Transcript Document

HOT TOPICS
Controversie Oncologiche
Prima linea di Trattamento
Roberto Sabbatini
Azienda Ospedaliero Universitaria di Modena
Policlicnico di Modena
Scuola di UrOncologia
Tumore del rene
Roma 23-24 maggio 2014
My disclosures
Consultancies
Speaking
bureau
Research
funding
Clinical trial
support
Pfizer
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GSK
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Roche
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Astellas
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Bayer-Schering
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Novartis
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Renal Cell Carcinoma
The epidemiology
• RCC accounts for:
– 80–85% of renal cancers1
– 2–3% of all adult malignancies2
– 63,000 new cases/year in
Europe
– 26,000 mortalities annually
• RCC is:
Incidence
Mortality
– More common in men than
women3,4
– Most frequently occurs in 60–70
year olds4
– More common in people from
Northern European and North
American countries3,4
1. Motzer RJ et al. N Engl J Med 1996;335:865–75; 2. Levine E et al. Adult malignant renal parenchymal neoplasms. In Clinical urography, 2nd edition. 2000, Saunders: Philiadelphia, USA. p. 1440–559; 3.
GLOBOCAN 2002; Cancer Incidence, Mortality and Prevalence Worldwide 2002 estimates. 2006 http://www-dep.iarc.fr/; 4. Cancer Research UK, UK kidney cancer statistics. 2008
http://info.cancerresearchuk.org/cancerstats/types/kidney/?a=5441.
Renal Cell Carcinoma:
an unrelenting, progressive disease
Presentation at diagnosis1:
45% with localized disease
25% with locally advanced disease
20–30% metastatic disease
33% of patients treated for localized disease will
develop metastatic disease2
Common sites of metastasis include lung (75%), liver (18%), bone
(20%), brain (8%)3
Median survival for patients with metastatic RCC
in the era of cytokine was 6–12 months4–7
1. National Cancer Institute. SEER cancer statistics fact sheet: cancer of the kidney and renal pelvis. Accessed 2009; 2. Flanigan RC et al. Curr Treat Options Oncol 2003;4:385–90. 3. Sachdeva K et al.
Renal cell carcinoma., in eMedicine. 2008; 4. Gay PC et al. J Neurooncol 1987;5:51–6; 5. Decker DA et al. J Clin Oncol 1984;2:169–73; 6. Culine S et al. Cancer 1998;83:2548–53; 7. Doh LS et al.
Oncology 2006;20:603–13.
Disease-Specific Survival in de novo mRCC
in the Cytokine and Targeted Therapy Era
Disease specific survival by Time Period of
Clear Cell RCC pts
Disease specific survival by Time Period of
non-Clear Cell RCC pts
Pal SK, PLoS ONE 2013
Explosion of Targeted Therapy for
mRCC (phase III trial)
Sorafenib
Temsirolimus
Pazopanib
Cytokine-resistant
Poor prognosis
I line and
cytokine-failure
2005
20062006
2007 2007 2008
Sunitinib
2009
2008
I line therapy
2014
Everolimus
Axitinib
VEGFi-failure
Cytokine/Suniti
nib failure
I line therapy
Bevacizumab + IFNα
2010
2009
Key drivers in first-line treatment selection:
Efficacy and Experience
Targeted agents:
Standard of care for mRCC
Clinical efficacy = primary
driver to guide treatment
decisions
Schmidinger M, Kidney Cancer Symposium, Vienna 2012
Ist-line phase III trials in mRCC
Progression Free Survival
Temsirolimus (Hudes 2007)
3.7/5.5
Sorafenib (Escudier , 2007)
5.7*
