`COMPARZ` trial … Pazopanib vs Sunitinib

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HOW TO SELECT AMONG AVAILABLE OPTIONS FOR THE
TREATMENT OF ADVANCED RCC:
FAVORABLE AND INTERMEDIATE RISK PATIENTS
Dr. Camillo Porta
S.C. di Oncologia Medica,
I.R.C.C.S. Fondazione Policlinico San Matteo,
Pavia
Risk stratification: Motzer or Heng? (I)
1999 MSKCC (or Motzer’s) prognostic stratification system1
• low KPS (<80%),
• high LDH levels (>1.5 x ULN),
• low Hb levels,
• high corrected Ca++ (>10 mg/dL) and
• the absence of previous nephrectomy
2000 MSKCC (or Motzer’s) prognostic stratification system2
• low KPS (<80%),
• high LDH levels (>1.5 x ULN),
• low Hb levels,
• high corrected Ca++ (>10 mg/dL) and
• time from diagnosis to treatment < 1 year
1Motzer
RJ, et al. J Clin Oncol 1999;
et al. J Clin Oncol 2000
2Motzer RJ,
Risk stratification: Motzer or Heng? (II)
2009 Heng’s prognostic stratification system1
• low KPS (<80%),
• low Hb levels,
• time from diagnosis to treatment < 1 year
• high Ca++ levels
• high platelet count
• high neutrophil count
0 risk factors – favorable risk
1-2 risk factors – intermediate risk
3-6 risk factors – poor risk
1Heng
DY, et al. J Clin Oncol 2009
My choice is …
Keep it simple,
folks!!!
2012 ESMO Guidelines
Escudier B, et al. Ann Oncol 2012
Standard 1st-line treatment options
Motzer RJ, et al. N Engl J Med 2007;
Escudier B, et al. Lancet 2007;
Sternberg CN, et al. J Clin Oncol 2010
Why differences in the levels of evidence?
Sunitinib – right comparator, good study
design, primary end-point met
Bevacizumab + Interferon-a – ideal
comparator (+ placebo), reasonable study
design, primary end-point NOT met
Pazopanib – criticizable study design
(placebo-controlled, mix of Tx-naïve and pretreated pts), primary end-point met
Escudier B, et al. Ann Oncol 2012
Any other option?
High-dose i.v. IL_2
Rosenberg SA, et al. Ann Surg 1998
Escudier B, et al. Ann Oncol 2012
And, what about Sorafenib?
Sorafenib registrative study1 was performed in a 2nd-line setting (mainly in
patients refractory to cytokines), but its label, at least in the EU, allows the
treatment also of patients unsuitable for cytokines, leaving open the
opportunity of using it 1st-line
Despite this, a randomized phase II study of Sorafenib or Interferon in 1stline failed to demonstrate any PFS benefit for Sorafenib over Interferon2
1Escudier
2Escudier
B, et al. N Engl J Med 2007;
B, et al. J Clin Oncol 2009
Furthermore, …
12
PFS
10
PFS (months)
7.5
8
8.1
6
6.2
5.7
7.4
9.0
9.1
6.9
4
2
0
2005
2006
2007
2008
2009
2010
2011
Year that data were first presented
2012
2013
Adapted from the slide presented by Professor Tim Eisen at ASCO 2012 to show only first-line data; to show data according to
time of first presentation, rather than final publication (hence variation between publication year and year on graph); and to
indicate how many patients were included in the sorafenib arm/analysis (using bubble size)
Motzer RJ, et al. ASCO 2012; Rini B, et al. Cancer 2012; Stadler WM, et al. Cancer 2010; Bellmunt J, et al. Clin Transl Oncol 2010; Jonasch E, et
al. Cancer 2010; Procopio G, et al. Br J Cancer 2011; Beck J, et al. ECCO 2007; Escudier B, et al. J Clin Oncol 2009.
Now, let’s try to address an embarassing question …
Should we move from Sunitinib to Pazopanib?
