Sorafenib

Report
Managing Advanced Renal Cell
Carcinoma: Balancing Efficacy with Quality of
Life
19th Annual Meeting of the Network for Oncology
Communication and Research
Las Vegas 16th March 2013 25 minutes
David I. Quinn
MBBS (Hons) PhD FRACP FACP
Associate Professor of Medicine
Chief, Section of GU Medical
Oncology
Division of Medical Oncology
Medical Director, Norris Cancer
Hospital & Clinics
Co-Leader, Developmental
Therapeutics Program
Member, USC Institute of
Urology
Kenneth J. Norris Comprehensive
Cancer Center
Keck School of Medicine
University of Southern California
Objectives
– Cover the following clinical issues
• Choosing a frontline agent
• Selecting an agent for relapsed disease
• Who are candidates for immunotherapy?
Survival Rates by MSKCC Risk Factor
Model
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
0.9
Proportion surviving
0.8
Median survival
30 months
14 months
5 months
Risk factors associated with worse prognosis
0.7
• KPS <80
0.6
• Low serum haemoglobin (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 diagnosis to IFN- <1 year
0.2
0.1
0
0
1 2 3
4 5 6 7 8 9 10 11 12 13 14 15 16
Time from start of IFN- (years)
MSKCC = Memorial Sloan-Kettering Cancer Center; KPS = Karnofsky Performance Status
Motzer RJ, et al. J Clin Oncol. 2002;20:289-296.
Pathogenesis of RCC
Endothelial
cell
EGF
IGF-1
IGF-1R
EGFR
HER2
VEGF
VEGFR
Tumor
cell
FGFs
RAS
IL-8
RAF
Dll4/Notch
PTEN
HGF/c-MET
TSC1/2
MEK
ERK
Growth and
proliferatio
n
VHL gene
inactivated
mTOR
Metabolism
HIF1a
accumulation
PDGFR
PDGF
Angiopoietin,
epinephrine
 Angiogenic
factors
Angiogenesis
FGF = fibroblast growth factor; IL-8 = interleukin 8; HGF = hepatocyte growth factor; Dll4 = delta-like ligand 4; EGF = epidermal growth factor;
IGF = insulin-like growth factor; VEGF = vascular endothelial growth factor; PDGF = platelet-derived growth factor.
1. Ellis LM, et al. Clin Cancer Res. 2008;14:6371-6375; 2. Sjolund J, et al. J Clin Invest. 2008;118:217-228;
3.
Huang D, et al. Cancer Res. 2010;1063-1071. Figure adapted from: Rini BI, Atkins MB. Lancet Oncol. 2009;10:992-1000.
Pathogenesis of RCC
Endothelial
cell
EGF
IGF-1
EGFR
IGF-1R
HER2
VEGF
VEGFR
Tumor
cell
FGFs
RAS
IL-8
RAF
PTEN
 Activation of
AKT and mTOR
MEK
ERK
Dll4/Notch
PTEN
inactivated
HGF/c-MET
PDGF
TSC1/2
Angiopoietin,
epinephrine
mTOR
mTOR
Cell cycle
entry
Growth
and
Growth and
proliferatio
proliferation
n
Metabolism
Metabolism
PDGFR
HIF1a
accumulation
 Angiogenic
factors
Angiogenesis
Angiogenesis
FGF = fibroblast growth factor; IL-8 = interleukin 8; HGF = hepatocyte growth factor; Dll4 = delta-like ligand 4; EGF =
epidermal growth factor; IGF = insulin-like growth factor; VEGF = vascular endothelial growth factor; PDGF = platelet-derived
growth factor.
1. Ellis LM, et al. Clin Cancer Res. 2008;14:6371-6375; 2. Sjolund J, et al. J Clin Invest. 2008;118:217-228;
Treatment options for RCC have been
revolutionized in a short period of time…
Bevacizumab + IFN5,6
Everolimus7
High dose
interleukin-21
Temsirolimus4
Sorafenib2 Sunitinib3
Pazopanib8
Axitinib9
Tivozanib
Dovitinib?
1992-2005
Interferon-
2005
2006
2007 2008
2009 2010 2012
...but this rapid change has left many
unanswered questions, including the optimal
sequence of therapy
1. Fyfe G et al. J Clin Oncol 13:688-696, 1995
2. Escudier B et al. N Engl J Med 356:125-134,2007
3. Motzer RJ et al. N Engl J Med 356:115-124,2007
4. Hudes G et al. N Engl J Med 356:2271-2281 2007
5. Escudier B et al. Lancet 370:2103-211, 2007
6. Rini BI et al. J Clin Oncol 33:5422-8, 2008
7. Motzer RJ et al. Lancet 372:449-456, 2008
8. Sternberg CN et al. J Clin Oncol 28: 1061-8, 2010
9. Rini BI et al ASCO 2011
Objectives
– Cover the following clinical issues
• Choosing a frontline agent
• Selecting an agent for relapsed disease
• Who are candidates for immunotherapy?