8.5*
Bev + INF-α (Rini, 2008)
Bev + INF-α (Escudier 2007)
Sunitinib (Motzer 2007)
10.2*
1.9
CALGB 90206
5.2 (IFN)
AVOREN
5.4 (IFN)
11.0*
A6181034
Pazopanib (Sternberg 2010) 11.1*
VEG105192
11
*p<.05
10 8
3 (Placebo)
Target
5
Sperimental Arm
5.1 (IFN)
2.8 (Placebo)
0
4
8
mos
Control Arm
Phase III trials in mRCC
Overall Survival
Kane 2006
Best supportive care
7–9
IFN
Temsirolimus
Temsirolimus
7.3
10.9*
2007 to present
Placebo
Sorafenib
TARGET
15.2
17.4
18.3
IFN Rini ASCO 2009
BEV/IFN
CALGB 90206
18.5
18.7
Gore ASCO 2008
IFN-α + IL-2 + 5-FU
AVOREN
IFN
Bevacizumab + IFN
Pazopanib
Placebo
Sternberg EJC 2010
17.8
19.8
NR
20.5
22.9
21.8
IFN
Motzer JCO 2009
Sunitinib
26.4
29.3
28.4
Sunitinib
Motzer 2013
Pazopanib
0
5
10
15
20
25
30
35
*p<.05
Algorithm for Clear Cell RCC 2012
Setting
First-line
Therapy
Secondline
Therapy
Therapy
Level 1
Level 2
Low+Intermed
Risk
Sunitinib
Beva/IFN
Pazopanib
HD Il-2
Sorafenib
Poor
Risk
Temsirolimus
Sunitinib
Clinical trial
Prior
Cytokine
Sorafenib
Pazopanib
Axitinib
Sunitinib
Clinical trial
Prior TKi
Everolimus
Axitinib
Sequential
TKi
2nd-generation trials: Head to Head studies 1st-line
phase III trial in mRCC
Agents
N. pts
Tivozanib vs
Sorafenib1
Everolimus–Sunitinib
vs
500
Line of
treatment
First or
CK treated
Median
PFS
(mos)
Median
OS
(mos)
11.9 vs 9.1*
NA
7.8 vs 10.7*
NA
471
First
288
First
1110
First
8.4 vs 9.5
28.4 vs 29.3
First
16.6 (not eligible)
vs
NA
Sunitinib-Everolimus2
Axitinib vs
Sorafenib
Pazopanib vs
Sunitinib4
Axitinib
“dose
tritation”5
213
10.1 vs 6.5*
NA
14.5 (eligible)
1. Motzer R, ASCO 2012; 2. Motzer R. ASCO 2013; 3. Hudson TE, ASCO-GU 2013
4. Motzer R, NEJM 2013; 5. Rini B, ASCO-GU 2013
* p< .05
Case study: TIVO-1
Treatment allocation imbalance?
• Recurrent or mRCC with
a clear cell component
• Measurable disease
• Treatment-naïve or 1
prior treatment: cytokines,
investigational agent,
hormonal therapy,
chemotherapy
• Prior nephrectomy
• ECOG PS 0 or 1
n=517
1:1
R
A
N
D
O
M
I
S
A
T
I
O
N
Tivozanib 1.5 mg/day
(3 weeks on-treatment;
1 week off-treatment)
(n=260)
Cross-over with Tivozanib 1.5 mg/day
permitted upon disease progression;
extension protocol (NCT01076010)
Sorafenib
400 mg BID (n=257)
Phase III randomized, open label multicenter trial:
• Primary endpoint: PFS by independent review (assessment of response every 8 wks)
• Secondary endpoints: overall survival, ORR, quality of life
Motzer RJ, et al. J Clin Oncol 2013
Primary endpoint: Tivozanib significantly prolonged
PFS versus sunitinib
1.0
Overall population
n
PFS probability
0.8
Median PFS
(95% CI)
P
value
HR
Tivozan
11.9 mos (9.3–
260
ib
14.7)
0.79
0.042
7
Sorafen
9.1 mos (7.3–
257
ib
9.5)
0.6
0.4
0.2
0.0
0
5
10
15
20
Time, months
Motzer RJ, et al. J Clin Oncol 2013
BUT - No significant difference
in OS (secondary endpoint)
Overall population
100
Tivozani
28.8 mos (22.5–
260
b
NR)
80
% survival
Median OS
(95% CI)
n
Sorafeni
29.3 mos (29.3–
257
b
NR)
60
HR
P
value
1.25 0.105
40
20
0
0
2
4
6
8
10
12
14
16
18
20
22
24
Time (months)
Motzer RJ, et al. J Clin Oncol 2013
FDA. Tivozanib, June 2013.
26
28
30
32
Why no OS benefit?
R
A
N
D
O
M
I
S
A
T
I
O
N
Tivozanib 1.5 mg/day
(3 weeks on-treatment;
1 week off-treatment)
(n=260)
Infrequent second
line treatment at time
of disease
progression*
Balanced?
