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UK/PAZ/0030/13
February 2013
®
PISCES
PazopanIb versus Sunitinib patient
preferenCE Study in treatment naïve locally
advanced or metastatic renal cell carcinoma
(A randomised, double-blind, cross-over patient preference study of pazopanib versus
sunitinib in treatment-naïve locally advanced or metastatic renal cell carcinoma)
GSK has been involved in the preparation of this presentation
UK/PAZ/0030/13
February 2013
Prescribing information can be found at the end of the main presentation
www.votrient.co.uk
Pazopanib indication
• Pazopanib is indicated in adults for the first-line treatment of advanced
renal cell carcinoma (RCC) and for patients who have received prior cytokine
therapy for advanced disease1
• Pazopanib’s licence is conditional pending further clinical data from GSK,
including the outcome of the head-to-head study (COMPARZ) of Pazopanib
versus sunitinib.
1. Votrient Summary of Product Characteristics. January 2013
Pazopanib NICE Technology Appraisal Guidance (TA 215)1
• Pazopanib is recommended as a first-line treatment option for people with
advanced renal cell carcinoma
• who have not received prior cytokine therapy and have an Eastern
Cooperative Oncology Group (ECOG) performance status of 0 or 1
and
• under the terms of the agreed Patient Access Scheme which provides
pazopanib with a 12.5% discount on the list price, and a possible future
rebate linked to the outcome of the head-to-head COMPARZ trial
1. NICE. Pazopanib for the first-line treatment of advanced renal cell carcinoma. Final appraisal guidance no. 215. February 2011.
Pazopanib Scottish Medicines Consortium Advice No. 676/111
• Pazopanib is accepted for restricted use within NHS Scotland for the firstline treatment of advanced RCC.
• This SMC advice takes account of the benefits of a Patient Access Scheme
(PAS) that improves the cost-effectiveness of Pazopanib and is contingent
upon the continuing availability of the PAS in NHS Scotland.
1. Scottish Medicines Consortium. Pazopanib 200mg, 400mg film-coated tablets (Votrient). Advice no. 676/11. March 2011
Patient preference as a clinical endpoint
• Previous oncology trials have shown a strong association between
toxicity/tolerability and quality of life (QoL), suggesting that patient
preference is a useful endpoint for cross-over studies1,2
• PISCES was designed to understand how the differences in tolerability
between pazopanib and sunitinib translated into a patient preference
• The cross-over design allows patients to be exposed to both drugs in a
comparable health state and then choose which they prefer
• This is the first study of its kind in advanced renal cell carcinoma (RCC)
1. Thomas R, et al. Clin Oncol 2004;16:485-491.
2. Twelves C, et al. Ann Oncol 2006;17:239-245.
Study design1
Pazopanib
800 mg OD,
10 weeks
Randomisation
1:1
Double blind
N-169*
Sunitinib
50 mg 4/2§
10 weeks
Tablets were over encapsulated
Pazopanib
800 mg OD,
10 weeks
Sunitinib
50 mg 4/2§
10 weeks
*1 patient
randomised in error
n=168
Period 1
2-week washout
(placebo)
§4
weeks on, 2 weeks
placebo, 4 weeks on
Period 2
Off study
Double-blind
0
Stratification factors
Patient and
physician
preference
(prior to
unblinding &
disclosure of
final tumour
assessment)
10
12
Time (weeks)
22
• ECOG performance status (0 vs. 1) • Number of metastatic sites (0 and 1 vs. 2+)
1. Escudier BJ, Porta C, Bono P, et al. Abstract and oral presentation at the American Society of Clinical Oncology Annual Congress 2012. J Clin Oncol 2012; 30
(suppl.): Abstract CRA4502.
Study design and testing1
Randomisation
1:1
Double blind
N-169*
*1 patient
randomised in error
n=168
Pazopanib
800 mg OD,
10 weeks
Sunitinib
50 mg 4/2§
10 weeks
Sunitinib
50 mg 4/2§
10 weeks
Pazopanib
800 mg OD,
10 weeks
2-week washout
(placebo)
Period 1
§4
weeks on, 2 weeks
placebo, 4 weeks on
Week
Patient preference
EQ-5D
0
Period 2
2
4
6
8
10
12
Off study
CT
CT^
CT
Patient and
physician
preference
(prior to
unblinding &
disclosure of
final tumour
assessment)
14
16
18
20
22
^Could occur earlier if
the patient crossed over
early due to AE
FACIT-Fatigue
SQLQ
1. Escudier BJ, Porta C, Bono P, et al. Abstract and oral presentation at the American Society of Clinical Oncology Annual Congress 2012. J Clin Oncol 2012; 30
(suppl.): Abstract CRA4502.
Primary endpoint1
Primary endpoint
Assessed by
Patient preference (pazopanib vs. sunitinib)
Patient preference questionnaire
• Collected at the end of treatment period 2
• Prior to unblinding
• Prior to disclosure of final tumour assessment
• By patients who had received ≥ 1 dose in both treatment periods
• Patients selected
• Which drug they preferred or whether they had no preference
• The factors which influenced this preference
• The most important reason for their preference
• Patient preference questionnaire currently unvalidated. Developed in conjunction with
Professor David Cella, USA
1. Escudier BJ, Porta C, Bono P, et al. Abstract and oral presentation at the American Society of Clinical Oncology Annual Congress 2012. J Clin Oncol 2012; 30
(suppl.): Abstract CRA4502.