Advances in PFS in RCC: First-line
Select Trial Results Since ASCO 2005: Median PFS
5.3
INF+IL-2+5-FU [Gore 2008]
INF-α+ IL-2+5-FU2
Temsirolimus [PI]
Temsirolimus3*
Sorafenib4*
Bevacizumab + INF-α5
5.5
Escudier [2009]
5.7
IFN
5.4
2005-Present
10.2
Bevacizumab + INF-α [Escudier 2008]
IFN
Bevacizumab + INF-α6
5.2
8.5
Bev + INF-α [Rini 2009]]
IFN
Sunitinib7*
5
11.0
Sunitinib [Motzer JCO 2009]
2.8
Placebo
Pazopanib8*
11.1
Pazopanib [Sternberg 2010]
9.1
Placebo
Sorafenib
Tivozanib vs. Sorafenib9*
12.7
Tivozanib [Motzer ASCO 2012]
14.5
Axitinib [Rini ASCO 2012]
Axitinib10
Time (months)
3-5
Multiple studies
INF-α alone1
0
1
2
3
4
5
6
7
1. Kane et al. Clin Cancer Res. 2006;12:7271. 2. Gore et al. ASCO; 2008. Abstract 5039.
4. Escudier et al. J Clin Oncol. 2009;27:1280-9. 5. Escudier ASCO; 2008. Abstract 5025.
7. Motzer. J Clin Oncol. 2009;27:3584-90
8. Sternberg et al. J Clin Oncol.2010;28: 1061-8.
8
9 10 11 12 13
3. Torisel PI
6. Rini et al. J Clin Oncol 2008;26: 5422-8
* Central Review
RCC Treatment Algorithm: 2013
Patients
Therapy
Other Options
Has anything
changed
for
2013?
(level 1)
(≥ level 2)
Setting
Untreated
Previously treated
Good or
Intermediate risk
Sunitinib
Bevacizumab +
IFN
Pazopanib
Tivozanib (?)
Axitinib (?)
Clinical trial
HD IL-2
Sorafenib
Axitinib
Clinical trial
Observation
Poor risk
Temsirolimus
Clinical trial
Sunitinib
Clinical trial
Cytokine
Sorafenib
Pazopanib
Axitinib
Tivozanib
Clinical trial
Sunitinib,
Bevacizumab
Clinical trial
VEGF
Everolimus
Axitinib
Clinical trial
Everything
Sorafenib
Other VEGF TKIs
mTORi
Nil
VEGFTKI
? Dovitinib
*Adapted from M Atkins, ASCO 2006 & R Bukowski ASCO 2007; Rini B ASCO 2008
Original Article
Sunitinib versus Interferon Alfa in
Metastatic Renal-Cell Carcinoma
Robert J. Motzer, M.D., Thomas E. Hutson, D.O., Pharm.D., Piotr Tomczak, M.D., M.
Dror Michaelson, M.D., Ph.D., Ronald M. Bukowski, M.D., Olivier Rixe, M.D., Ph.D.,
Stéphane Oudard, M.D., Ph.D., Sylvie Negrier, M.D., Ph.D., Cezary Szczylik, M.D.,
Ph.D., Sindy T. Kim, B.S., Isan Chen, M.D., Paul W. Bycott, Dr.P.H., Charles M. Baum,
M.D., Ph.D., and Robert A. Figlin, M.D.
N Engl J Med
Volume 356(2):115-124
January 11, 2007
Progression-Free Survival
Progression Free Survival Probability
(Independent Central Review)
Sunitinib
Median: 11 months
(95% CI: 10–12)
1.0
0.9
0.8
0.7
PFS Doubled
0.6
0.5
IFNMedian: 5 months
(95% CI: 4–6)
0.4
0.3
0.2
Hazard Ratio = 0.415
(95% CI: 0.320–0.539)
P <0.000001
0.1
0
0
1
2
3
No. at Risk Sunitinib: 235
No. at Risk IFN-:
152
4
5
6
7
8
Time (Months)
90
42
9
32
18
10
11
12
13
14
2
0
Motzer RJ et al. New Engl J Med 356: 115-124, 2007.
