Transcript COMPARZ Results LOC Training VEG108844

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COMPARZ Results
COMParing the efficacy, sAfety and
toleRability of paZopanib vs. sunitinib in
first-line advanced and/or metastatic renal cell
carcinoma
VEG108844
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UK/PAZ/0029/13 February 2013
Prescribing information can be found at the end of the main presentation
Treatment options for advanced RCC have been
revolutionised in a short period of time…
Timelines based on EMA approval
Bevacizumab +
IFN-α
Sorafenib
Temsirolimus
High-dose
interleukin-2
1992-2005
Pazopanib
Axitinib
Everolimus
Sunitinib
2005
2006
IFN-α
EMA = European Medicines Agency
2007
2008
2009
2010
2011
2012
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 COMPARZ
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
first-line 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
COMPARZ Study Background
Rationale
• COMPARZ was initiated in 2008
– Provide comparative data to inform and aid
prescribers and payers
• In 2010 pazopanib was granted a conditional approval
in the EU based on the VEG105192 data (pazopanib vs.
placebo)1
– As COMPARZ was already underway it became part
of the obligation of the conditional approval
1. Sternberg CN et al. J Clin Oncol 2010;28:1061-1068.
Primary endpoint obligations
• Protocol-defined primary endpoint
– Non inferiority in PFS at a margin of 1.25 (upper 95% CI)
• EMA-defined primary endpoint
– Non inferiority in PFS at a margin of 1.22 (upper 95% CI)
– Linked to pazopanib’s conditional marketing authorisation
– Subsequently linked to pazopanib’s NICE and SMC
guidance
– EMA, NICE and SMC have been informed of the results
and GSK await to hear from them
Trial design
Number of patients recruited
UK centres
25
20
15
10
5
0
Centre
Study design1
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 OD
Continuous dosing
N=1110
Randomised
1:1
Sunitinib
50 mg OD
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)
1. Motzer R, et al. ESMO 2012 oral presentation; abstract LBA8_PR.
Endpoints
Primary
• Non-inferiority in progression free survival (PFS) between pazopanib
and sunitinib
Secondary
• Overall survival (OS)
• Objective response rate (ORR)
• Duration of response
• Time to response
• Safety
• Quality of Life (QoL)
• Medical resource utilisation
1. Motzer R, et al. ESMO 2012 oral presentation; abstract LBA8_PR.
Why did GSK use a non-inferiority trial design?
• To establish that the efficacy of pazopanib is non inferior to sunitinib
• A non-inferiority study is designed to show that the experimental
treatment is not less effective than an existing treatment, by more
than a pre-specified amount1
– This amount is known as the non-inferiority margin
– To show non-inferiority, the upper bound of the 95% CI should lie
entirely to the left of the non-inferiority margin (in this case, 1.25 as
defined in the protocol, 1.22 as defined by the EMA which is linked
to the NICE/SMC guidance)
1. CHMP. Guideline on the choice of the non-inferiority margin. EMEA 2005.
Why did GSK use a non-inferiority trial
design?
1.25
Non-inferiority shown
Inferiority shown
New agent
1
better
Treatment difference Hazard Ratio (HR)
New agent
worse
• With a margin of 1.25, at least 631 PFS events (independently
reviewed) were required to provide 80% power
• GSK took the risk to evaluate pazopanib vs. the standard of care
Study assessments1
• Disease assessments (CT/MRI) performed at:
– Baseline
– Every 6 weeks to week 24
– Every 12 weeks thereafter until disease progression, death or
unacceptable toxicity
• Other assessments performed in 6-week cycles
– Safety
• Baseline, day 28 & day 42 of every cycle through to cycle 9, day 42 of every
cycle from cycle 10
– Patient-reported outcomes
• Baseline (except for CTSQ), day 28 every cycle through to cycle 9, day 42 of
every cycle from cycle 10
– FACIT-Fatigue
– Functional Kidney Symptom Index (FKSI-19)
– Cancer Therapy Satisfaction Questionnaire (CTSQ)
– Supplementary Quality of Life Questionnaire (SQLQ)
1. Motzer R, et al. ESMO 2012 oral presentation; abstract LBA8_PR
Results
Key baseline characteristics1
Pazopanib (n=557)
Sunitinib (n=553)
61 (18-88)
62 (23-86)
Male, %
71
75
Prior nephrectomy, %*
82
84
90-100%
75
76
70-80%
25
24
≤1.5 x ULN
93
95
>1.5 x ULN
7
5
Favourable
27
27
Intermediate
58
59
Poor
12
9
Unknown
3
4
Age, median years (range)