Sorafenib
400 mg BID
(n=257)
Cross over to
tivozanib at time of
disease progression
*Due to lack of available TKIs in Eastern Europe
•FDA
A conclusion:
sequential trial of two agents, sorafenib followed by tivozanib,
“Inconsistent PFS and OS results and imbalance in post-study treatments
compared with one agent, tivozanib
make the trial results inconclusive when making
a risk-benefit assessment
1
•necessary
“The sanctity
of
OS
was
compromised”
for approval.”2
1. Garnick MB. J Clin Oncol 2013
2. FDA. Tivozanib, June 2013. http://www.fda.gov
COMPARZ: a non-inferiority trial
Key Eligibility Criteria
• Advanced/metastatic RCC
• Clear-cell histology
• No prior systemic therapy
• Measurable disease (RECIST 1.0)
• KPS ≥ 70
• Adequate organ function
Pazopanib
800 mg qd
Continuous dosing
Randomized 1:1
(N = 1110)
NCT00720941,
n = 927
NCT01147822, n = 183
Sunitinib
50 mg qd
4 wk on/2 wk off
• Stratification factors:
• Karnofksy Performance Status (KPS; 70/80 vs. 90/100)
• Prior nephrectomy (yes vs. no)
• Baseline lactate dehydrogenase (LDH; >1.5 vs. ≤1.5 x ULN)
Motzer R, NEJM 2013
Primary Endpoint: PFS
(Independent Review)
Median PFS (95% CI)
Pazopanib
8.4 mo (8.3, 10.9)
Sunitinib
9.5 mo (8.3, 11.1)
HR (95% CI ) = 1.047 (0.898,1.220)
Motzer R, NEJM 2013
17
Laboratory Abnormalitiesa
Pazopanib (n = 554) %
Chemistry labs
Sunitinib (n = 548) %
All Grades
Grade 3/4
All Grades
Grade 3/4
61
60
54
36
36
35
33
32
11/1
15/2
5/0
3/<1
4/0
7/<1
<1/0
<1/0
60
43
57
27
52
32
42
46
3/0
4/<1
4/<1
2/<1
8/<1
7/<1
2/0
<1/<1
Leukopenia
43
1/0
78
6/0
Neutropenia
37
4/<1
68
19/1
Thrombocytopenia
41
3/<1
78
18/4
Lymphopenia
38
5/0
55
14/<1
Anemia
31
1/<1
60
6/1
AST
ALT
Hyperglycemia
Total bilirubin
Hypophosphatemia
Hyponatremia
Hypoalbuminemia
Creatinine
Hematology labs
a Reported
in (≥30%) of patients in either arm.
Rows highlighted in yellow indicate events for which relative risk of occurrence is higher with pazopanib.
Rows highlighted in blue indicate events for which relative risk of occurrence is higher with sunitinib.
Motzer R, NEJM 2013
18
Common Treatment-Emergent
Adverse Eventsa
Pazopanib (n = 554) %
Adverse Eventa
Sunitinib (n = 548) %
All Grades
Grade 3/4
All Grades
Grade 3/4
Any eventb
>99
59/15
>99
57/17
Diarrhea
63
9/0
57
7/<1
Fatigue
55
10/<1
63
17/<1
Hypertension
46
15/<1
41
15/<1
Nausea
45
2/0
46
2/0
Decreased appetite
37
1/0
37
3/0
Hair color changes
30
0/0
10
<1/0
Hand-foot syndrome
29
6/0
50
11/<1
a Adverse
events ≥30% in either arm
of patients in pazopanib arm and 3% of patients in sunitinib arm had grade 5 adverse events.
Rows highlighted in yellow indicate events for which relative risk of occurrence is higher with pazopanib.
Rows highlighted in blue indicate events for which relative risk of occurrence is higher with sunitinib.
b 2%
Motzer R, NEJM 2013
19
COMPARZ trial: Adverse Events
……. The median duration of treatment was similar in the
two groups: 8.0 months (range, 0 to 40) in the pazopanib
group and 7.6 months (range, 0 to 38) in the sunitinib
group. Similar percentages of patients in the pazopanib
and sunitinib groups had a dose interruption of 7 days or
more (44% and 49%, respectively) or a reduction in the
dose (44% and 51%, respectively). The proportion of
patients who discontinued the study drug because of
adverse events was 24% in the pazopanib group and
20% in the sunitinib group (Table S5 in the Supplementary
Appendix); the higher discontinuation
rate observed for pazopanib, as compared with sunitinib,
was primarily due to abnormalities in liver-function tests
(6% vs. 1%).