Final Overall Survival
OS benefit
Total Death
Sunitinib 190
IFN-
200
Figlin R et al. , ASCO 2008, abstract #5024
12
Phase III Pazopanib Versus Placebo
Advanced RCC
S
T
R
A
T
I
F
Y
R
A
N
D
O
M
I
Z
E
Pazopanib 800 mg qd
n=290
Matching placebo
n=145
2:1
•
•
•
•
Patients stratified for ECOG PS 0 vs 1, prior nephrectomy, treatment naïve
(N=233) vs 1 cytokine failure (N=202)
Primary endpoint: PFS (by independent review)
Secondary endpoints: OS, ORR (by independent review), duration of response,
safety, health-related QoL
Patients had an option to receive pazopanib via an open-label study at
progression
Sternberg. ASCO. 2009 (abstr 5021).
Pazopanib Versus Placebo in Overall Study Population:
PFS and OS Interim Analysis
Median PFS
Pazopanib: 9.2 mos
Placebo: 4.2 mos
HR=0.46 (95% CI, 0.340.62)
P<0.0000001
0.8
PFS Doubled
0.6
0.4
0.2
1.0
Pazopanib
Placebo
0.0
0
5
48% of patients receiving
placebo received pazopanib
after PD
0.8
Proportion Surviving
Proportion Progression Free
1.0
0.6
0.4
Median OS
Pazopanib: 21.1 mos
Placebo: 18.7 mos
HR=0.73 (95% CI, 0.47-1.12)
P=0.02 (1-sided)
OS Improved but …
0.2
Pazopanib
Placebo
0.0
10
15
Time (months)
20
Overall Study Population
PFS
5
Treatment-Naïve
Patients
10
15
Time (months)
Cytokine Pretreated
Pazopanib
Placebo
Pazopanib
Placebo
Pazopanib
Placebo
9.2
4.2
11.2
2.8
7.4
4.2
HR=0.46; P<0.0001
ORR
0
30%
3%
HR=0.40; P<0.0001
32%
4%
HR=0.54; P<0.001
29%
3%
P<0.001
mDOR
<1 year
O’Brien-Fleming boundary for futility/superiority: P=0.201/0.004 (1-sided).
Sternberg. ASCO. 2009 (abstr 5021). Sternberg CN et al. J Clin Oncol. January 25, 2010 [Epub ahead of print].
20
25
First-line therapy in RCC
Intermediate
Poor
TKI or
BV+IFN?
mTOR or
Sunitinib?
Good
TKI or
HDIL2/cyt
okine or
BV+IFN?
Randomized, Open Label, Phase III Trial
of Pazopanib versus Sunitinib in First-line
Treatment of Patients with Metastatic
Renal Cell Carcinoma (mRCC): Results of
the COMPARZ Trial
Robert Motzer1, T. E. Hutson2, James Reeves3, Robert Hawkins4, Jun
Guo5, Paul Nathan6, Michael Staehler7, Paul de Souza8, Jaime R.
Merchan9, Kate Fife10, Jie Jin11, Robert Jones12, Hirotsugu Uemura13,
Ugo De Giorgi14, Ulrika Harmenberg15, Jinwan Wang16, David Cella17,
Lauren McCann18, Keith Deen18, and Toni K. Choueiri19
1Memorial
Sloan Kettering Cancer Center, NY, NY, USA; 2Baylor Sammons Cancer Center/Texas Oncology, Dallas, TX, USA;
3Florida Cancer Specialists, Fort Myers, FL, USA; 4University of Manchester and The Christie Hospital, NHS Foundation Trust,
Manchester, United Kingdom; 5 Renal Cancer and Melanoma Unit, Peking University Cancer Hospital, Beijing, China; 6Mount
Vernon Hospital, Middlesex, United Kingdom;7 Department of Urology, Interdisciplinary Centre on Renal Tumors, University of
Munich, Munich, Germany; 8University of Western Sydney School of Medicine, MMRG, CRG, Sydney, Australia; 9 University
of Miami, Sylvester Cancer Center, Miami, FL, USA:10 Oncology Centre, Addenbrooke's Hospital, Cambridge, United
Kingdom; 11 Peking University First Hospital, Beijing, China; 12Institute of Cancer Sciences University of Glasgow, Glasgow,
United Kingdom;13 Department of Urology, Kinki University Faculty of Medicine, Osaka, Japan; 14IRCCS Istituto Scientifico
Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.), Meldola, Italy; 15Department of Oncology, Radiumhemmet Karolinska
University Hospital, Stockholm, Sweden; 16 Cancer Hospital, CAMS & PUMC, Beijing, China; 17Robert H. Lurie
Comprehensive Cancer Center of Northwestern University, Chicago, IL , USA; 18GlaxoSmithKline, Inc., Collegeville, PA, USA;
10Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
Study Objectives
Primary
• To evaluate and compare PFS in patients treated