KPS, %*
LDH,%*
MSKCC risk category, %
* Stratification factor
1. Motzer R, et al. ESMO 2012 oral presentation; abstract LBA8_PR.
Key baseline characteristics (cont’d)1
Pazopanib (n=557)
Sunitinib (n=553)
1 or 2
58
56
≥3
42
44
Lung
76
77
Lymph node
40
45
Bone
20
15
Liver
15
20
Number of organs involved, %
Most common metastatic site, %
1. Motzer R, et al. ESMO 2012 oral presentation; abstract LBA8_PR.
Primary endpoint: Pazopanib is non-inferior to
sunitinib (independent review)
PFS HR (95% CI): 1.047 (0.898-1.220)
N
Median months PFS (95% CI)
Pazopanib
557
8.4 (8.3-10.9)
Sunitinib
553
9.5 (8.3-11.1)
Pazopanib
Sunitinib
1. Motzer R, et al. ESMO 2012 oral presentation; abstract LBA8_PR.
Primary endpoint: Pazopanib is non-inferior to
sunitinib (investigator review)
PFS HR (95% CI ): 0.998 (0.863-1.154)
N
Median months PFS (95% CI)
Pazopanib
557
10.5 (8.3-11.1)
Sunitinib
553
10.2 (8.3-11.1)
Pazopanib
Sunitinib
1. Motzer R, et al. ESMO 2012 oral presentation; abstract LBA8_PR.
Response rate
(independent review)
Objective response rate (%)
100
Best overall
response, %
80
Pazopanib
(n=557)
Sunitinib
(n=553)
Complete response
<1
<1
Partial response
31
24
Stable disease
39
44
Progressive disease
17
19
Not evaluable
13
12
60
p=0.032
40
20
31%
(n=173)
25%
(n=138)
0
Pazopanib (n=557) Sunitinib (n=553)
1. Motzer R, et al. ESMO 2012 oral presentation; abstract LBA8_PR.
Clinical benefit rate (CR+PR+SD)
• 70% pazopanib
• 69% sunitinib
No significant difference in OS between
pazopanib and sunitinib (interim analysis)
OS HR (95% CI ): 0.908 (0.762-1.082); p=0.275
N
Median months OS (95% CI)
Pazopanib
557
28.4 (26.2-35.6)
Sunitinib
553
29.3 (25.3-32.5)
Pazopanib
Sunitinib
1. Motzer R, et al. ESMO 2012 oral presentation; abstract LBA8_PR.
Based on 502
death events
(May 2012)
Most common adverse events ≥30%1
(treatment-emergent)
Pazopanib (n = 554) %
Adverse Event
Sunitinib (n = 548) %
All Grs
Gr 3/4
All Grs
Gr 3/4
Any event a
>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
ALT increased
31
10/2
18
2/<1
Hair colour changes
30
0/0
10
<1/0
Hand-foot syndrome
29
6/0
50
11/<1
Taste Alteration
26
<1/0
36
0/0
Thrombocytopenia
10
2/<1
34
12/4
a
2% of patients in pazopanib arm and 3% of patients in sunitinib arm had grade 5 adverse events.
1. Motzer R, et al. ESMO 2012 oral presentation; abstract LBA8_PR.
Most common adverse events ≥30%1
(treatment-emergent)
Pazopanib
(n = 554) %
Sunitinib
(n = 548) %
All Grades
All Grades
Any event a
>99
>99
Diarrhea
63
57
Fatigue
55
63
Hypertension
46
41
Nausea
45
46
Decreased appetite
37
37
ALT increased
31
18
Hair colour changes
30
10
Hand-foot syndrome
29
50
Taste alteration
26
36
Thrombocytopenia
10
34
Adverse Event
a 2%
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
Yellow highlight: Risk greater for pazopanib and 95% CI for relative risk does not cross 1