Other endpoints and data collected1
Other endpoints included:
Assessed by:
Reason for patient preference
Patient preference questionnaire
Health-related quality of life (QoL):
- General
EQ-5D
- Fatigue
FACIT-Fatigue scale
- Mouth, throat, foot and hand soreness
Supplementary QoL questionnaire (SQLQ)
Dose modification & time to dose modifications
Physician recorded
Safety
Incidence and severity of adverse events (AEs)
Serious AEs
Withdrawal of treatment due to AEs
Other data collected:
Assessed by:
Physician preference
Physician preference questionnaire
Investigator assessed best response
RECIST 1:1
Pharmacokinetics and biomarkers
1. Escudier BJ, Porta C, Bono P, et al. Abstract and oral presentation at the American Society of Clinical Oncology Annual Congress 2012. J Clin Oncol 2012; 30
(suppl.): Abstract CRA4502.
Statistical design1
Assumptions
• Difference of ≥ 20% in preference between agents is clinically relevant
• 50% of subjects preferring one drug, 30% preferring the other, and 20%
having no preference2
Target sample size of 160 patients needed
• 80% power, α = 0.10
• Sample size accounted for patients lost to follow-up and those with
progressive disease at end of period 1
• Analysis performed using Prescott’s test
1. Escudier BJ, Porta C, Bono P, et al. Abstract and oral presentation at the American Society of Clinical Oncology Annual Congress 2012. J Clin Oncol 2012;
30 (suppl.): Abstract CRA4502.
2. Clinical results summary for VEG113046. GSK clinical trials register: http://www.gskclinicalstudyregister.com/result_detail.jsp?protocolId=113046&studyId=5492502E-9541-4FAD-8E7E-8C4FE1AD6B49&compound=pazopanib
Key inclusion and exclusion criteria1
Inclusion criteria
• Locally advanced or metastatic RCC of any histology
• Measurable and non-measurable disease
• Treatment-naïve for metastatic RCC
• ECOG performance status of 0 or 1
• Adequate cardiac and renal function
Exclusion criteria
• Poor MSKCC risk group
• History of other malignancy
• CNS metastases
1. Escudier BJ, Porta C, Bono P, et al. Abstract and oral presentation at the American Society of Clinical Oncology Annual Congress 2012. J Clin Oncol 2012; 30
(suppl.): Abstract CRA4502.
Key baseline characteristics1
Age, median years (range)
Male, %
ECOG PS 0 vs. 1, %
Nephrectomy, %
Metastatic sites 1 vs. ≥ 2, %
Measurable disease, %
Median time since diagnosis,
months (range)
Clear cell histology, %
Sun / Paz
(n=82)
Paz / Sun
(n=86)
Total
62 (37 – 82)
64 (29 – 83)
63 (29 – 83)
63
71
67
74 / 26
70 / 30
72 / 28
85
92
89
28 / 72
23 / 77
26 / 74
91
93
92
6.7 (1 – 222)
9.1 (0 – 241)
7.7 (0 – 241)
93
87
90
1. Escudier BJ, Porta C, Bono P, et al. Abstract and oral presentation at the American Society of Clinical Oncology Annual Congress 2012. J Clin Oncol 2012; 30
(suppl.): Abstract CRA4502.
Results: Period 1 study withdrawals1
•
•
•
•
9 Adverse event
6 Disease progression
n=18
2 Withdrew consent
1 Investigator discretion
Period 1
Period 2
Pazopanib
N = 86
Sunitinib
N = 68
Sunitinib
N = 82
Pazopanib
N = 68
•
•
•
•
7 Adverse event
3 Disease progression n=14
2 Withdrew consent
2 Investigator discretion
1. Escudier BJ, Porta C, Bono P, et al. Abstract and oral presentation at the American Society of Clinical Oncology Annual Congress 2012. J Clin Oncol 2012; 30
(suppl.): Abstract CRA4502.
Results: Period 2 study withdrawals and primary analysis
population1
• 1 Adverse event
• 5 Disease progression
Period 1
n=6
PD after
period 1
n=8
Period 2
Primary Analysis
Population
Pazopanib
N = 86
Sunitinib
N = 68
54
Sunitinib
N = 82
Pazopanib
N = 68
60
PD = progressive disease
• 1 Adverse event
• 2 Disease progression
• 1 Other
n=4
PD after
period 1
n=4
• Completed questionnaire
• ≥ 1 dose from each period
• No PD after Period 1
1. Escudier BJ, Porta C, Bono P, et al. Abstract and oral presentation at the American Society of Clinical Oncology Annual Congress 2012. J Clin Oncol 2012; 30
(suppl.): Abstract CRA4502.
Patient preference significantly favoured pazopanib1
100
90
90% CI (for difference): 37.0%-61.5%; p<0.001
80
Patients (%)
70
60
50
70%
(n=80)
40
30
20
10
22%
(n=25)
0
Preferred pazopanib
Preferred sunitinib
8%
(n=9)
No preference
*Question asked: “Now that you have completed both treatments, which of the two drugs would you prefer to
continue to take as the treatment for your cancer, assuming that both drugs will work equally well in treating your
cancer?” (patients selected either first treatment, second treatment or no preference)
1. Escudier BJ, Porta C, Bono P, et al. Abstract and oral presentation at the American Society of Clinical Oncology Annual Congress 2012. J Clin Oncol 2012; 30
(suppl.): Abstract CRA4502.