with pazopanib to those treated with sunitinib as
initial systemic therapy
Secondary
• Overall survival (OS)
• Objective response rate (ORR)
• Safety
• Patient-reported outcomes
Study Design
Pazopanib
800 mg qd
continuous dosing
Key Eligibility
Criteria
•
•
•
•
•
•
Advanced/metastatic RCC
Clear-cell histology
No prior systemic therapy
Measurable disease (RECIST 1.0)
KPS ≥ 70
Adequate organ function
Dose reductions to
600 mg or 400 mg
Randomized
1:1
Stratification Factors
• KPS 70/80 vs 90/100
• Prior nephrectomy
• Baseline LDH >1.5 vs ≤1.5×ULN
Sunitinib
50 mg qd
4 wk on/2 wk off
Dose reductions to
37.5 mg or 25 mg
Primary Endpoint: Progression-free Survival
(independent review)
N
Median PFS (95% CI)
Pazopanib
557
8.4 mo (8.3, 10.9)
Sunitinib
553
9.5 mo (8.3, 11.1)
HR (95% CI ) = 1.047 (0.898,1.220)
Pazopanib
Sunitinib
Best Response by RECIST 1.0
(independent review)
Pazopanib
(n = 557)
Sunitinib
(n = 553)
Complete response (CR)
Partial response (PR)
Stable disease
Progressive disease
Not evaluable
<1
31
39
17
13
<1
24
44
19
12
Objective Response Rate
(CR +PR), %
31
25
26.9, 34.5
21.2, 28.4
Best overall response, %
95% CI
P value
0.032
Interim Analysis of Overall Survival
N
Median OS (95% CI)
Pazopanib
557
28.4 mos (26.2, 35.6)
Sunitinib
553
29.3 mos (25.3, 32.5)
HR (95% CI ) = 0.908 (0.762,1.082)
P-value = 0.275
Pazopanib
Sunitinib
Treatment Duration and Dose Adjustments
Pazopanib
(n = 554)
Sunitinib
(n = 548)
8.0 (0−40)
7.6 (0−38)
Dose reductions, %
44
51
Discontinuations due to AEs1, %
24
19
Median duration of treatment
(months, range)
1. Most common reason: pazopanib arm (liver event, 6%); sunitinib arm (cytopenia, 3%)
Most Common Adverse Events
(treatment-emergent)
Pazopanib
(n = 554) %
Sunitinib
(n = 548) %
Adverse Event 1
All Grades
All Grades
Any event 2
Diarrhea
Fatigue
Hypertension
Nausea
Decreased appetite
ALT increased
Hair color changes
Hand-foot syndrome
Taste alteration
Thrombocytopenia
>99
63
55
46
45
37
31
30
29
26
10
>99
57
63
41
46
37
18
10
50
36
34
1 AE
≥30% in either arm
of patients in pazopanib arm and 3% of patients in sunitinib arm had grade 5 adverse events
Yellow highlight: Risk greater for pazopanib and 95% CI for relative risk does not cross 1
2 2%
Most Common Adverse Events
(treatment-emergent)
Adverse Event 1
Any event 2
Diarrhea
Fatigue
Hypertension
Nausea
Decreased appetite
ALT increased
Hair color changes
Hand-foot syndrome
Taste alteration
Thrombocytopenia
1 AE
Pazopanib
(n = 554) %
Sunitinib
(n = 548) %
All Grades
All Grades
>99
63
55
46
45
37
31
30
29
26
10
>99
57
63
41
46
37
18
10
50
36
34
≥30% in either arm
of patients in pazopanib arm and 3% of patients in sunitinib arm had grade 5 adverse events
Blue Highlight: Risk greater for sunitinib and 95% CI for relative risk does not cross 1
2 2%
Quality of Life Results (first 6 months1)
Treatment difference :
mean change from
baseline 2
P -value
Fatigue/Total score
2.32
<0.001
Kidney Symptom Index/Total score
1.41
0.018
Physical
0.78
0.027
Emotional
0.05
0.409
Treatment Side Effects
0.31
0.033
Functional Well Being
0.31
0.098
Expectations of Therapy
1.41
0.284
Feelings about Side Effects
8.50
<0.001
Satisfaction with Therapy
3.21
<0.001
Worst mouth/throat soreness
0.505
<0.0001
Worst foot soreness
0.204
0.0016
Worst hand soreness
0.267
0.0008
Limitations due to mouth/throat soreness
0.94
<0.001
Limitations due to foot soreness
0.65
0.014
Instrument
FACIT-F
FKSI-19
Cancer
Treatment
Satisfaction
Questionnaire
(CTSQ)
Supplementary
Quality of Life
Questionnaire
(SQLQ)
1Pre-specified
Domain Description
analysis. HRQoL changes in mean scores over time were analyzed with a repeated measures analysis of
covariance (ANCOVA).
