PO bid for 6 wk
+
Sunitinib malate placebo for 6 wk
Placebo for sunitinib malate
and sorafenib for 6 wk
Primary end point: Disease-free
survival
Secondary end points: OS, safety,
analysis of molecular markers
Future Directions for Individualized
Treatments for RCC
• Predict tumor behavior by molecular signatures
– Patient prognosis
• Stratify patients into risk categories by
clinical/molecular parameters
– Predict disease recurrence and cancerrelated death
• Select treatment approach and predict response
– Based on the target expression
– Minimize unnecessary exposure to treatment
toxicity
Adapted from Eppert JT, et al. BJU Int. 2007;99:1208-1211.
Future Directions for Individualized
Treatments for RCC
• Individualizing treatment; attention for possible
age-related effects on PK and PD in older adults
• Optimal duration of treatment and timing for
changing treatments
• Selecting treatment for patients with comorbid
conditions
• Integration of molecular targeted therapies with
surgery
Conclusions
• The treatment of patients with metastatic RCC
continues to evolve with several drugs already
FDA approved
• Preclinical and clinical trials will determine the
most effective dosing schemes, optimal
sequencing, and treatment combinations
• The goal remains individualized treatments to
optimize patient outcomes