Patient preference according to treatment order1
Pazopanib / sunitinib
100
100
90
90
80
80
70
70
60
50
Preference (%)
Preference (%)
Sunitinib / pazopanib
62%
(n=37)
40
30
7%
(n=4)
10
60
50
40
30
32%
(n=19)
20
80%
(n=43)
0
20
10
11%
(n=6)
0
Preferred
pazopanib
Preferred
sunitinib
No preference
Preferred
pazopanib
Preferred
sunitinib
9%
(n=5)
No preference
1. Clinical results summary for VEG113046. GSK clinical trials register: http://www.gskclinicalstudyregister.com/result_detail.jsp?protocolId=113046&studyId=5492502E-9541-4FAD-8E7E-8C4FE1AD6B49&compound=pazopanib
Pre-planned sensitivity analyses of patient preference1
Pazopanib
Sunitinib
Alpha (significance) level: 0.1
Increasing rate of preference (%)
1. Escudier BJ, Porta C, Bono P, et al. Abstract and oral presentation at the American Society of Clinical Oncology Annual Congress 2012. J Clin Oncol 2012; 30
(suppl.): Abstract CRA4502.
Reasons for preference - patients who preferred pazopanib (n=80)1,2*
Quality of life in general was better
65
Fatigue had less impact on my life
47
Change in food taste had less impact on my life
44
Nausea/vomiting had less impact on my life
32
Soreness in mouth/throat had less impact on my life
32
Soreness in hands/feet had less impact on my life
30
Loss of appetite had less impact on my life
28
Pain in stomach area had less impact on my life
23
Diarrhoea had less impact on my life
21
Other
14
Change in hair colour had less impact on my life
*Question asked:
“Please indicate which factors had an
influence on your choice of treatment”
(patients could select >1 reason)
9
0
10
20
30
40
50
Number of patients
60
70
80
1. Escudier BJ, Porta C, Bono P, et al. Abstract and oral presentation at the American Society of Clinical Oncology Annual Congress 2012. J Clin Oncol 2012;
30 (suppl.): Abstract CRA4502.
2. Clinical results summary for VEG113046. GSK clinical trials register: http://www.gskclinicalstudyregister.com/result_detail.jsp?protocolId=113046&studyId=5492502E-9541-4FAD-8E7E-8C4FE1AD6B49&compound=pazopanib
Reasons for preference - patients who preferred sunitinib (n=25)1,2*
Diarrhoea had less impact on my life
16
Quality of life in general was better
15
Fatigue had less impact on my life
12
Nausea/vomiting had less impact on my life
11
Loss of appetite had less impact on my life
10
Pain in stomach area had less impact on my life
9
Soreness in mouth/throat had less impact on my life
6
Soreness in hands/feet had less impact on my life
6
Change in food taste had less impact on my life
5
Change in hair colour had less impact on my life
5
Other
5
0
5
*Question asked:
“Please indicate which factors had an
influence on your choice of treatment”
(patients could select >1 reason)
10
15
Number of patients
20
25
1. Escudier BJ, Porta C, Bono P, et al. Abstract and oral presentation at the American Society of Clinical Oncology Annual Congress 2012. J Clin Oncol 2012;
30 (suppl.): Abstract CRA4502.
2. Clinical results summary for VEG113046. GSK clinical trials register: http://www.gskclinicalstudyregister.com/result_detail.jsp?protocolId=113046&studyId=5492502E-9541-4FAD-8E7E-8C4FE1AD6B49&compound=pazopanib
Most important reason for preference – pazopanib1*
Of the 80 patients who preferred pazopanib, the most important reasons were:
Fatigue had less impact on my life
21
No single reason
21
Nausea/vomiting had less impact on my life
7
Soreness in hands/feet had less impact on my life
6
Soreness in mouth/throat had less impact on my life
6
Not reported
6
Diarrhoea had less impact on my life
4
Change in food taste had less impact on my life
4
Pain in stomach area had less impact on my life
3
Loss of appetite had less impact on my life
2
Change in hair colour had less impact on my life
0
0
10
20
30
40
50
60
Number of patients
70
80
* Question asked:
“If you had to choose one reason, which of the above symptoms is the most important reason for your preference?”
(patients could only select one reason; If none of the symptoms were the most important reason for preference, patients could select N/A)
1. Clinical results summary for VEG113046. GSK clinical trials register: http://www.gskclinicalstudyregister.com/result_detail.jsp?protocolId=113046&studyId=5492502E-9541-4FAD-8E7E-8C4FE1AD6B49&compound=pazopanib
Most important reason for preference – sunitinib1*
Of the 25 patients who preferred sunitinib, the most important reasons were:
No single reason
7
Diarrhoea had less impact on my life
6
Fatigue had less impact on my life
4
Nausea/vomiting had less impact on my life
3
Soreness in hands/feet had less impact on my life
2
Pain in stomach area had less impact on my life
2
Change in hair colour had less impact on my life
1
Change in food taste had less impact on my life
0
Loss of appetite had less impact on my life
0
Soreness in mouth/throat had less impact on my life
0
Not reported
0
0
5
10
15
Number of patients
20
25
* Question asked:
“If you had to choose one reason, which of the above symptoms is the most important reason for your preference?”
(patients could only select one reason; If none of the symptoms were the most important reason for preference, patients could select N/A)
1. Clinical results summary for VEG113046. GSK clinical trials register: http://www.gskclinicalstudyregister.com/result_detail.jsp?protocolId=113046&studyId=5492502E-9541-4FAD-8E7E-8C4FE1AD6B49&compound=pazopanib
Physician preference1*
70
Physician preference (%)
60
50
61%
(n=69)
* Question asked: “Which of the two drugs would
you prefer to be taken by the patient as the cancer
treatment, assuming that both drugs will work
equally well in treating the cancer?”
