Best of ASCO
GU Session
Sandy Srinivas.MD
Stanford University
Outline
Abstract #4: Intermittent (IAD) versus continuous androgen deprivation (CAD) in
hormone sensitive metastatic prostate cancer (HSM1PC) patients (pts): Results of
S9346 (INT-0162), an international phase III trial. (M. Hussain)
Abstract #LBA4518: Interim analysis results of COU-AA-302, a randomized,
phase III study of abiraterone acetate in chemotherapy-naive patients with
metastatic castration-resistant prostate cancer (mCRPC). (C. J. Ryan)
Abstract #LBA4512: Final overall survival analysis results from the phase III,
double-blind, randomized, multinational study of radium-223 chloride in the
treatment of patients with castration-resistant prostate cancer (CRPC) with bone
metastases (ALSYMPCA). (C. Parker)
Abstract #4519: Primary, secondary, and quality-of-life endpoint results from the
phase III AFFIRM study of MDV3100, an androgen receptor signaling inhibitor. (J.
S. De Bono)
Abstract #CRA4501: Tivozanib versus sorafenib as initial targeted therapy for
patients with advanced renal cell carcinoma: Results from a phase III randomized,
open-label, multicenter trial. (R. J. Motzer)
Prostate Cancer
SWOG 9346 trial
Armstrong, Oncologist 2009
Intermittent versus Continuous Androgen Deprivation in
Hormone Sensitive Metastatic Prostate Cancer Patients:
Results of SWOG 9346 (INT-0162) an International Phase
III Trial
Primary
- Determine if survival with IAD is Not Inferior to
survival with CAD.
-
QOL*: To compare 3 treatment-specific symptoms
(Impotence, Libido, Energy/Vitality) and physical and
emotional functioning between arms- Abstract # 4571
Rationale for Intermittent Therapy
ADT has side effects
Hormonal Therapy in the recurrent state is
non curative
Possibility of delaying “Castrate
Resistance”
Widely adopted
Differing schedules of start /stop times
Intermittent Androgen Deprivation
Group
Population
# patients
Endpoint
NCIC PR7
PSA after RT
1386
OS
EC 507
PSA after RRP
167
TTP
AP1795
Locally adv
335
TTP
SEUG
Locally adv
766
TTP
Finn
Locally adv
554
TTP
TULP
Metastatic
193
TTP
Adapted Oh ASCO 2012;
NCIC PR7: Intermittent vs. Continuous
Androgen Suppression
Median follow-up: 6.9 yrs
Patients had RT and rise in
PSA
IAS noninferior to CAD by
statistical criteria
– OS HR: 1.02 (95% CI: 0.861.21)
– P for noninferiority (HR ≥ 1.25)
= .009
Time to hormone-refractory
state improved with IAS vs.
CAD
– HR: 0.80 (95% CI: 0.67-0.98;
P = .024)
Crook, ASCO 2011
Outcome
IAS
(n = 690)
CAD
(n = 696)
Median OS, yrs
8.8
9.1
Deaths, n
268
256
Disease related
122
97
Unrelated
134
146
No difference in AEs between
arms, except for fewer hot
flashes with IAS
– Includes similar incidence of
myocardial events and
osteoporotic fractures
Study Design
Induction Registration
STEP 1 Newly diagnosed metastatic prostate cancer & a PSA  5 ng/mL
Induction AD = Goserelin + Bicalutamide X 7 months
If PSA  4 ng/mL on months 6&7 (PSA
normalization criteria)
STEP 2
Randomly Assign
Continuous AD
Intermittent AD
Discontinue AD, monthly PSAs. Resume AD
based on pre-specified criteria
Statistical Methods
•
Primary outcome: Survival post-randomization
• Hypothesis: “IAD is NOT inferior to CAD”
•
Design specifications:
• Survival with IAD is not inferior if the 95%
confidence interval for the hazard ratio (IAD vs.
CAD) excludes 1.2, α=0.05, power=90%, adjusting
for stratification factors in proportional hazards model.
•
Assumptions: post-randomization median survival
for CAD = 3 years:
• Sample size: 1500 eligible, randomized patients
• accrual: 6.25 yrs. + 2 additional yrs. of follow-up.