• The ‘PISCES’ trial1 showed that:
– Pazopanib is preferred by patients over Sunitinib
– Pazopanib is better tolerated and induces less AEs
• The ‘COMPARZ’ trial2 showed that:
– Pazopanib is not inferior as compared to Sunitinib in terms
of efficacy
– Pazopanib is able to induce higher objective response
rates as compared to Sunitinib
1. Escudier B, et al. J Clin Oncol 2012;
2. Motzer RJ, et al. ESMO 2012 (Presidential Symposium II)
Let’s go for bugs in the ‘PISCES’ trial …
‘PISCES’: patients’ preference trial of Pazopanib vs Sunitinib
R
Period 1
Period 2
Pazopanib
800 mg OD
Sunitinib
50 mg 4/2a
Patient
preference
of further
treatment
1:1
n = 169
Pazopanib
800 mg OD
Sunitinib
50 mg 4/2a
10 weeks
0
2-week
10 weeks
washout
Double-blind phase
12
10
Time (weeks)
End of study
22
Stratification factors:
• ECOG PS (0 vs 1)
• metastatic sites (1 vs ≥ 2)
a4 weeks on treatment → 2 weeks matching placebo → 4 weeks on treatment
Escudier B, et al. J Clin Oncol 2012;30(suppl.):abs. CRA4502
‘PISCES’: patients’ preference trial of Pazopanib vs Sunitinib
R
Period 1
Period 2
Pazopanib
800 mg OD
Sunitinib
50 mg 4/2a
Patient
preference
of further
treatment
1:1
n = 169
Pazopanib
800 mg OD
Sunitinib
50 mg 4/2a
10 weeks
0
2-week
10 weeks
washout
Double-blind phase
12
10
Time (weeks)
End of study
22
Stratification factors:
• ECOG PS (0 vs 1)
• metastatic sites (1 vs ≥ 2)
a4 weeks on treatment → 2 weeks matching placebo → 4 weeks on treatment
Escudier B, et al. J Clin Oncol 2012;30(suppl.):abs. CRA4502
1. The lenght of the observation period
n
Median PFS,
months (95% CI)
HR
P
Tivozanib
181
12.7 (9.1–15.0)
0.756
0.037
Sorafenib
181
9.1 (7.3–10.8)
Motzer RJ, et al. J Clin Oncol 2012
Furthermore, we know that … (1)
New occurrence of AE (%)*
35
Sorafenib
30
Hypertension
25
Fatigue
Diarrhoea
20
HFSR
15
10
5
0
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Cycle
*Percentage of new events occurring in a particular cycle
Hutson TE, et al. Eur J Cancer 2010
Furthermore, we know that … (2)
Sunitinib (EAP)
<6 months of
sunitinib treatment
(n=1,696)
≥6 months of
sunitinib treatment
(n=1,264)
Adverse event
217 (13)
77 (6)
Consent withdrawn
115 (7)
114 (9)
Lack of efficacy
570 (34)
540 (43)
Death
487 (29)
188 (15)
Other*
307 (18)
345 (27)
Reason for discontinuation,
n (%)
*Includes protocol violation, lost to follow-up, laboratory abnormality(ies), sponsor decision,
not meeting entrance criteria, and missing patients
Porta C, et al. ASCO 2008
Furthermore, we know that … (2)
Sunitinib (EAP)
<6 months of
sunitinib treatment
(n=1,696)
≥6 months of
sunitinib treatment
(n=1,264)
Adverse event
217 (13)
77 (6)
Consent withdrawn
115 (7)
114 (9)
Lack of efficacy
570 (34)
540 (43)
Death
487 (29)
188 (15)
Other*
307 (18)
345 (27)
Reason for discontinuation,
n (%)
*Includes protocol violation, lost to follow-up, laboratory abnormality(ies), sponsor decision,
not meeting entrance criteria, and missing patients
Porta C, et al. ASCO 2008
2. The timing of QoL assessment (I)
• Timing of assessment of patients’ preference clearly
unfavoured Sunitinib [in both the ‘PISCES’1 and COMPARZ’2
trial]
• Indeed, end of week 22 = Day 28 (i.e., the worst possible in
terms of toxicity) in a typical Sunitinib cycle3
1Schmidinger M,
2Eisen
ESMO 2012 GU Posters Discussion;
T, ESMO 2012 Presidential Symposium II Discussion;
3Cella D, et al. Ann Oncol 2012
2. The timing of QoL assessment (II)
• Two recent analyses1,2 examined the impact of Sunitinib dosing
schedule on measurement of patient-reported fatigue and
HRQoL
Fatigue
– Compared with baseline, patients reported worse fatigue during the first
cycle of Sunitinib treatment; however, less fatigue was reported in all
consecutive treatment cycles1
– Sunitinib Schedule 4/2 was associated with an “on–off” effect, with patients
reporting more fatigue on Day 29 of each cycle following 4 weeks on
treatment and less fatigue on Day 1 of each cycle following the 2-week offtreatment period1
HRQoL
– Variability in patient experience of HRQoL on Day 1 compared with Day 28
for Sunitinib on Schedule 4/2 is statistically significant, and should be
accounted for when collecting HRQoL data2
1Cella
D, et al. J Clin Oncol 2012; 2Bushmakin A, et al. Ann Oncol 2012
3. Patients’ perception and their level of information
• Were the patients informed that side-effects [at least,
some of them, e.g., hypertension and HFSR] are regarded
as predicitve of efficacy? How would preference then look