40
30
20
22%
(n=25)
10
17%
(n=19)
0
Preferred pazopanib
Preferred sunitinib
Physician preference
based on 113 patients
No preference
Regardless of treatment order, physicians preferred Votrient2:
• Sunitinib/pazopanib: 48% preferred pazopanib, 32% preferred sunitinib; 20% no preference
• Pazopanib/sunitinib: 75% preferred pazopanib, 11% preferred sunitinib; 13% no preference
1. Escudier BJ, Porta C, Bono P, et al. Abstract and oral presentation at the American Society of Clinical Oncology Annual Congress 2012. J Clin Oncol 2012;
30 (suppl.): Abstract CRA4502.
2. Clinical results summary for VEG113046. GSK clinical trials register: http://www.gskclinicalstudyregister.com/result_detail.jsp?protocolId=113046&studyId=5492502E-9541-4FAD-8E7E-8C4FE1AD6B49&compound=pazopanib
Concordance between patient and physician preference1
100
90
Preference (%)
80
70
60
50
70%
61%
(n=80)
61%
(n=690)
(n=69)
40
22%
(n=25)
30
20
10
22%
(n=25)
22%
(n=25)
Physician
Patient
0
Physician
Patient
Preferred pazopanib
Preferred sunitinib
17%
(n=19)
Physician
8%
(n=9)
Patient
No preference
1. Escudier BJ, Porta C, Bono P, et al. Abstract and oral presentation at the American Society of Clinical Oncology Annual Congress 2012. J Clin Oncol 2012; 30
(suppl.): Abstract CRA4502.
Health-related quality of life1
Instrument
Timing
Description
FACITFatigue
Every 2
weeks
13 items on fatigue
3 items on
(1) mouth & throat soreness
(2) hand soreness
(3) foot soreness
SQLQ*
Scale
0-52
0-3
Every 2
weeks
2 items on limitations due to
(1) mouth & throat soreness
(2) foot soreness
0-15
Points difference in mean
scores in favour of
pazopanib1,2
P-value
2.5**
(mean: 38.1 paz / 35.6 sun)
0.002
0.38
(mean: 0.40 paz / 0.78 sun)
<0.001
0.08
(mean: 0.21 paz / 0.29 sun)
0.026
0.16
(mean: 0.36 paz / 0.52 sun)
0.005
0.6
(mean: 14.32 paz / 13.72 sun)
<0.001
0.58
(mean: 13.82 paz / 13.24 sun)
0.003
*Validation analyses ongoing
** The minimally important difference (MID) threshold is >3 points. Therefore this is not clinically meaningful
1. Escudier BJ, Porta C, Bono P, et al. Abstract and oral presentation at the American Society of Clinical Oncology Annual Congress 2012. J Clin Oncol 2012;
30 (suppl.): Abstract CRA4502.
2. Clinical results summary for VEG113046. GSK clinical trials register: http://www.gskclinicalstudyregister.com/result_detail.jsp?protocolId=113046&studyId=5492502E-9541-4FAD-8E7E-8C4FE1AD6B49&compound=pazopanib
EQ5D data1
• The EQ-5D data presented at ESMO 2012 were inconclusive
• EQ-5D assessment showed that utility scores deteriorated in pazopanib-treated patients
in treatment period 1, but the deterioration in period 2 was numerically greater in
sunitinib-treated patients compared with those on pazopanib
1. Cella D, Kaiser K, Beaumont J, et al. Quality of life (QOL) among renal cell carcinoma (RCC) patients in a randomised double blind cross-over patient
preference study of pazopanib (P) versus sunitinib (S). Abstract and poster presentation at European Society of Medical Oncology Congress 2013. Abstract
no. 792PD
Dose modifications1
Pazopanib
Sunitinib
Patients with dose reductions*
13%
20%
Prematurely discontinued from Period 1 due to AE’s**
Prematurely discontinued from Period 2 due to AE’s***
14%
15%
18%
31%
*Across period 1 + period 2: Pazopanib n=153 (patients who received at least one dose of pazopanib)
Sunitinib n=148 (patients who received at least one dose of sunitinib)
** n=86 (pazopanib): n=82 (sunitinib) i.e. n=168 patients (All randomised population: number of patients who were
randomised to treatment and entered period 1)
*** n=68 (pazopanib): n=68 (sunitinib) i.e. n=136 (Intent-to-treat population: Patients who received at least one dose of
drug from each treatment period i.e. those who entered treatment period 2)
1. Escudier BJ, Porta C, Bono P, et al. Abstract and oral presentation at the American Society of Clinical Oncology Annual Congress 2012. J Clin Oncol 2012; 30
(suppl.): Abstract CRA4502.
Most common AEs irrespective of causality (≥15%)1
Pazopanib (n = 153)
Adverse Event
Any AE
Diarrhoea
Nausea
Decreased appetite
Vomiting
Dyspepsia
Dysgeusia
Mucositis
Stomatitis
Hand-foot syndrome
Hair colour changes
Hypertension
Asthenia
Fatigue
All Grades
97%
42%
33%
20%
14%
10%
16%
16%
5%
16%
17%
23%
16%
29%
Grade 3/4
38%
< 1%
< 1%
0
< 1%
0
0
0
< 1%
1%
0
8%
< 1%
4%
Sunitinib (n = 148)
All Grades
> 99%
32%
30%
19%
16%
16%
27%
22%
16%
26%
14%
26%
24%
30%
Grade 3/4
47%
< 1%
0
<1%
< 1%
0
0
1%
2%
4%
0
9%
3%
5%
Subjects who have received at least one dose of either drug.