Overall Survival: Intermittent Therapy is Inferior Compared
to Continuous Therapy
7 yr
Survival
Median
At Risk Death in Years
Continuous therapy 765
422
5.8
Intermittent therapy 770
455
5.1
100%
80%
42%
38%
HR: 1.09 95% CI (0.95, 1.24)
60%
40%
20%
0%
0
At risk
Intermittent
Continuous
5
10
Years from Randomization
267
301
47
53
15
PRESENTED BY: Maha Hussain, MD, FACP
Results- Subgroup Analysis
Authors Conclusions
In this international phase III trial in patients with metastatic hormone
sensitive prostate cancer :
1.IAD was inferior to CAD based on our pre-specified definition of survival
comparability [HR: 1.09, 95% CI (0.95, 1.24)]. Therefore, CAD continues to
be the standard of care.
1.In a secondary analysis:
– IAD was not-inferior to CAD in patients with extensive disease. [HR:
0.96 95% CI (0.80, 1.16)].
– IAD was inferior in patients with minimal disease & CAD was
statistically significantly superior [HR: 1.23, 95% CI (1.02, 1.49),
p=0.034].
( HR: 1.09 95% CI (0.95, 1.24)
Superiority: Detects a difference between 2 drugs
Equivalence: confirms absence of significant difference between 2 drugs
Non Inferior: New Rx is no worse than active by a prespecified
amount
Conclusions
Authors were unable to show that IAD was no worse than
CAD ( Did not prove that CAD is superior)
Improvement in QOL with impotence, libido and E/V with
IAD
Accrual was twice as long as planned (6 vs 13 yrs)
Subgroup of extensive vs minimal was not preplanned
NCIC was in non metastatic (which is minimal ds)
Patients should be counseled about risks and benefits of
any therapy
IAD remains a reasonable option for patients with both
PSA alone ds and those with metastases
COUGAR
Armstrong, Oncologist 2009
Interim Analysis: a Randomized, Phase 3 Study of
Abiraterone Acetate in Chemotherapy-Naïve
Patients With mCRPC
OS Benefit Shown in Post-Chemotherapy mCRPC Patients- FDA apprved
4/2011
Median Survival was 14.8 months
Improvement of 3.9 months over Prednisone control arm
Overall Study Design of COUAA-302
Patients
• Progressive chemonaïve mCRPC
patients
(Planned N = 1088)
• Asymptomatic or
mildly symptomatic
R
A
N
D
O
M
I
Z
E
D
Efficacy end points
AA 1000 mg daily
Prednisone 5 mg BID
(Actual n = 546)
Placebo daily
Prednisone 5 mg BID
(Actual n = 542)
1:1
Co-Primary:
• rPFS by central review
• OS
Secondary:
• Time to opiate use
(cancer-related pain)
• Time to initiation of
chemotherapy
• Time to ECOG-PS
deterioration
• TTPP
Phase 3 multicenter, randomized, double-blind, placebo-controlled study conducted
at 151 sites in 12 countries; USA, Europe, Australia, Canada
Stratification by ECOG performance status 0 vs 1
COU-AA-302 Statistical Plan
Overall
Assumption
rPFS
OS
α
0.01
0.04
Power
91%
85%
HR
0.67
0.80
Expected events
378
773
Planned OS Analysis
1Q10
2Q10
3Q10
4Q10
1Q11
IA1
(~15% OS Events)
116 Events
 < 0.0001
IA = interim analysis. Ho, HR=1.0.
2Q11
3Q11
4Q11
1Q12
2Q12
3Q12
IA3
IA2
(40% OS Events) (55% OS events)
425 Events
311 Events
 = 0.0034
 = 0.0005
4Q12
Statistically Significant Improvement in rPFS
Primary End Point
100
AA + P (median, mos):
NR
PL + P (median, mos):
8.3
HR (95% CI):
Progression-Free (%)
80
P value:
0.43 (0.35-0.52)
< 0.0001
60
40
20
AA + P
PL + P
0
0
3
6
9
12
15
18
Time to Progression or Death (Months)
AA
PL
546
542
Data cutoff 12/20/2010.