….. There were no between-group differences in
the rates of cardiovascular adverse events. The
percentages of patients meeting cardiac-dysfunction
criteria15 were similar: 13% in the pazopanib group and
11% in the sunitinib group (Table S7 in the Supplementary
Appendix). The incidence of myocardial infarction or
ischemia was similar in the pazopanib and sunitinib
groups (2% and 4%, respectively).
Motzer R, NEJM 2013
RECORD-3: Phase II randomized trial comparing sequential
1st-line everolimus and 2nd-line sunitinib vs 1st-line sunitinib
and 2nd-line everolimus
R
A
N
1:1
D
O
M
I
Z
E**
S
C
R
E
E
N
Everolimus
10 mg/day
Sunitinib
50 mg/day***
Cross-over upon
progression
Sunitinib
50 mg/day***
Everolimus
10 mg/day
1st Line
Study
endpoints
Primary
• PFS-1st line
Secondary
• Combined
PFS
• ORR-1st line
• OS
• Safety
2nd Line
*NCT00903175. **Stratified by MSKCC prognostic factors. ***4 weeks on and 2 weeks off.
Primary Endpoint: 1st-line PFS for non-inferiority of everolimus vs sunitinib
•
Bayesian method: non-inferiority declared if observed HR ≤1.1 (1-month difference in the
median first-line PFS)
•
318 first-line events needed (total 460 patients)
Motzer R, ECC 2013
Primary End Point: First-line PFS
Cumulative event-free probability (%)
100
90
K-M Median PFS (mo)
80
70
60
Everolimus
Sunitinib
7.85
10.71
Hazard Ratio = 1.43
Two-sided 95% CI [1.15, 1.77]
50
40
30
20
Everolimus (events/N = 182/238)
10
Sunitinib (events/N = 158/233)
0
0
3
Number of patients still at risk
Everolimus 238
164
Sunitinib
233
181
6
9
12
15
18
21
24
27
30
33
23
28
12
15
5
9
0
3
0
0
Time (months)
118
145
88
108
68
84
44
55
Motzer R, ECC 2013
31
42
RECORD-3: combined PFS*
Cumulative event-free probability (%)
100
90
EVE→SUN (events/N = 88/238)
80
SUN→EVE (events/N = 80/233)
70
60
50
K-M Median PFS (mo)
40
EVE→SUN
SUN→EVE
30
21.13
25.79
20
Hazard Ratio = 1.28
Two-sided 95% CI [0.94, 1.73]
10
Log-rank p-value = 0.116
*Time
from randomization to progression
following second-line treatment or death (any time).
0
0
3
6
9
12
15
18
21
24
27
30
33
37
35
19
19
6
12
0
4
0
0
Time (months)
Number of patients still at risk
EVE→SUN
SUN→EVE
238
233
186
196
145
171
112
135
88
105
65
74
48
52
Motzer R, ECC 2013
RECOR-3: Overall Survival
Cumulative event-free probability (%)
100
EVE→SUN (events/N = 108/238)
90
SUN→EVE (events/N = 96/233)
80
70
60
50
40
30
K-M Median OS (mo)
20
10
EVE→SUN
SUN→EVE
22.41
32.03
Hazard Ratio = 1.24
Two-sided 95% CI [0.94, 1.64]
0
0
3
6
9
12
15
18
21
24
27
30
33
36
66
71
43
38
15
22
2
6
0
1
0
0
Time (months)
Number of patients still at risk
EVE→SUN 238
208
220
SUN→EVE 233
189
198
165
185
151
164
137
152
103
115
PISCES
Timing assessments
Pazopanib
800 mg once
daily, 10 weeks
Sunitinib
50 mg 4/2,
10 weeks
Patient choice
of treatment
to progression
1:1
Randomisation
n=169
Pazopanib
800 mg once
daily, 10 weeks
Sunitinib
50 mg 4/2,
10 weeks
Period 1
2-week washout
Period 2
Off study
Double-blind
0
Cross-over design:
10 Time (weeks)12
22
• Drugs blinded by over-encapsulation
• Patients on sunitinib received matchingplacebo during 2-week
‘off-period’
Escudier B, et al. JCO 2014
Primary endpoint:
Significantly more pts preferred PAZO over SUNI
100
p<0.001
90
80
Patients, %
70
60
50
70%
(n=80)
40
30
20
22%
(n=25)
10
8%
(n=9)
0
Preferred pazopanib
Preferred sunitinib
No preference
Patients were still blinded when they stated their preference
Escudier B, et al. JCO 2014
Ist-line phase III trials in mRCC