Graded by Investigators according to National Cancer Institute - Common Toxicity Criteria of Adverse Events, Version 4.0 (NCI-CTCAE v4.0)
1. Escudier BJ, Porta C, Bono P, et al. Abstract and oral presentation at the American Society of Clinical Oncology Annual Congress 2012. J Clin Oncol 2012; 30
(suppl.): Abstract CRA4502.
Clinical laboratory abnormalities1
Pazopanib (n = 153)
Sunitinib (n = 148)
Parameter
ALP elevations
Any Grade
Grade 3/4
Any Grade
Grade 3/4
18%
1%
20%
0%
ALT elevations
39%
7%
28%
3%
AST elevations
38%
4%
44%
< 1%
Total bilirubin elevations
24%
< 1%
12%
0%
Albumin elevations
10%
2%
20%
1%
Creatinine elevations
34%
0
15%
0%
Anaemia
11%
1%
25%
< 1%
Lymphopenia
17%
0
35%
8%
Neutropenia
13%
1%
45%
7%
Thrombocytopenia
15%
0
47%
5%
Leukopenia
15%
0
49%
1%
Subjects who have received at least one dose of either drug.
Graded by Investigators according to National Cancer Institute - Common Toxicity Criteria of Adverse Events, Version 4.0 (NCI-CTCAE v4.0)
1. Escudier BJ, Porta C, Bono P, et al. Abstract and oral presentation at the American Society of Clinical Oncology Annual Congress 2012. J Clin Oncol 2012; 30
(suppl.): Abstract CRA4502.
PISCES summary
• Significantly more patients preferred pazopanib over sunitinib (70% vs. 22%; p<0.001),
with the remaining 8% of patients expressing no preference for either treatment
• The most important reason for preferring pazopanib was less fatigue or no single reason
• The most important reason for preferring sunitinib was no single reason
• High level of concordance between patient and physician preference, with 61% of
physicians preferring pazopanib over sunitinib (22% preference)
• FACIT-fatigue tool showed that patients experienced statistically significantly less fatigue
on pazopanib than sunitinib (mean scores differed by 2.5 points, p=0.002). However, this
did not achieve the minimally important difference (MID) threshold of >3 points.
• SQLQ showed patients experienced less hand, foot and mouth/throat soreness with
pazopanib than sunitinib. Mean scores favoured pazopanib
PISCES summary
• Notable differences in some AEs between pazopanib and sunitinib include:
• Diarrhoea (more frequent with pazopanib; 42% vs. 32%)
• Stomatitis (more frequent with sunitinib; 16% vs. 5%)
• Mucositis (more frequent with sunitinib; 22% vs. 16%)
• Hand-foot syndrome (more frequent with sunitinib; 26% vs. 16%)
• Asthenia (more frequent with sunitinib; 24% vs. 16%)
• Interestingly, the incidence of fatigue as recorded as an AE was similar between the two
drugs (29% vs. 30%)
• Greater incidence of haematological toxicity with sunitinib
• Pazopanib was associated with fewer dose reductions and discontinuations due to AEs
Posology and special warnings (1)1
•
Please refer to full SmPC before prescribing
•
Votrient tablets should be taken
– 800mg daily
– Whole (not broken or crushed)
– Without food - at least 1 hour before or 2 hours after a meal
•
Dose modifications
– Should be in 200mg decrements/increments
•
Drug interactions
– The concomitant use of strong CYP3A4 inhibitors and inducers, UGT1A1 substrates and medicines that
increase gastric pH, should be avoided unless medically necessary.
– Concomitant use of simvastatin (and potentially other statins) can increase risk of ALT elevations and
should be undertaken with caution and close monitoring
•
Renal impairment
– No dose adjustment is required in patients with creatinine clearance >30 ml/min
– Caution is advised in patients with creatinine clearance <30 ml/min
1. VOTRIENT Summary of Product Characteristics. January 2013.
Posology and special warnings (2)1
•
Hepatic impairment & Hepatic effects
– Cases of hepatic failure have been reported during Votrient use
– Votrient is not recommended in patients with severe hepatic impairment
– Use with caution and close monitoring in patients with mild or moderate hepatic impairment
– Patients with mild hepatic impairment should be treated with 800mg once daily
– A reduced dose of 200 mg once daily is recommended in moderate hepatic impairment
– Serum liver tests should be monitored at baseline, at least once every 4 weeks for the first 4 months of
treatment, and as clinically indicated with periodic monitoring thereafter.
– More frequent monitoring, dose interruption, modification or discontinuation may be warranted if
liver test abnormalities are detected.
•
Hypertension
– Blood pressure should be well controlled prior to initiating Votrient
– Patients should be monitored for hypertension within 1 week of starting treatment and frequently
thereafter to ensure blood pressure control
– Hypertension should be managed using a combination of anti-hypertensive therapy and dose
modification of Votrient (interruption and re-initiation at a reduced dose based on clinical judgement)
– Events of hypertensive crisis have occurred during clinical studies with Votrient (<1% of patients)
– Votrient should be discontinued if there is evidence of persistently elevated blood pressure (140/90
mmHg) or if arterial hypertension is severe and persists despite antihypertensive therapy and Votrient
dose reduction
1. VOTRIENT Summary of Product Characteristics. January 2013.
Posology and special warnings (3)1
•
PRES / RPLS
– Posterior reversible encephalopathy syndrome (PRES)/Reversible posterior leukoencephalopathy
syndrome (RPLS) has been reported in association with pazopanib.