NR, not reached; PL, placebo.
489
400
340
204
164
90
46
30
12
3
0
0
Strong Trend in OS Primary End Point
100
Survival (%)
80
60
40
AA + P (median, mos):
NR
PL + P (median, mos):
27.2
HR (95% CI):
20
AA + P
PL + P
P value:
0.75 (0.61-0.93)
0.0097
0
0
3
6
9
12
15
18
21
24
27
30
33
0
2
0
0
Time to Death (Months)
AA 546
PL 542
538
534
524
509
503
493
482
465
452
437
412
387
258
237
120
106
27
25
Data cutoff 12/20/2011.
Pre-specified significance level by O’Brien-Fleming Boundary = 0.0008.
21
PRESENTED
PRESENTEDAT
AT
rPFS Benefit Demonstrated Across Full Spectrum of
Patient Subgroups
Favors
AA
Variable
All subjects
Baseline ECOG
Baseline BPI
Bone metastasis only at entry
Age
Baseline PSA above median
Baseline LDH above median
Baseline ALK-P above median
Region
Subgroup
Favors
Placebo
Median (months)
AA
Placebo
HR
95% CI
ALL
NE
8.3
0.43
(0.35-0.52)
0
13.7
8.3
0.45
(0.36-0.57)
1
NE
7.4
0.35
(0.23-0.54)
0-1
NE
8.4
0.42
(0.32-0.54)
2-3
11.1
8.2
0.51
(0.35-0.75)
YES
NE
13.7
0.48
(0.34-0.69)
NO
11.3
5.6
0.38
(0.30-0.49)
< 65
13.7
5.6
0.36
(0.25-0.53)
≥ 65
NE
9.7
0.45
(0.35-0.58)
≥ 75
NE
11.0
0.57
0.39-0.83)
YES
11.9
8.0
0.44
(0.33-0.58)
NO
NE
8.5
0.40
(0.29-0.54)
YES
NE
5.6
0.37
(0.28-0.49)
NO
NE
9.0
0.48
(0.36-0.65)
YES
11.5
8.2
0.50
(0.38-0.66)
NO
NE
8.3
0.34
(0.25-0.47)
N.A.
NE
8.2
0.36
(0.27-0.48)
Other
11.5
8.4
0.52
(0.39-0.69)
0.2
0.75 1
1.5
Serologic and Clinical
Responses
AA + P
(n = 546)
Placebo + P
(n = 542)
RR (95%
CI)
P Value
62%
24%
NA
<0.0001
N=220
N=218
RECIST: Defined
objective response
36%
16%
2.273
(1.591, 3.247)
<0.0001
Complete response
11%
4%
Partial response
25%
12%
Stable disease
61%
69%
Progressive disease
2%
15%
PSA decline ≥50%
Adverse Events
AA + P
(n = 542)
%
Placebo + P
(n = 540)
%
All Grades
Grades 3/4
All Grades
Grades 3/4
Fatigue
39
2
34
2
Fluid retention
28
0.7
24
1.7
Hypokalemia
17
2
13
2
Hypertension
22
4
13
3
Cardiac disorders
19
6
16
3
4
1.3
5
0.9
ALT increased
12
5.4
5
0.8
AST increased
11
3.0
5
0.9
Atrial fibrillation
Most ALT and AST increases occurred during the first 3 months of treatment
Conclusions
Authors: In patients with asymptomatic and mildly
symptomatic, chemotherapy-naïve mCRPC, treatment with
abiraterone acetate plus prednisone:
– Delays disease progression
– Increases survival
– Extends time with minimal or no symptoms
– No new important safety signals
Valuable drug; Will become a standard pre chemotherapy
Approval pending
Earlier closure will not impact clinical use
ALMSYMCA
AFFIRM
Armstrong, Oncologist 2009
Phase 3 Trial (AFFIRM) of (MDV3100), an
Androgen Receptor Signaling Inhibitor:
Primary, Secondary, and
QOL Results
Chemo-naïve (n = 65)
Chemo-naïve (n = 65) Post-chemo (n = 75)
Tran C, et al. Science. 2009;324:787-790.