2Yellow Font: favors pazopanib. Blue Font: favors sunitinib. P-value <0.05 is statistically significant
Quality of Life Results (first 6 months1)
Treatment difference :
mean change from
baseline 2
P -value
Fatigue/Total score
2.32
<0.001
Kidney Symptom Index/Total score
1.41
0.018
Physical
0.78
0.027
Emotional
0.05
0.409
Treatment Side Effects
0.31
0.033
Functional Well Being
0.31
0.098
Expectations of Therapy
1.41
0.284
Feelings about Side Effects
8.50
<0.001
Satisfaction with Therapy
3.21
<0.001
Worst mouth/throat soreness
0.505
<0.0001
Worst foot soreness
0.204
0.0016
Worst hand soreness
0.267
0.0008
Limitations due to mouth/throat soreness
0.94
<0.001
Limitations due to foot soreness
0.65
0.014
Instrument
FACIT-F
FKSI-19
Cancer
Treatment
Satisfaction
Questionnaire
(CTSQ)
Supplementary
Quality of Life
Questionnaire
(SQLQ)
1Pre-specified
Domain Description
analysis. HRQoL changes in mean scores over time were analyzed with a repeated measures analysis of
covariance (ANCOVA).
2Yellow Font: favors pazopanib. Blue Font: favors sunitinib. P-value <0.05 is statistically significant
Conclusions
• This phase III trial demonstrates non-inferiority of
pazopanib compared to sunitinib for progression-free
survival
• Pazopanib efficacy is further supported by similar
response rates and overall survival
• The differentiated safety profile of pazopanib includes:
– Lower incidence of hand-foot syndrome, fatigue, and
mucositis
– Higher incidence of liver function test abnormalities and
weight loss
• Quality of life assessment favors pazopanib over
sunitinib
Same, Same but different?
Take away points ..
• Non-inferiority … is there a winner?
• Less toxicity or different but with better QoL?
• Impact in clinical practice?
• Wither axitinib or tivozanib?
Objectives
– Cover the following clinical issues
• Choosing a frontline agent
• Selecting an agent for relapsed disease
• Who are candidates for immunotherapy?
a zen moment
un momento del zen
RECORD-1: Everolimus / BSC vs
BSC: Study Design
Everolimus + BSC
mRCC
Stratification by
prior VEGFR TKI,
MSKCC risk group1
Randomized
2:1
(double blind)
everolimus: 10 mg po
daily repeated 28-day
cycle
Upon
disease
progression
Placebo + BSC
Eligibility: Clear cell component;
prior bevacizumab and cytokines
permitted
Matching placebo po daily
repeated 28-day cycle
Primary endpoint: PFS
Secondary endpoints: Safety, response
, patient-reported outcomes, and OS
Motzer, et al. Lancet. 2008;372:449-456.
Motzer, et al. J Clin Oncol. 2004;22:454-463.
ORR %
1.0 vs 0.0
PFS mos
4.9 vs 1.9
(HR=0.33; P<0.001)
OS mos
14.8 vs 14.4
(HR=0.87;
P=0.177)
Everolimus: Progression-Free Survival
Central Radiology Review
PFS Doubled
Motzer, ESMO 2008, abstract 720
Axitinib versus sorafenib as secondline therapy for metastatic renal cell
carcinoma (mRCC): Results of phase
III AXIS trial
Abstract 4503
B. I. Rini, B. Escudier, P. Tomczak, A. Kaprin, T. E. Hutson, C.
Szczylik, J. C. Tarazi, B. Rosbrook, S. Kim, R. J. Motzer
Cleveland Clinic Taussig Cancer Institute, Cleveland, OH; Institut Gustave Roussy, Villejuif,
France; Klinika Onkologii, Oddzial Chemioterapii, Poznan, Poland; Russian Oncology Centre, Moscow,
Russia; Baylor Sammons Cancer Center-Texas Oncology PA, Dallas, TX; Wojskowy Instytut
Medyczny, CSK MON Klinika Onkologii, Warszawa, Poland; Pfizer Oncology, La Jolla, CA; Memorial
Sloan-Kettering Cancer Center, New York, NY
J Clin Oncol 29: 2011 (suppl; abstr 4503)
AG-013736 (axitinib) vs. Sorafenib
as Second-Line Therapy For
Metastatic Renal Cell Cancer
Patients after
disease progression
to one prior
systemic
first-line
treatment (N=540)
R
A
N
D
O
M
I
Z
A
T
I
O
N
Axitinib 5 mg BID
1:1
Sorafenib (2x200 mg) BID
Primary end point: Compare PFS of patients receiving AG-013736 versus sorafenib
in mRCC after disease progression to one prior systemic first-line regimen containing
one or more of the following agents: sunitinib, bevacizumab + IFN alfa, temsirolimus
or cytokine(s).