– PRES/RPLS can present with headache, hypertension, seizure, lethargy, confusion, blindness and other
visual and neurological disturbances, and can be fatal
– Patients developing PRES/RPLS should permanently discontinue pazopanib
•
Cardiac dysfunction/heart failure
– The safety and pharmacokinetics of Votrient in patients with moderate to severe heart failure or those
with a below normal left ventricular ejection fraction (LVEF) has not been studied
– In clinical trials with pazopanib, events of cardiac dysfunction such as congestive heart failure and
decreased left ventricular ejection fraction have occurred.
– The risks and benefits of Votrient should be considered before beginning therapy in patients who have
pre-existing cardiac dysfunction
– Baseline & periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction
– Patients should be carefully monitored for clinical signs or symptoms of congestive heart failure
– Interruption of Votrient and/or dose reduction should be combined with treatment of hypertension in
patients with significant reductions in LVEF, as clinically indicated
•
Thrombotic microangiopathy (TMA)
– Thrombotic microangiopathy (TMA) has been reported in clinical trials of pazopanib as monotherapy, in
combination with bevacizumab, and in combination with topotecan
– Patients developing TMA should permanently discontinue pazopanib; reversal of effects of TMA has been
observed after pazopanib treatment was discontinued
1. VOTRIENT Summary of Product Characteristics. January 2013.
Posology and special warnings (4)1
•
Other warnings
– Events of pneumothorax have occurred in clinical studies with Votrient in advanced soft tissue sarcoma.
Patients on Votrient should be observed closely for signs and symptoms of pneumothorax
– Venous thromboembolic events (VTEs) including venous thrombosis and pulmonary embolus have occurred
in clinical studies with Votrient (incidence of 2% in RCC studies and 5% in STS studies)
– Use with caution in patients who are at increased risk for arterial thrombotic events, those with significant
risk of haemorrhage, GI perforation or fistula. Votrient is not recommended in patients with a history of
haemoptysis, cerebral or clinically significant GI haemorrhage in the past 6 months.
– Use with caution in patients with a history of QT interval prolongation, those taking antiarrhythmics or with
pre-existing cardiac disease. Baseline and periodic monitoring of electrocardiograms and maintenance of
electrolytes within normal range is recommended.
– Votrient may impair wound healing, and should be stopped at least 7 days prior to scheduled surgery
– Hypothyroidism has occurred in clinical studies with Votrient. Baseline and periodic monitoring is
recommended.
– Proteinuria has occurred in clinical studies with Votrient. Baseline and periodic urinalysis is recommended,
with discontinuation of Votrient if the patient develops grade 4 proteinuria
– Cases of serious infection (with/without neutropenia) have been reported
– Combination with other systemic anti-cancer therapies: Safe and effective dose in combination with
pemetrexed or lapatinib has not been established
1. VOTRIENT Summary of Product Characteristics. January 2013.
Posology and special warnings (5)1
•
Instances where Votrient should be permanently discontinued include:
–
–
–
–
–
•
In patients with re-occurrence of elevated transaminases (>3 x ULN) following treatment interruption, or
with aminotransferases elevations >3 x ULN and bilirubin elevations >2 x ULN, where direct bilirubin fraction
>35%
In patients with persistently elevated blood pressure or if hypertension is severe and persists despite antihypertensive therapy and Votrient dose reduction
In patients with wound dehiscence
In patients with grade 4 proteinuria
In patients developing PRES/RPLS or TMA
Serious adverse events have been associated with Votrient, with the most important events each
being reported in <1% of treated patients
1. VOTRIENT Summary of Product Characteristics. January 2013.
Prescribing Information (Please refer to full SmPC before prescribing)
Votrient®▼(pazopanib) 200mg and 400mg film-coated tablets. Each tablet contains
pazopanib hydrochloride, equivalent to 200mg and 400mg of pazopanib, respectively.
Indication In adults for first-line treatment of advanced renal cell carcinoma (RCC) and those
with prior cytokine therapy. Dosage and administration Only to be initiated by physician
experienced in use of anti-cancer agents. 800mg once daily. Take without food (≥1 hour
before or ≥2 hours after a meal). Take tablets whole; do not break or crush. Dose
modification: In 200mg steps based on individual tolerability to manage ADRs. Not to exceed
800mg. Renal impairment: No dose adjustment required in patients with CrCl >30ml/min.
Caution advised in patients with CrCl <30ml/min. Hepatic impairment: Severe hepatic
impairment - Not recommended. Undertake with caution and close monitoring in
mild/moderate impairment. Mild impairment - 800mg once daily; Moderate impairment 200mg once daily. Elderly: Limited data in patients ≥ 65 yrs. Paediatrics: Not to be used in
children <2 yrs. Safety & efficacy not established in children 2-18 yrs; no data available.
Contra-indications Hypersensitivity to active substance or excipients. Special Warnings
and Precautions Hepatic effects: Hepatic failure reported during pazopanib use; increases in
serum transaminases (ALT, AST) and bilirubin also observed. Monitor liver function before
initiation of treatment and ≥once every 4 weeks for first 4 months, and periodically thereafter.