AFFIRM Trial Design
Patient
Population:
1199 patients with
progressive CRPC
* Failed docetaxel
chemotherapy
R
A
N
D
O
M
I
Z
E
D
Enzalutamide
160 mg daily
n = 800
Placebo
Primary
Endpoint:
Overall Survival
n = 399
2:1
Glucocorticoids were not required but allowed.
PCWG2 criteria used (continue therapy through minor PSA changes;
confirm bone scan ‘progression’; focus on benefit not response).*
Recruitment in 156 centers from 15 countries and 5 continents.
Enrollment between September 2009 and November 2010.
* Scher et al, 2008
End Points
Primary endpoint: Overall
survival
Stratification variables:
– ECOG Performance Status
(0-1, 2)
– Mean Brief Pain Inventory
Q#3 Score (<4, ≥ 4)
Statistical design:
– Cumulative alpha: 0.05 (2sided)
– Power: 90% to detect a 24%
reduction in mortality (target
HR = 0.76)
– One planned interim analysis
at 520 events
Secondary Endpoints:
Response Indicators
PSA Response
Soft Tissue Objective
Response
FACT-P Quality of Life
Pain Palliation
Circulating Tumor Cells
Progression Indicators
Time to PSA Progression
Radiographic Progressionfree Survival
Time to First Skeletal-Related
Event
Enzalutamide Prolonged Survival,
Reducing Risk of Death
HR = 0.631 (0.529, 0.752) P <0.0001
37% reduction in risk of death
Enzalutamide: 18.4 months
(95% CI: 17.3, NYR)
Placebo: 13.6 months
(95% CI: 11.3, 15.8)
Enzalutamide
800
775
701
627
400
211
72
7
0
Placebo
399
376
317
263
167
81
33
3
0
Survival Benefit Across All Subgroups
Hazard Ratio for Death Overall Survival median (mo)
Enzalutamide / Placebo
(95% CI)
Favors Enzalutamide*
*Based on data analysis cutoff date for the planned interim analysis.
Favors Placebo*
Enzalutamide had a high PSA Response
Rate
>50% confirmed PSA fall:
Enza 54% ; Placebo 2% (p<0.0001)
>90% confirmed PSA fall:
Enza 25%; Placebo 1% (p<0.0001)
Placebo
Enzalutamide
All the secondary endpoint measures favored the treatment arm
PSA Progression Free Survival
HR = 0.248 P <0.0001
Enzalutamide: 8.3 months
(95% CI: 5.8, 8.3)
Placebo: 3.0 months
(95% CI: 2.9, 3.7)
Enzalutamide
800
603
287
145
68
27
7
1
0
Placebo
399
107
12
5
2
1
0
0
0
PSA progression defined by PCWG2 criteria
Enzalutamide RECIST Response Rate
Response
Enzalutamide
Placebo
P-value
28.9%
3.8%
< 0.0001
Complete response (CR)
3.8%
1.0%
Partial response (PR)
25.1%
2.9%
Stable disease
39.2%
29.3%
Objective Response (CR +PR)
Best Overall Response for
Study
Enzalutamide (n= 446); placebo (n= 208) with measurable disease
Response categories defined by RECIST 1.1
Time to First Skeletal Related Event
HR = 0.621 P <0.0001
Enzalutamide: 16.7 months
(95% CI: 14.6, 19.1)
Placebo: 13.3 months
(95% CI: 5.5, NYR)
Enzalutamide
800
676
548
379
209
87
19
2
0
Placebo
399
278
196
128
68
33
11
0
0
Quality-of-Life Responses by FACT-P
Number With Baseline and
Post-baseline Assessment
Responders*
Difference in Response
Rate with 95% Confidence
Interval
Enzalutamide
(n = 800)
Placebo
(n = 399)
651
257
43.2%
18.3%
24.9% (18.8%, 30.9%)
p < 0.0001
*Response is defined as 10-point increase in the overall score (Cella, 2009).