1. Motzer R, et al. ESMO 2012 oral presentation; abstract LBA8_PR.
Laboratory abnormalities (≥35%)1
Pazopanib (n = 554) %
Sunitinib (n = 548) %
All Grs
Gr 3/4
All Grs
Gr 3/4
ALT
60
15/2
43
4/<1
AST
61
11/1
60
3/0
Hypoalbuminaemia
33
<1/0
42
2/0
Bilirubin
36
3/<1
27
2/<1
Creatinine
32
<1/0
46
<1<1
Hyperglycaemia
54
5/0
57
4/<1
Hyponatraemia
35
7/<1
32
7/<1
Hypophosphataemia
36
4/0
52
8/<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
Anaemia
31
1/<1
60
6/1
Chemistry labs (≥35%)
Haematology labs
1. Motzer R, et al. ESMO 2012 oral presentation; abstract LBA8_PR.
Laboratory abnormalities (≥35%)1
Pazopanib (n = 554), %
Sunitinib (n = 548),%
All Grades
All Grades
ALT
60
43
AST
61
60
Hypoalbuminaemia
33
42
Bilirubin
36
27
Creatinine
32
46
Hyperglycaemia
54
57
Hyponatraemia
35
32
Hypophosphataemia
36
52
Leukopenia
43
78
Neutropenia
37
68
Thrombocytopenia
41
78
Lymphopenia
38
55
Anaemia
31
60
Chemistry labs
Haematology labs
Blue Highlight: Risk greater for sunitinib and 95% CI for relative risk does not cross 1
Yellow highlight: Risk greater for pazopanib and 95% CI for relative risk does not cross 1
1. Motzer R, et al. ESMO 2012 oral presentation; abstract LBA8_PR.
Relative Risk in Adverse Events
AE occurrence ≥10% in either arm; 95% CI for RR does not cross 1 1
Adverse event
Relative risk (95% CI)
Hair colour change
Weight decreased
Serum ALT increased
Alopecia
Upper abdominal pain
Serum AST increased
Fatigue
Rash
Pain in extremity
Constipation
Taste alteration
LDH increased
Serum creatinine increased
Peripheral oedema
Hand-foot syndrome
Dyspepsia
Pyrexia
Leukopenia
Hypothyroidism
Epistaxis
Serum TSH increased
Mucositis
Neutropenia
Anaemia
Thrombocytopenia
Note: AEs >10% where there was no
statistical difference in incidence
between the arms are not included on
the graph:
Diarrhoea / hypertension / nausea /
decreased appetite / bilirubin / albumin /
hyperglycaemia
Favours pazopanib
Favours sunitinib
Log scale
1. Motzer R, et al. ESMO 2012 oral presentation; abstract LBA8_PR.
Treatment duration and dose adjustments1
Pazopanib
(n = 554)
Sunitinib
(n = 548)
8.0 (0−40)
7.6 (0−38)
Dose reductions, %
44
51
Discontinuations due to AEsa, %
24
19
Median duration of treatment
(months, range)
a. Most common reason: pazopanib arm (liver event, 6%); sunitinib arm (cytopenia, 3%)
1. Motzer R, et al. ESMO 2012 oral presentation; abstract LBA8_PR.
Quality of Life Results (first 6 monthsa)1
Treatment difference: mean
change from baseline b
Reported
MIDs
P-value
Fatigue/Total score
2.32
3
<0.001
Kidney Symptom Index/Total score
1.41
5
0.018
Physical
0.78
3
0.027
Emotional
0.05
N/A
0.409
Treatment Side Effects
0.31
N/A
0.033
Functional Well Being
0.31
N/A
0.098
Expectations of Therapy
1.41
8.3
0.284
Feelings about Side Effects
8.50
10.3
<0.001
Satisfaction with Therapy
3.21
5.9
<0.001
Worst mouth/throat soreness
0.505
N/A
<0.0001
Worst foot soreness
0.204
N/A
0.0016
Worst hand soreness
Limitations due to mouth/throat
soreness
Limitations due to foot soreness
0.267
N/A
0.0008
0.94
N/A
<0.001
0.65
N/A
0.014
Instrument
FACIT-F
FKSI-19
Cancer
Treatment
Satisfaction
Questionnai
re (CTSQ)
Supplement
ary Quality
of Life
Questionnai
re (SQLQ)*
Domain Description
a Pre-specified analysis. HRQoL changes in mean scores over time were analysed with a repeated measures analysis of covariance
(ANCOVA).
b Yellow font: favours pazopanib. Blue font: favours sunitinib. P-value <0.05 is statistically significant
* Undergoing validation N/A = No standard has been established for minimal clinical important difference for these tools/domains.