Secondary end point: OS, ORR, evaluate safety and tolerability, DR, compare
symptoms’ severity
AXIS: Randomized Phase III
Trial, Axitinib vs Sorafenib in
Refractory Metastatic RCC
Progression-Free
Survival (probability)
• Primary endpoint: PFS
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
mPFS, mo
Axitinib
6.7
Sorafenib 4.7
95% CI
6.3-8.6
4.6-5.6
• Treatments generally well
tolerated; similar toxicity
P < 0.0001 (log-rank)
Stratified HR 0.665
(95% CI 0.544-0.812)
0
2
4
6
Subjects
at risk, n
Axitinib 361 256 202 145
Sorafenib 362 224 157 100
8 10 12 14
Time (months)
96
51
64
28
38
12
20
6
Rini BI, et al. ASCO 2011. Abstract 4503
16
10
3
18 20
1
1
0
0
– All-grade hypertension
and hypothyroidism more
common with axitinib
– All-grade hand-foot
syndrome, rash, and
alopecia more common
with sorafenib
– Discontinuation due to
treatment-related AEs:
• 3.9% in axitinib group
• 8.2% in sorafenib group
PFS by Prior Regimen
Prior Treatment
Regimen
Axitinib
(n=361)
Sorafenib
(n=362)
HR
P
value*
Cytokines (n=251)
IRC
Investigator
12.1
12.0
6.5
8.3
0.464
0.636
<0.0001
0.005
Sunitinib (n=389)
IRC
Investigator
4.8
6.5
3.4
4.5
0.741
0.636
0.011
0.0002
Temsirolimus (n=24)
IRC
Investigator
10.1
2.6
5.3
5.7
0.511
1.210
0.142
0.634
Bevacizumab (n=59)
IRC
Investigator
4.2
6.5
4.7
4.5
1.147
0.753
0.637
0.213
*One-sided log-rank test stratified by ECOG PS
ESMO 2012: Abstract No. 918
Temsirolimus vs Sorafenib as Second-Line
Therapy in Metastatic Renal Cell Carcinoma:
Results From the INTORSECT Trial
T. E. Hutson,1 B. Escudier,2 E. Esteban,3
G.A. Bjarnason,4 H. Y. Lim,5 K. Pittman,6 P. Senico,7
A. Niethammer,8 D. Lu,8 S. Hariharan,9 R. Motzer10
1Baylor
University Medical Center, Dallas, TX/UNITED STATES; 2Institut Gustave Roussy,
Villejuif/FRANCE; 3Hospital Universitario Central de Asturias, Oviedo, Asturias/SPAIN; 4Odette Cancer
Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario/CANADA; 5Samsung Medical Center,
Seoul/KOREA; 6The Queen Elizabeth Hospital, Woodville South, Adelaide/AUSTRALIA; 7Pfizer Inc,
Collegeville, PA/UNITED STATES; 8Pfizer Inc, La Jolla, CA/UNITED STATES; 9Pfizer Inc, New York,
NY/UNITED STATES; 10Dept, Memorial Sloan-Kettering Cancer Center, New York, NY/UNITED STATES
INTORSECT* Study Design
R
Patients with mRCC
and PD on 1st-line
sunitinib
(N=512)
Stratification factors:
•Duration of sunitinib therapy (≤ or >6 mo)
•MSKCC risk group
•Histology (clear cell or
non–clear cell)
•Nephrectomy status
A
N
D
Temsirolimus
25 mg IV weekly†
(n=259)
O
M
I
Z
E
Sorafenib
Primary
end point:
PFS
(per IRC)
400 mg oral BID†
(n=253)
Treat until PD, unacceptable toxicity,
or discontinuation for any other reason
1:1
*ClinicalTrials.gov Identifier: NCT00474786
†Dose reductions were allowed: temsirolimus (to 20 mg then 15 mg), sorafenib (to 400 mg/day then every other day).
BID, twice daily; IRC, independent review committee; IV, intravenous; mRCC, metastatic renal cell carcinoma;
MSKCC, Memorial Sloan-Kettering Cancer Center; PD, progressive disease; PFS, progression-free survival.