Adverse Events
All Grades
Grades >3*
Enzalutamide
(n = 800)
Placebo
(n = 399)
Enzalutamide
(n = 800)
Placebo
(n = 399)
AEs
98.1%
97.7%
45.3%
53.1%
Serious AEs
33.5%
38.6%
28.4%
33.6%
Discontinuations
due to AEs
7.6%
9.8%
4.6%
7.0%
AEs leading to
death
2.9%
3.5%
2.9%
3.5%
*AEs graded for severity; grades 1 and 2 milder and grades 3-5 more severe
Adverse Events of Special Interest
All Grades
Grade ≥ 3 Events
Enzalutamide
(n = 800)
Placebo
(n = 399)
Enzalutamide
(n = 800)
Placebo
(n = 399)
Fatigue
33.6%
29.1%
6.3%
7.3%
Cardiac Disorders
6.1%
7.5%
0.9%
2.0%
Myocardial
Infarction
0.3%
0.5%
0.3%
0.5%
LFT Abnormalities*
1.0%
1.5%
0.4%
0.8%
Seizure
0.6%
0.0%
0.6%
0.0%
*Includes terms hyperbilirubinaemia, AST increased, ALT increased, LFT abnormal,
transaminases increased, and blood bilirubin increased.
Conclusions
Authors: Enzalutamide, a once a day oral Androgen
Receptor Signaling Inhibitor, is well tolerated and
prolongs survival in men with CRPC by almost 5 months.
Probably will be used post chemo now and
abiraterone will be used pre chemo
Optimum sequence unknown
Zytiga
Armstrong, Oncologist 2009
MDV3100
Phase III of radium-223 chloride in
castration-resistant prostate cancer (CRPC)
patients with bone metastases (ALSYMPCA)
Range of alpha-particle
Radium-223
Bone surface
ALSYMPCA (ALpharadin in SYMptomatic
Prostate CAncer) Phase III Study Design
PATIENTS
STRATIFICATION
• Confirmed
symptomatic
CRPC
• ≥ 2 bone
metastases
• No known
visceral
metastases
• Postdocetaxel or
unfit for
docetaxel
• Total ALP:
< 220 U/L vs ≥ 220 U/L
• Bisphosphonate use:
Yes vs No
• Prior docetaxel:
Yes vs No
TREATMENT
R
A
N
D
O
M
I
S
E
D
2:1
N = 921
Planned follow-up is 3 years
6 injections at
4-week intervals
Radium-223 (50 kBq/kg)
+ Best standard of care
Placebo (saline)
+ Best standard of care
ALSYMPCA Updated Analysis
Overall Survival
100
90
HR = 0.695
80
95% CI, 0.581, 0.832
P = 0.00007
70
60
%
50
Radium-223, n = 614
Median OS: 14.9 months
40
30
20
Placebo, n = 307
Median OS: 11.3 months
10
0
Month 0
3
6
9
12
15
18
21
24
27
30
33
36
39
Radium-223 614
578
504
369
274
178
105
60
41
18
7
1
0
0
Placebo 307
288
228
157
103
67
39
24
14
7
4
2
1
0
ALSYMPCA Updated Analysis
Survival Benefit Across Patient Subgroups
ALSYMPCA Updated Analysis
AEs of Interest
All Grades
Patients with AEs
n, (%)
Grades 3 or 4
Radium-223
n = 600
Placebo
n = 301
Radium-223
n = 600
Placebo
n= 301
187 (31)
92 (31)
77 (13)
39 (13)
Neutropenia
30 (5)
3 (1)
13 (2)
2 (1)
Thrombocytopenia
69 (12)
17 (6)
38 (6)
6 (2)
Bone pain
300 (50)
187 (62)
125 (21)
77 (26)
Diarrhea
151 (25)
45 (15)
9 (2)
5 (2)
Nausea
213 (36)
104 (35)
10 (2)
5 (2)
Vomiting
111 (19)
41 (14)
10 (2)
7 (2)
Constipation
108 (18)
64 (21)
6 (1)
4 (1)
Hematologic
Anemia