1. Motzer R, et al. ESMO 2012 oral presentation; abstract LBA8_PR.
Quality of Life:
FACIT-Fatigue results up to cycle 81
Measured day 28 every cycle (end of sunitinib 4-week on cycle)
1. Motzer R, et al. ESMO 2012 oral presentation; abstract LBA8_PR.
Health-related quality of life in PISCES1
A randomised, double-blind, cross-over patient preference study of pazopanib vs.
sunitinib in treatment-naïve locally advanced or metastatic renal cell carcinoma
Instrument
FACIT-F
SQLQ
Domain name
Fatigue/Total score
Three items on Mouth
and Throat Soreness
(MTS), Hand soreness
(H) and Foot soreness (F)
Two items on limitations
due to MTS and F
Scale
0-3
0-3
0-15
Results (cross-over analyses)1,2
P-value
Favoured pazopanib by 2.5 points
MID = 3.0
(mean: 38.1 paz / 35.6 sun)
0.002
MTS - Favoured pazopanib by 0.38
(mean: 0.40 paz / 0.78 sun)
<0.001
H - Favoured pazopanib by 0.08
(mean: 0.21 paz / 0.29 sun)
0.026
F - Favoured pazopanib by 0.16
(mean: 0.36 paz / 0.52 sun)
0.005
MTS - Favoured pazopanib by 0.60
(mean: 14.32 paz / 13.72 sun)
<0.001
F - Favoured pazopanib by 0.58
(mean: 13.82 paz / 13.24 sun)
0.003
QoL assessments in PISCES were measured every 2 weeks
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.gsk-clinicalstudyregister.com/result_detail.jsp?protocolId=113046&studyId=5492502E-9541-4FAD-8E7E-8C4FE1AD6
B49&compound=pazopanib
COMPARZ Conclusions
Conclusions
• Largest head-to-head study in advanced RCC, demonstrates non-inferiority of
pazopanib relative to sunitinib for progression-free survival
– (HR: 1.047; 95% CI: 0.898-1.220) (independent review)
• Both the protocol-defined and EMA-defined primary endpoints have been met
• Pazopanib efficacy is further supported by similar overall survival and higher response
rates
– Pazopanib and sunitinib achieved more than 2 years median interim OS
(28.4 months vs. 29.3 months; p=0.275)
– Significantly greater response rate with pazopanib than sunitinib
(31% vs. 25%; p=0.032) (independent review)
• The differentiated safety profile of pazopanib includes:
– Lower incidence of fatigue, hand-foot syndrome and mucositis
– Lower incidence of haematological toxicities
– Higher incidence of liver function test abnormalities
• QoL assessment favours pazopanib over sunitinib on the majority (11/14) of the QoL
scales for patients receiving pazopanib
The COMPARZ results complement the data
from the registrational trial
PFS (Independent)
pazopanib vs. placebo1
ORR (independent)
pazopanib vs. placebo1
Treatmentnaïve (n=233)
PFS: 11.1m vs. 2.8m
HR 0.40 (0.27-0.60) p<0.0001
32% vs. 4%
p<0.001
All patients
(n=435)
PFS: 9.2m vs. 4.2m
HR 0.46 (0.34-0.62) p<0.0001
30% vs. 3%
p<0.001
• Pazopanib has a well characterised and manageable safety profile in advanced RCC1,2
• Most adverse events in the pazopanib group were grade 1 or 21,2
• Low incidence of grade 3 or 4 fatigue, hand-foot syndrome and mucositis/stomatitis1,2
• The most common grade 3/4 laboratory abnormalities were ALT and AST elevations1,2
• Low incidence of grade 3/4 haematological adverse events1,2
• Pazopanib maintained health-related quality of life compared with placebo1
1. Sternberg CN, Davis ID, Mardiak J, et al. J Clin Oncol 2010; 28: 1061–1068.
2. Sternberg CN, et al. A randomized, double-blind phase III study of pazopanib in treatment-naïve and cytokine-pre-treated patients with
advanced renal cell carcinoma (RCC). Oral presentation at ASCO 2009: abstract 5021.
The COMPARZ results complement the
PISCES data1
PazopanIb versus Sunitinib patient preferenCE Study in
treatment naïve locally advanced or metastatic renal cell carcinoma1
• Randomised, double-blind, cross-over study over a 22 week period
– Total 168 patients randomised; 114 patients in primary analysis
population
• Patients completed the patient preference questionnaire at the end of the
study before unblinding
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.
The COMPARZ results complement the
PISCES data – continued1
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.