38
Study Objectives
 Primary objective
─ To compare safety and efficacy (PFS as determined
by IRC) of temsirolimus and sorafenib in the 2nd-line
setting for patients with mRCC after failure on prior
sunitinib
 Secondary objectives
–
–
–
–
PFS determined by investigator assessment
Objective response rate
Overall survival (OS)
Proportion of patients with PFS at 12, 24, and 36
weeks
– Duration of response
IRC, independent review committee; mRCC, metastatic renal cell carcinoma; PFS, progression-free survival.
39
Statistical Methods
 Primary end point: PFS (assessed by blinded IRC)
─ 80% power to detect a 33% improvement in PFS
with a stratified 2-sided log-rank test at 0.05 alpha
level
─ Sample size of 480 patients required to observe
380 progression events with 15% drop-out rate
─ Analysis based on ITT population, compared using
stratified log-rank test
 Secondary end point: OS
IRC, independent review committee; ITT, intent to treat; OS, overall survival; PFS, progression-free
survival; RCC, renal cell carcinoma.
40
Progression-Free Survival
(IRC Assessment)
Median PFS,
95% CI
months
4.28 4.01, 5.43
Temsirolimus
3.91 2.80, 4.21
Sorafenib
1.0
PF S (probability)
0.9
0.8
P=0.1933 (log-rank)
Stratified HR: 0.87
(95% CI: 0.71, 1.07)
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
5
15
20
25
6
5
0
0
Time (months)
Patients at risk, n
Sorafenib
Temsirolimus
10
252
259
72
96
22
28
11
9
CI, confidence interval; HR, hazard ratio; IRC, Independent Review Committee; PFS, progression-free survival. 41
Objective Response by RECIST
(IRC Assessment)
Response Parameter, n (%)
Overall confirmed ORR*
Complete response
Partial response
Stable disease
Progressive disease
Median duration of response,
months (95% CI)
Temsirolimus
(n=259)
Sorafenib
(n=253)
20 (8)
0
20 (8)
151 (61)
59 (23)
20 (8)
1
19 (8)
153 (61)
61 (24)
8.26
(6.71, 10.36)
6.96
(4.18, 17.50)
*Stratified 1-sided Cochran-Mantel-Haenszel test of treatment.
CI, confidence interval; IRC, independent review committee; ORR, objective response rate; RECIST,
Response Evaluation Criteria in Solid Tumors.
42
Overall Survival
Median OS,
95% CI
months
12.27 10.13, 14.80
Temsirolimus
16.64 13.55, 18.72
Sorafenib
Overall Survival (probability)
1.0
0.9
0.8
P=0.014 (log-rank)
Stratified HR: 1.31
(95% CI: 1.05, 1.63)
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
10
30
40
50
13
8
0
0
Time (months)
Patients at risk, n
Sorafenib
Temsirolimus
20
253
259
158
132
74
54
CI, confidence interval; HR, hazard ratio; OS, overall survival.
34
22
43
OS by Duration of Prior Sunitinib
(ITT Population)
Prior Sunitinib
Use
Temsirolimus
(n=259)
Sorafenib
(n=253)
HR
(95% CI)
≤180 days, n (%)
Median OS, mo
(95% CI)
97 (38%)
10.1
(8.5, 13.4)
92 (36%)
11.4
(8.9, 16.8)
1.30
(0.94, 1.81)
0.111
>180 days, n (%)
Median OS, mo
(95% CI)
162 (62%)
14.4
(11.3, 16.9)
161 (64%)
17.8
(15.4, 22.9)
1.37
(1.04, 1.80)
0.025
P value*
*Unstratified log-rank test.
CI, confidence interval; HR, hazard ratio; ITT, intent to treat; OS, overall survival.
44
OS by Subgroup
Subgroup
N
HR
95% CI
All patients
511
1.31
1.05, 1.63
Prior nephrectomy
442
1.45
1.15, 1.82
No prior nephrectomy
70
0.84
0.49, 1.43
≤180 days sunitinib therapy
189
1.30
0.94, 1.81
>180 days sunitinib therapy
323
1.37
1.04, 1.80
Clear cell histology
422
1.34
1.06, 1.69
Non–clear cell histology
90
1.42
0.86, 2.35
MSKCC favorable subgroup
94
0.95
0.55, 1.64
MSKCC intermediate subgroup
355
1.50*
1.17, 1.94
MSKCC poor subgroup
63
1.37
0.81, 2.32
0.1
Favors Temsirolimus
1
Favors Sorafenib
10
*P=0.002.
CI, confidence interval; HR, hazard ratio; MSKCC, Memorial Sloan-Kettering Cancer Center; OS, overall survival.
