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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

UK/PAZ/0029/13 February 2013

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GSK has been involved in the preparation of this presentation 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…

High-dose interleukin-2 Sorafenib Sunitinib

Timelines based on EMA approval

Bevacizumab + IFN α Temsirolimus Everolimus Pazopanib Axitinib 1992-2005 2005 2006 2007 2008 2009 2010 2011 2012 IFN α EMA = European Medicines Agency

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 disease 1 • 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. 676/11

1

• 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

25 20 15 10 5 0

UK centres

Centre

Study design

1 N=1110 Randomised 1:1 Pazopanib 800 mg OD Continuous dosing Key Eligibility Criteria

• Advanced/metastatic RCC • Clear-cell histology • No prior systemic therapy • Measurable disease (RECIST 1.0) • KPS ≥ 70 • Adequate organ function • 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.

Sunitinib 50 mg OD 4 wk on/2 wk off

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 amount

1 – 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

New agent better 1 Treatment difference Hazard Ratio (HR) Non-inferiority shown Inferiority shown 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 assessments

1

•

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

Age, median years (range) Male, % Prior nephrectomy, %* KPS, %* 90-100% 70-80% LDH,%* ≤1.5 x ULN >1.5 x ULN MSKCC risk category, % Favourable Intermediate Poor Unknown * Stratification factor

Key baseline characteristics

1 Pazopanib (n=557)

61 (18-88) 71 82 75 25 93 7 27 58 12 3

Sunitinib (n=553)

62 (23-86) 75 84 76 24 95 5 27 59 9 4 1.

Motzer R,

et al.

ESMO 2012 oral presentation; abstract LBA8_PR.

Key baseline characteristics (cont’d)

1

Number of organs involved, % 1 or 2 ≥3 Most common metastatic site, % Lung Lymph node Bone Liver

Pazopanib (n=557)

58 42 76 40 20 15

Sunitinib (n=553)

56 44 77 45 15 20 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)

Pazopanib Sunitinib

N

557 553

Median months PFS (95% CI)

8.4 (8.3-10.9) 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)

Pazopanib Sunitinib

N

557 553

Median months PFS (95% CI)

10.5 (8.3-11.1) 10.2 (8.3-11.1)

Pazopanib Sunitinib

1.

Motzer R,

et al.

ESMO 2012 oral presentation; abstract LBA8_PR.

Response rate (independent review)

100 80 60 p=0.032

40 20 31% (n=173) 25% (n=138) 0 Pazopanib (n=557) Sunitinib (n=553) Best overall response, %

Complete response Partial response Stable disease Progressive disease Not evaluable

Pazopanib (n=557)

<1 31 39 17 13

Sunitinib (n=553)

<1 24 44 19 12 Clinical benefit rate (CR+PR+SD) • 70% pazopanib • 69% sunitinib 1.

Motzer R,

et al.

ESMO 2012 oral presentation; abstract LBA8_PR.

No significant difference in OS between pazopanib and sunitinib (interim analysis)

OS HR (95% CI ): 0.908 (0.762-1.082); p=0.275

Pazopanib Sunitinib

N

557 553

Median months OS (95% CI)

28.4 (26.2-35.6) 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) % Sunitinib (n = 548) % Adverse Event

Any event

a

Diarrhea Fatigue Hypertension Nausea Decreased appetite ALT increased Hair colour changes Hand-foot syndrome Taste Alteration Thrombocytopenia

All Grs

>99 63 55 46 45 37 31 30 29 26 10

Gr 3/4

59/15 9/0 10/<1 15/<1 2/0 1/0 10/2 0/0 6/0 <1/0 2/<1

All Grs

>99 57 63 41 46 37 18 10 50 36 34 a 2% of patients in pazopanib arm and 3% of patients in sunitinib arm had grade 5 adverse events.

Gr 3/4

57/17 7/<1 17/<1 15/<1 2/0 3/0 2/<1 <1/0 11/<1 0/0 12/4 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) % Adverse Event

Any event a Diarrhea

Fatigue

Hypertension Nausea Decreased appetite ALT increased Hair colour changes

Hand-foot syndrome Taste alteration Thrombocytopenia All Grades

>99 63

55

46 45 37 31 30

29 26 10 All Grades

>99 57

63

41 46 37 18 10

50 36 34

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 Chemistry labs (≥35%)

ALT AST Hypoalbuminaemia Bilirubin Creatinine Hyperglycaemia Hyponatraemia Hypophosphataemia

Haematology labs

Leukopenia Neutropenia Thrombocytopenia Lymphopenia Anaemia

Pazopanib (n = 554) %

All Grs 60 61 33 36 32 54 35 36 43 37 41 38 31 1.