If transaminases ≤8xULN, continue pazopanib with weekly monitoring until they return to
≤Grade 1. If transaminases >8xULN, interrupt pazopanib until they return to ≤Grade 1. If
transaminases >3xULN occur following re-introduction, discontinue pazopanib. If
transaminases >3xULN occur concurrently with bilirubin >2xULN, perform bilirubin
fractionation. If direct (conjugated) bilirubin is >35% of total, discontinue pazopanib.
Concomitant use of pazopanib and simvastatin increases risk of ALT elevations: undertake
with caution and close monitoring. Hypertension: Events of hypertension, including
hypertensive crisis, have occurred in pazopanib studies. Control BP prior to initiating
pazopanib. Monitor for hypertension early (≤1 week after starting treatment) and frequently
thereafter. Manage elevated BP with anti-hypertensive therapy and pazopanib dose
modification. Discontinue pazopanib if BP is persistently elevated (140/90 mmHg) or if arterial
hypertension is severe and persists despite anti-hypertensive therapy and dose reduction.
Posterior reversible encephalopathy syndrome (PRES) / Reversible posterior
leukoencephalopathy syndrome (RPLS): PRES/RPLS has been reported in association with
pazopanib. Patients developing PRES/RPLS should permanently discontinue pazopanib.
Cardiac dysfunction/heart failure: Consider risks/benefits of pazopanib in patients with preexisting cardiac dysfunction. Safety and pharmacokinetics of pazopanib not studied in patients
with moderate to severe heart failure or those with below normal LVEF. Events of cardiac
dysfunction (e.g. CHF and LVEF decline) have occurred in pazopanib trials. Monitor patients
for signs and symptoms of CHF. Baseline and periodic LVEF evaluation recommended. QT
prolongation and Torsade de Pointes: Use with caution in patients (i) with history of QT
interval prolongation, (ii) taking antiarrythmics or other medications that may prolong QT
interval or (iii) with relevant pre-existing cardiac disease. Baseline and periodic ECGs, and
maintenance of electrolytes within normal range recommended. Arterial thrombotic events:
Use with caution in patients at increased risk for these events. Base treatment decision on
individual patient’s benefit/risk assessment. Venous thromboembolic events (VTEs): VTEs
including venous thrombosis and fatal PE have occurred in pazopanib trials. Thrombotic
microangiopathy (TMA): (including thrombotic thrombocytopenic purpura and haemolytic
uraemic syndrome) has been reported in clinical trials of pazopanib. Patients developing TMA
should permanently discontinue pazopanib. Reversal of effects of TMA has been observed
after pazopanib treatment was discontinued. Haemorrhagic events: Not recommended in
patients with history of haemoptysis, cerebral, or significant GI haemorrhage in past 6 months.
Use with caution in patients with significant risk of haemorrhage. GI perforations and fistula:
Use with caution in patients at risk for GI perforation or fistula. Wound healing: Stop treatment
≥7 days prior to surgery. Resume after surgery based on clinical judgement of adequate
wound healing. Discontinue pazopanib in patients with wound dehiscence. Hypothyroidism:
Baseline measurement of thyroid function recommended prior to start of pazopanib treatment;
monitor periodically during treatment. Monitor patients for signs and symptoms of thyroid
dysfunction and manage as per standard medical practice. Proteinuria: Baseline and periodic
urinalysis recommended. Monitor patients for worsening proteinuria. Discontinue pazopanib if
Grade 4 proteinuria develops. Pneumothorax: Observe patients closely for signs and
symptoms of pneumothorax. Infections: Cases of serious infection (with/without neutropenia)
reported. Interactions Avoid concomitant use with strong inhibitors of CYP3A4, pglycoprotein (P-gp) or breast cancer resistance protein (BCRP) and CYP3A4 inducers.
Hyperglycaemia observed during concomitant administration with ketoconazole. Avoid coadministration with medicines that increase gastric pH (e.g. PPIs and H2 receptor antagonists)
unless medically necessary. Undertake concomitant administration with uridine diphosphate
glucuronosyl transferase 1A1 (UGT1A1) substrates and simvastatin (and other statins) with
caution. Avoid grapefruit juice during pazopanib treatment. Pregnancy and lactation No
adequate data on use in pregnant women. Not to be used unless clearly necessary;
appropriate contraception advised. Not known whether pazopanib excreted in human milk;
breastfeeding should be discontinued. Animal studies indicate fertility may be affected.
Effects on ability to drive and use machines No studies conducted. Avoid driving or using
machines if affected. Undesirable effects Most important serious ADRs associated with
pazopanib in clinical studies were: TIA, ischaemic stroke, myocardial ischaemia, myocardial
and cerebral infarction, cardiac dysfunction, GI perforation and fistula, QT prolongation;
pulmonary/GI/cerebral haemorrhage. All events occurred in <1% of patients. Fatal events
possibly
related
to
pazopanib
included:
GI
haemorrhage,
pulmonary
haemorrhage/haemoptysis, abnormal hepatic function, intestinal perforation, ischaemic stroke.
Treatment-related events reported with pazopanib in advanced RCC patients with following
frequencies: Very common: Decreased appetite; Dysgeusia; Hypertension; Diarrhoea,
nausea, vomiting, abdominal pain; Hair colour changes; Fatigue; Increased ALT and AST.