45
Grade ≥3 Adverse Events*
Temsirolimus
(n=249)
Sorafenib
(n=252)
All grades
Grade 3/4
All
grades
Grade 3/4
Hand-foot syndrome
4
0
52
15
Fatigue
40
6
34
7
Anemia
34
9
14
3
Hypophosphatemia
11
5
12
7
Hyperglycemia
19
8
6
2
Diarrhea
31
2
63
6
Event, %
*Incidence ≥5% in either treatment arm.
46
Conclusions

Temsirolimus did not show superiority over sorafenib in
the primary end point of PFS nor in the secondary end
point of OS
─ Median PFS was slightly longer with
temsirolimus compared to sorafenib (4.28
months vs. 3.91 months), but this difference
was not statistically significant.
─ The sorafenib arm had longer median OS than
the temsirolimus arm (16.64 months vs 12.27
months; P=0.014)

Safety data were as expected for both agents

Further evaluation is needed to define the optimal
treatment sequence after prior sunitinib in patients with
advanced RCC
OS, overall survival; PFS, progression-free survival; RCC, renal cell carcinoma.
47
Discussion points, thoughts
 PFS vs. OS in RCC
 Temsirolimus is used in 30% of patients
second line in USA
 Sequential therapy issues in question:
VEGFrTKI vs. mTORi
 Real efficacy of sorafenib
48
Objectives
– Cover the following clinical issues
• Choosing a frontline agent
• Selecting an agent for relapsed disease
• Who are candidates for immunotherapy?
High-Dose IL-2 Therapy: PLA Database:
Response Durations in 255 Patients
1.0
CR (n = 17)
PR (n = 20)
CR + PR (n = 37)
Probability of Continuing Response
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
80
10
90
20
100
30
110
40
50
60
Duration of Response (Months)
Fisher et al. J Sci Am 1997
70
PD-1/PD-L1 Pathway: Tumor cells—T cells
• PD-L1 can be expressed on tumor cells either endogenously or induced by
association with T cells (adaptive immune resistance)1,2
• In RCC, PD-L1 expression has been shown to be associated with adverse
clinical/pathologic features, including3:
– More aggressive disease
– Shorter survival
1. Topalian et al. Curr Opin Immunol. 2012. 2. Taube JM et al. Science Transl Med. 2012;4:127ra37. 3.
Thompson RH et al. PNAS 2004.
Anti-PD-1: Blocking T-cell Suppression1,2
1. Keir ME et al. Ann Rev Immunol. 2008. 2. Pardoll DM. Nat Rev Cancer. 2012.
Clinical Activity of Nivolumab in RCC
Patients1
All RCC
Nivolumab dose
ORR, n (%)
DOR, mo
SD ≥ 2 wk, n (%)
24-wk PFS, %
RCC
1, 10 (n = 33)
1 (n = 17)
10 (n = 16)
9 (27)
4 (24)
5 (31)a
5.6+-22.3+
5.6+-17.5+
8.4-22.3+
9 (27)
4 (24)
5 (31)
56
47
67
• ORR was assessed using modified RECIST v1.0
• 2 RCC patients had a persistent reduction in baseline target lesions in the
presence of new lesions, but were not classified as responders for the ORR
calculation
a
1 CR.
1. McDermott DF et al. J Clin Oncol. 2012;30:Abstract 4505.
Partial Regression of Metastatic RCC in a
Patient Treated With 1 mg/kg Nivolumab1
Pretreatment
6 months
• The 57-year-old patient had developed progressive disease after receiving
sunitinib, temsirolimus, sorafenib, and pazopanib
• Currently in cycle 6 with ongoing PR
1. McDermott DF et al. J Clin Oncol. 2012;30:Abstract 4505. Images courtesy of C. Drake. Johns Hopkin’s University.
[TITLE]
Nivolumab: Phase 3 Trial vs Everolimus in
Pretreated Advanced/Metastatic RCC
Patients with clear
cell
metastatic/advanced
RCC after disease
progression to 1 or 2
prior VEGF systemic
treatment(s)
(N = 860)
Nivolumab
R
Everolimus
• Primary endpoint: OS
• Secondary endpoints: PFS, ORR, DOR, duration of OS, safety, diseaserelated symptom progression rate
Renal Cell Cancer: Summary
• Choosing a frontline agent
• We have a choice of agents even within drug classes
• Newer agents may not offer incremental efficacy but may
be less morbid
• Selecting an agent for relapsed disease
• We have choice between VEGF and mTOR targeted
therapy, this is an evolving story
• Who are candidates for immunotherapy?
• The old definitions of who is a candidate are being
questioned by better delivery of old agents and novel
targeted immunotherapeutics

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