Non-Hematologic
ALSYMPCA Updated Analysis
OS by Stratification Variables:
Prior Docetaxel Use
Prior docetaxel use
NO prior docetaxel use
100
100
HR = 0.710
95% CI,
0.565, 0.891
P = 0.00307
9
0
80
7
0
60
% 5
7
0
60
% 5
Radium-223, n = 352
Median: 14.4 months
0
40
3
0
20
0
40
Placebo, n = 174
Median: 11.3 months
152
104
61
35
15
Radium-223, n = 262
Median: 16.1 months
3
0
20
1
0
0
Month0 4 8 1 16 2 24 2 32 3 4
Radium-223 352 327 238 155
2 88 045 27 85 1 60 00
Placebo 174
HR = 0.745
95% CI,
0.562, 0.987
P = 0.03932
9
0
80
5
4
1
1
0
Placebo, n = 133
Median: 11.5 months
10
0
Month 0
4
8
Radium-223 262
236
168
Placebo 133
113
74
1
2
42
119
1 2
70
31
6
0
24
14
2
49
14
2
7
83
3
1
21
3
0
60
ALSYMPCA Updated Analysis
Time To First SRE*
1
0
090
HR = 0.64
95% CI, 0.52, 0.78
80
P < 0.0001
70
60
%
Radium-223, n = 614
Median: 12.2 months
50
40
30
Placebo, n = 307
Median: 6.7 months
20
10
0
Month
0
3
6
9
12
15
18
21
24
27
30
Radium-223 614
487
332
193
125
62
31
8
8
1
0
Placebo 307
207
108
51
33
17
8
6
3
1
0
ALYSMPCA Updated Analysis Conclusions
Radium-223 compared with placebo in CRPC
patients with bone metastases:
– Significantly prolonged median OS by 3.6 months
Significantly prolonged median time to first SRE by 5.5
months
My Comments:
– Useful drug in patients with significant pain
– Only bone metastases/not visceral disease
– Post docetaxel/docetaxel ineligible patients
– Nuclear Medicine Referral
Renal Cell Carcinoma
Current State & Challenges in mRCC
• Explosion of choices in the last 7 years
• 8 FDA approved agents yet median OS still ~2 years
• Few cures
• Efficacy at the expense of toxicity
• Limited selection and prediction criteria
Current Landscape in mRCC
Drug
Comparator
Line of Rx
RR (%)
PFS(mos)
Sunitinib
IFN
I
47
11
Sorafenib
Placebo
II
10
5.5
Pazopanib
Placebo
I
30
9.2
Bev +IFN
IFN
I
25-30
10-11
Axitinib
Sorafenib
II
Temsirolimus
IFN
I
8
3.8
Everolimus
Placebo
II/III
2
4.9
6.7 vs 4.7
First Line TKI Rx: RR- 25-50% PFS- 9-11 months
Reported Potencies of Tyrosine
Kinase Inhibitors
0.01
VEGFR-1
More
potent
VEGFR-3
approximate: adjustment in
consideration of 2.3% BSA
0.1
sunitinib4
1
tivozanib1,2
(AV-951)
Less
potent
VEGFR-2
pazopanib5
(GW-786034)
sorafenib5
axitiniba,3
(AG13736)
10
100
Note: Reported potenciesa are either biochemical- or cell-based IC50s (nM); cell-based data are shown when available.
aAxitinib data for VEGFR-2 are from an ELISA assay; all other axitinib data are from an immunoprecipitation assay. In addition, Chow
LQM, Eckhardt SG reported an axitinib IC50 of 1.2, 0.25, and 0.29 nM for VEGFR-1, -2, and -3 (J Clin Oncol. 2007;25(7):884-895).
1. Eskens FALM, et al. In: Proceedings of the 99th Annual Meeting of the
AACR. San Diego, CA: AACR; 2008. Abstract LB-201.