like?1
1Schmidinger M,
ESMO 2012 GU Posters Discussion
Let’s go for bugs in the ‘COMPARZ’ trial …
Pazopanib vs Sunitinib: the ‘COMPARZ’ trial
•
Locally advanced or
metastatic RCC, with clear
cell component histology
•
No prior systemic therapy
•
•
a4
R
A
N
D
O
M
I
n = 876 S
A
T
I
O
N
Primary endpoint:
– PFS (non-inferiority)
Secondary endpoints:
– OS
– ORR (objective response rate)
– duration of response
– safety
– QoL (quality of life)
Pazopanib
800 mg OD
Sunitinib
50 mg 4/2a
‘COMPARZ’ trial (NCT00720941)
Start date: August 2008
Recruitment: complete
weeks on treatment → 2 weeks off treatment = 1 treatment cycle
‘COMPARZ’ trial: statistical design
PFS non-inferiority demonstrated if upper bound of
95% CI for HR<1.25
Cox proportional hazard analysis adjusted for stratification
factors
By independent review
631 PFS events needed for 80% power
Planned enrollment of 1100 patients*
* original sample of 876 increased during study conduct to 1100 to obtain
the 631 prespecified number of PFS events
Motzer RJ, et al. ESMO 2012 (Presidential Symposium II)
Methodology of non-inferiority studies (1)
In non-inferiority studies, the non-inferiority bounds of 95% CI for
HR is usually comprised between 1.15 and 1.20; for example:
S9346 Study1 (ASCO 2012) – the upper bound of 95% CI for HR was
1.20
For an HR for OS = 1.09 (0.95-1.24), the study was declared as
negative
PHARE Study2 (ESMO 2012) – the upper bound of 95% CI for HR was
1.15
For an HR for DFS = 1.28 (1.04-1.56), the study was declared as
negative
1Intermittant
Androgen Deprivation vs Continuous Androgen Deprivation (prostate);
2Six months vs twelve months adjuvant Trastuzumab (breast)
Methodology of non-inferiority studies (2)
BOUND
Non-inferiority NOT
demonstrated
Non-inferiority NOT
demonstrated
Non-inferiority NOT
demonstrated
Non-inferiority
demonstrated
1
Favor experimental arm
(Pazopanib)
1.25
Favors control arm
(Sunitinib)
Non-inferiority CIs in the ‘COMPARZ’ trial
BOUND
1.22
0.898
1.15
1.20
1
Favor experimental arm
(Pazopanib)
Non-inferiority
demonstrated
1.25
Favors control arm
(Sunitinib)
‘COMPARZ’ trial: statistical design
PFS non-inferiority demonstrated if upper bound of
95% CI for HR<1.25
Cox proportional hazard analysis adjusted for stratification
factors
By independent review
631 PFS events needed for 80% power
Planned enrollment of 1100 patients*
* original sample of 876 increased during study conduct to 1100 to obtain
the 631 prespecified number of PFS events
Motzer RJ, et al. ESMO 2012 (Presidential Symposium II)
‘COMPARZ’ trial: the issue of a mixed population
Asian patients and Sunitinib
In Asian patients, Sunitinib is less tolerated, leading to higher toxicity rates
and the widespread use of reduced doses1,2; since a clear-cut relationship
exists between exposure and efficacy3, an inferior activity in these
patients could be expected. And indeed, Tx duration in Asia is definitely
lower than in the rest of the world1,2,4
1Yoo
3Houk
C, et al. Jpn J Clin Oncol 2010; 2Kim HS, et al. Eur J Cancer 2012;
BE, et al. Cancer Chemother Pharmacol 2010; 4Choueiri TK, et al. Manuscript in preparation.
So what?
‘PISCES’ and ‘COMPARZ’ clearly support the use of Pazopanib as a reasonable Tx option in 1st line
Pazopanib safety profile is superior as compared to Sunitinib; however, Sunitinib – despite the non-inferiority results
of the ‘COMPARZ’ trial – remains slightly more efficacious
As Medical Oncologists and Urologist, we should be happy
for the availability of different Tx options (and do not forget
other drugs!) to really tailor Tx on the basis of each given
patient’s needs
Considering all the above
Is there a reasonable Tx standard for mRCC today?
Try to make simple what is complex
“… Even though Physics tells us that chaos can be, and often is, a property of very
simple systems, meaning that simple questions usually have complicated answers ,
our only way out could be found turning upside-down this concept: in a complex
system (e.g., kidney cancer) we should look for an easy – and credible – answer to
our doubts. And such an answer probably is Chris Ryan’s ‘simplified algorythm’
statement: “choose any agent You want. Use it well” … A shortcut, for sure, but a
smart one, and also a glowing glance of simplicity to move out from the fogs of
chaos”.
Porta C. Eur Urol 2011
Thank You for Your kind attention!!!
T
c.porta@smatteo.pv.it
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