Common: Thrombocytopenia, neutropenia, leucopenia; Hypothyroidism; Headache, dizziness,
lethargy, paraesthesia; Hot flush; Epistaxis, dysphonia; Dyspepsia, stomatitis, flatulence,
abdominal distension; Abnormal hepatic function, hyperbilirubinaemia; Rash, alopecia, PPE,
skin hypo/de-pigmentation, erythema, pruritus, dry skin, hyperhidrosis; Myalgia, muscle
spasms; Proteinuria; Asthenia, mucosal inflammation, oedema, chest pain; Decreased weight
/WBC, Increased creatinine/bilirubin/lipase/BP/TSH/GGT. Uncommon events include:
Hypophosphataemia; hypomagnesaemia; Peripheral sensory neuropathy; hypoaesthesia;
Eyelash discolouration; CVA, myocardial infarction, bradycardia; Flushing, hypertensive crisis;
Mouth ulceration, frequent bowel movements; pancreatitis, peritonitis; Hepatotoxicity, hepatic
failure, hepatitis; jaundice; Photosensitivity reaction, skin exfoliation; Menorrhagia,
metrorrhagia, Retroperitoneal/urinary tract/vaginal haemorrhage; Mucous membrane disorder;
Increased blood urea/amylase, decreased blood glucose, abnormal thyroid function test;
Infections (with/without neutropenia). Overdose No specific antidote. Treatment should
consist of general supportive measures. Basic NHS Cost 200mg x 30 tablet pack £560.50.
400mg x 30 tablet pack £1121.00. Marketing authorisation (MA) nos. EU/1/10/628/001-4.
MA holder Glaxo Group Limited, Berkeley Avenue, Greenford, Middlesex UB6 ONN. Legal
category POM. UK/PAZ/0012/13. January 2013.
Adverse events should be reported. Reporting forms and information can be found at:
http://www.mhra.gov.uk/yellowcard
Adverse events should also be reported to GlaxoSmithKline on 0800 221 441.
Further information is available from Customer Contact Centre, GlaxoSmithKline, Stockley
Park West, Uxbridge, Middlesex UB11 1BT; customercontactuk@gsk.com; Freephone: 0800
221 441.
Votrient is a trademark of the GlaxoSmithKline group of companies.
Additional slides
Patient preference questionnaire - question 1
1.
Now that you have completed both treatments, which of the two drugs
would you prefer to continue to take as the treatment for your cancer,
assuming that both drugs will work equally well in treating your cancer?
(place a tick mark ( ) for ONLY one response)
 Prefer the drug taken as the first treatment – Please answer questions 2-3
 Prefer the drug taken as the second treatment – Please answer questions
2-3
 Have no preference – if you have no preference, you need not answer
questions 2-3
Patient preference questionnaire - question 2
2.
Below are some factors that may have influenced your treatment preference.
Please indicate which factors had an influence on your choice of treatment.
Patient preference questionnaire - question 3
3.
If you had to choose one reason, which of the above symptoms is the
most important reason for your preference? (please circle only one
letter or “N/A” for “not applicable”, if none of the listed symptoms
were the most important reason for your preference)
A
B
C
D
E
F
G
H
I
N/A
Other endpoints and data collected – how were they assessed?
EQ-5D
• Collected on day one, wash out period and end of study.
•
Standardised, validated measure of health status.
FACIT-Fatigue
• Completed on day one, every two weeks during treatment and end of the study.
•
Validated tool which measures the severity and impact of fatigue on functioning and health-related quality of life
experienced in the past seven days.
SQLQ
• Completed on day one, every two weeks during treatment and at the end of the study.
•
Designed to assess the severity and impact of a patient’s mouth and throat soreness as well as hand and foot
soreness.
•
Unvalidated questionnaire, developed in collaboration with Professor David Cella.
Physician preference
• Prospectively collected at the end of treatment period 2, prior to unblinding.
•
Physicians selected which drug they preferred the patient to carry on taking and the reasons for this.
Tumour response
• Scans collected at baseline, wash out period and end of study.
Participating countries and UK recruitment
70
62
Patients numbers
60
50
40
40
37
30
20
16
14
10
0
Finland
France
Germany
Italy
UK
UK centres
• The Christie, Wolverhampton, Plymouth, Hull, Newcastle, Shrewsbury, Norwich,
Birmingham and Preston
Investigator-assessed best unconfirmed response per RECIST v1.1
End of treatment period 11 – collected for analysis purposes
Best response
Pazopanib (n=85)
Sunitinib (n=80)
Complete response (CR)
1%
1%
Partial response (PR)
18%
20%
Stable disease**
42%
53%
Progressive disease
20%
11%
Not evaluable
20%
15%
19%
12.2%-27.2%
21%
14.0%-30.2%
Objective response (CR + PR)
90% CI
Difference in response rate2
90% CI for difference2
P-value2
-2.4
(-12.7, 7.8)
0.703
**Includes non-CR/non-PD for patients with non measurable disease
• Study population (n=168) included patients with non-clear cell RCC histology (10.1%) and non-measurable disease (7.7%)
1. Escudier BJ, Porta C, Bono P, et al. Abstract and oral presentation at the American Society of Clinical Oncology Annual Congress 2012. J Clin Oncol 2012;
30 (suppl.): Abstract CRA4502.
2. Clinical results summary for VEG113046. GSK clinical trials register: http://www.gskclinicalstudyregister.com/result_detail.jsp?protocolId=113046&studyId=5492502E-9541-4FAD-8E7E-8C4FE1AD6B49&compound=pazopanib