Progression Free Survival
Temsirolimus (Hudes 2007)
3.7/5.5
Sorafenib (Escudier , 2007)
5.7*
8.5*
Bev + INF-α (Rini, 2008)
10.2*
Bev + INF-α (Escudier 2007)
Sunitinib (Motzer 2007)
1.9
CALGB 90206
5.2 (IFN)
AVOREN
5.4 (IFN)
11.0*
A6181034
Pazopanib (Sternberg 2010) 11.1*
VEG105192
Tivozanib (Motzer 2013) 11.9*
Pazopanib (Motzer 2013)
5.1 (IFN)
2.8 (Placebo)
9.1 (Sorafenib)
VEG105192
8.4
7.8
Everolimus (Motzer 2014)
*p<.05
3 (Placebo)
Target
11
10 8
9.5 (Sunitinib)
COMPARZ
10.7 (Sunitinib)
RECORD-3
5
Sperimental Arm
0
4
8
mos
Control Arm
Algorithm for Clear Cell RCC 2014
Setting
First-line
Therapy
Secondline
Therapy
Therapy
Level 1
Level 2
Low+Intermed
Risk
Sunitinib
Beva/IFN
Pazopanib
HD Il-2
Sorafenib
Poor
Risk
Temsirolimus
Sunitinib
Clinical trial
Prior
Cytokine
Sorafenib
Pazopanib
Axitinib
Sunitinib
Clinical trial
Prior TKi
Everolimus
Axitinib
Sequential
TKi
Key drivers in first-line treatment selection:
Efficacy and Experience
Targeted agents:
Standard of care for mRCC
Safety and Clinical experience
Clinical efficacy = primary
should also be considered
driver to guide treatment
when making treatment
decisions
decisions
Schmidinger M, Kidney Cancer Symposium, Vienna 2012
Multiple factors that should be considered when
selecting a targeted therapy for mRCC pts
EB
Guideline
Patient
Proflie
Efficacy
Safety
Safety
Major drugs suspected of potential
drug interaction with targeted agents
Multiple factors that should be considered
when selecting a targeted therapy for mRCC pts
Patient
Profile
Patient
Proflie
EB
Guideline
Efficacy
Safety
Safety
Tolerability Profiles Can Help to Guide
Selection of Treatment:
Patient-related Factors and Comorbidities
Patient with reduced EF
Consider
comedications
(drug interactions)3
Patient with nutrition
disorders
Chronic obstructive
pulmonary disease
Patients with impaired
mobility
Consider the
patient's profession
Thromboembolic disease
Diabetes Mellitus
Targeted Therapies Real World
clinical trial populations may not
represent real-life populations of
patients, because trial inclusion
and exclusion criteria often
eliminate numerous patients
from study
Multiple factors that should be considered when selecting
a targeted therapy for mRCC pts
Patient
Profile
Patient
Proflie
Clinician
Familiarity
Safety
EB
Guideline
Efficacy
Safety
Ist-line Targeted Therapy: rates of treatment
interruptions, reductions and discontinuations
SORA6 SORA8
n. 451 ARCCS
n.2504
SUNI1
n.
375
SUNI7
EAP
n. 1381
BEVA2
plus IFN
n. 337
PAZO3
n. 290
TIVO5
n. 259
TEM4
n. 208
Dose reduction
32
43
40
24
12
23
13
35
Treatment
interruption
38
NA
NA
NA
18
NA
21
50
8
14
28
14
4
7
10
10
% of pts
*Treatment
discontinuation
* No lack of efficacy
1. Motzer, et al. JCO 2009; 2. Escudier, et al. Lancet 2007; 3. Sternberg, et al JCO 2010
4. Hudes, et al. NEJM 2007; 5. Motzer, et al . ASCO 2012; 6. Escudier et al. NEJM 2007
7. Gore et al. Lancet 2009; 8. Stadler et al, Cancer 2010
Healthcare Resources and Increased Costs
Multiple factors that should be considered when
selecting a targeted therapy for mRCC pts
Patient
Profile
Patient
Proflie
Clinician
Familiarity
Safety
EB
PatientGuideline
Reported
Outcomes
Efficacy
Safety
39
Hot Question in mRCC
 Which targeted agent do you use
in 1st-line mRCC: some answers
more questions
 mRCC treatment: to personalize
or not to personalize?
 Patients Preferences: going
forward by going backward?
 Patient-reported Outcomes: what
can we do?