2. Nakamura K, et al. Cancer Res. 2006;66(18):9134-9142.
3. Hu-Lowe DD, et al. Clin Cancer Res. 2008;14(22):7272-7283.
4. Schmidinger M, Zielinski CC. Eur Urol Rev. 2010;5(2):31-36.
5. Chow LQM, Eckhardt SG. J Clin Oncol. 2007;25(7):884-896.
TIVO-1: Phase III superiority study of tivozanib vs.
sorafenib as first-line targeted therapy for mRCC
Key Eligibility Criteria:
• Advanced RCC
• Clear cell histology
• Measurable disease
• Prior nephrectomy
• 0–1 prior therapy for mRCC
• No prior VEGF or mTOR therapy
• ECOG PS 0–1
R
A
N
D
O
M
I
Z
E
1:1
Stratification Factors:
• Geographic region
• Prior treatments for mRCC
• # of metastatic lesions
Tivozanib 1.5 mg/day po,
3 weeks on/1 week off
Sorafenib 400 mg po bid,
continuous
Primary endpoint: Progression-free survival
(independent review)
Probability of PFS
1.0
N
Median PFS (95% CI)
Tivozanib
260
11.9 mos (9.3–14.7)
Sorafenib
257
9.1 mos (7.3–9.5)
HR
P value
0.797
0.042
0.8
0.6
0.4
0.2
0
0
5
10
Time (months )
15
20
Selected laboratory abnormalities
Tivozanib (N=259, %)
Sorafenib (N=257, %)
All Grade
Grade 3 (4)
All Grade
Grade 3 (4)
ALT increase
26
<1
34
3 (<1)
AST increase
34
2
49
3 (<1)
Amylase increase
40
4 (<1)
52
6 (<1)
Lipase increase
45
8 (2)
62
20 (4)
Hypophosphatemia
27
4
70
25
Proteinuria
68
3
72
2
Low hemoglobin
36
2 (2)
46
3 (<1)
Neutropenia
10
2 (<1)
9
1 (<1)
Thrombocytopenia
17
0 (<1)
11
0
Chemistries
Hematology
• Patients with normal TSH levels that increased to >10 mIU/L after treatment: tivozanib, 24%; sorafenib, 6%
- Few of these patients had low T3 (tivozanib 3%; sorafenib 2%) or low free T4 (tivozanib,2%; sorafenib,
<1%) on or after date elevations in TSH were observed
Treatment-emergent
Tivozanib (N=259, %)
a
AEs
Sorafenib (N=257, %)
All Grade
Grade 3 (4)
All Grade
Grade 3 (4)
Hypertension
44
24 (2)
34
17 (<1)
Diarrhea
22
2
32
6
Dysphonia
21
0
5
0
Fatigue
18
5
16
4
Weight decreased
17
<1
20
3
Asthenia
15
4 (<1)
16
3
Palmar-plantar
erythrodysesthesia
13
2
54
17
Back pain
14
3
7
2
Nausea
11
<1
8
<1
Dyspnea
10
2b
8
2
Decreased appetite
10
<1
9
<1
Alopecia
2
0
21
0
in ≥10% of patients. bOne grade 5 dyspnea event was reported.
Numbers highlighted in blue indicate difference between tivozanib and sorafenib, P<0.05 by Fisher exact
test.
aOccurring
Dose adjustments due to AEs
Tivozanib Sorafenib
(n=259a) (n=257)
Dose interruptions,b %
18
35
Dose reductions,b %
12
43
Discontinuations,c %
4
5
aOne
patient was randomized but never received treatment.
between tivozanib and sorafenib, P<0.001 by Fisher exact test.
cDue to treatment-related adverse events.
bDifference
Conclusions
Authors: Tivoanib demonstrated superior efficacy compared with
sorafenib as treatment for metastatic RCC
Tivozanib should be considered a first-line treatment option for
mRCC
Where will this fit in our practice?
Manage side effects/comfortable at it
GU - Updates
Intermittent (IAD) versus continuous androgen deprivation
(CAD): Remains an option; Need discussion with patients trade
offs
COU-AA-302, a randomized, phase III study of abiraterone
acetate in chemotherapy-naive patients with metastatic
castration-resistant prostate cancer (mCRPC). Reasonable pre
chemotherapy
Alpharadin trial: Good option for palliation of pain post
chemotherapy
MDV 3100: Useful agent post chmeotherapy
Tivozanib versus sorafenib: New TKI with less side effects for
mRCC