The COMPARZ results complement the
PISCES data – continued1
• The most important symptom which influenced this preference
– Pazopanib: Less fatigue (21 of the 80 patients who preferred
pazopanib)
– Sunitinib: Less diarrhoea (6 of the 25 patients who preferred
sunitinib)
• The most common adverse events (all grade) reported in ≥30% of
patients receiving pazopanib and sunitinib respectively were:
diarrhoea 42% vs. 32%, nausea 33% vs. 30% and fatigue 29% vs.
30%
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.
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. Pazopanib 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. Pazopanib 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. Pazopanib 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. Pazopanib 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 anti-hypertensive 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. Pazopanib 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; [email protected]; Freephone: 0800
221 441.
Votrient is a trademark of the GlaxoSmithKline group of companies.
Additional slides
Patient reported outcome tools
• FACIT-Fatigue (validated)
– Measures severity and impact of fatigue on functioning and
HRQoL experienced in past seven days1
– Used previously to evaluate fatigue with anti-angiogenesis
treatments, including assessments for sunitinib2,3
• FKSI-19 (validated)
– A disease-specific measure that measures disease and treatmentrelated symptoms specifically in renal cancer patients4,5,6
– Includes patient self-reports on experience of symptoms in the
past seven days such as lack of energy, pain, bone-pain,
shortness of breath, fatigue, blood in urine, etc.
1. Cella, 2002
2. Motzer, 2005
3. Beaumont, 2006
4. Rosenbloom, 2007
5. Rosenbloom, 2008
6. Rao, 2008
Patient reported outcome tools
• Cancer Therapy Satisfaction Questionnaire (CTSQ; validated)
– A questionnaire which has been well-validated for use in assessing
patients’ satisfaction with various key aspects of undergoing cancer
therapy (e.g. side effects, convenience of regimens, etc.)1
• Supplementary Quality of Life Questionnaire (unvalidated)
– An SQLQ form has been included in the trial which includes 5 question
items.
– There are two questions that ask for patients self-reports on severity of
symptoms and impact of these symptoms which refer to mouth and throat
soreness and also to hand and foot soreness.
– The questions on mouth and throat soreness are adapted from the Oral
Mucositis Daily Questionnaire (OMDQ), a validated questionnaire used
previously in clinical trials 2-5
– One question refers to days missed from work specifically due health
problems. This question was designed to follow general format of work
productivity assessments in the National Health and Nutrition Survey
(NHANES), which clearly refer to impact on work due to health (i.e.,
physical, mental, or emotional)6
1. Abetz, 2005; 2. Abrams, 2005 ; 3. Stiff, 2006a ; 4. Stiff, 2006b; 5. Syrjala, 2003 ; 6. National Center for Health Statistics, 2005-2006
Relative Risk in Adverse Events
AE occurrence ≥10% in either arm; 95% CI for RR does not cross 1
Forest plot
• To be included on the plot, the AE needs to meet two criteria:
Firstly, the absolute occurrence in either treatment arm needs to be
>10%
Secondly, there needs to be a statistically significant difference in the
risk of the adverse event between the two treatment arms – i.e.
occurrence >10% and 95% confidence interval for the relative risk
does not cross 1
VEG113078 - Asian sub-study
• COMPARZ was originally designed with a non-inferiority margin (upper bound 95% CI)
of 1.25. EMA requested a tighter margin (upper bound 95% CI) of 1.22, which would
require more events than COMPARZ could deliver alone.
• Therefore the EMA agreed that GSK could take a step-wise approach to pool the
results from COMPARZ and the identical Asian sub-study to meet the required number
of events
• The trials were designed almost identically and therefore the studies could be
combined for analysis without statistical concern
• Asian sub-study was originally conducted to meet the regulatory and reimbursement
requirements of China, South Korea and Taiwan to evaluate the efficacy and safety of
pazopanib in these ethnic groups
• Additional patients were also required due to:
– Drop-out due to adverse events or other reasons (decision by patient or
investigator, lost to follow-up) prior to assessment of progression
– Exclusion due to discordance between the independent review and investigator
assessments of progression
• The analysis for COMPARZ is based on 927 patients plus 183 from the Asian substudy
EQ5D data from PISCES1
• 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 crossover patient preference study of pazopanib (P) versus sunitinib (S). Abstract and poster presentation at European Society of Medical
Oncology Congress 2013. Abstract no. 792PD