Motzer R,

et al.

ESMO 2012 oral presentation; abstract LBA8_PR.

Gr 3/4 15/2 11/1 <1/0 3/<1 <1/0 5/0 7/<1 4/0 1/0 4/<1 3/<1 5/0 1/<1

Sunitinib (n = 548) %

All Grs 43 60 42 27 46 57 32 52 Gr 3/4 4/<1 3/0 2/0 2/<1 <1<1 4/<1 7/<1 8/<1 78 68 78 55 60 6/0 19/1 18/4 14/<1 6/1

Laboratory abnormalities (≥35%)

1 Pazopanib (n = 554), % Sunitinib (n = 548),% Chemistry labs

ALT AST

Hypoalbuminaemia

Bilirubin

Creatinine

All Grades 60 61

33

36

32

All Grades 43 60

42

27

46

1.

Hyperglycaemia Hyponatraemia

Hypophosphataemia Haematology labs Leukopenia Neutropenia

54 35

36 43 37

57 32

52 78 68 Thrombocytopenia Lymphopenia 41 38 78 55 Anaemia 31

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 Motzer R,

et al.

ESMO 2012 oral presentation; abstract LBA8_PR.

60

Relative Risk in Adverse Events

AE occurrence ≥10% in either arm; 95% CI for RR does not cross 1 1 Adverse event 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 Relative risk (95% CI) 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

1.

Favours pazopanib Favours sunitinib Log scale Motzer R,

et al.

ESMO 2012 oral presentation; abstract LBA8_PR.

Treatment duration and dose adjustments

1

Median duration of treatment (months, range) Dose reductions, %

Pazopanib (n = 554) Sunitinib (n = 548)

8.0 (0−40) 7.6 (0−38) 44 51 Discontinuations due to AEs

a

, % 24 19

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 months

a

)

1 Instrument

FACIT-F FKSI-19 Cancer Treatment Satisfaction Questionnai re (CTSQ)

Domain Description

Fatigue/Total score Kidney Symptom Index/Total score Physical Emotional Treatment Side Effects Functional Well Being Expectations of Therapy Feelings about Side Effects Satisfaction with Therapy

Treatment difference: mean change from baseline b 2.32

1.41

0.78

0.05

0.31

0.31

1.41

8.50

3.21

Reported MIDs

3 5 3 N/A N/A N/A 8.3

10.3

5.9

P-value <0.001

0.018

0.027

0.409

0.033

0.098

0.284

<0.001

<0.001

Supplement ary Quality of Life Questionnai re (SQLQ)* Worst mouth/throat soreness Worst foot soreness Worst hand soreness Limitations due to mouth/throat soreness Limitations due to foot soreness

0.505

0.204

0.267

0.94

N/A N/A N/A N/A

<0.0001

0.0016

0.0008

<0.001

0.65

N/A

0.014

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 8

1

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 PISCES

1 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

Favoured pazopanib by 2.5 points MID = 3.0

(mean: 38.1 paz / 35.6 sun) MTS - Favoured pazopanib by 0.38

(mean: 0.40 paz / 0.78 sun) H - Favoured pazopanib by 0.08

(mean: 0.21 paz / 0.29 sun) F - Favoured pazopanib by 0.16

(mean: 0.36 paz / 0.52 sun) MTS - Favoured pazopanib by 0.60

(mean: 14.32 paz / 13.72 sun) F - Favoured pazopanib by 0.58

(mean: 13.82 paz / 13.24 sun)

P-value

0.002 <0.001

0.026

0.005

<0.001

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

Treatment naïve (n=233) All patients (n=435)

PFS (Independent) pazopanib vs. placebo 1

PFS: 11.1m vs. 2.8m

HR 0.40 (0.27-0.60) p<0.0001

PFS: 9.2m vs. 4.2m

HR 0.46 (0.34-0.62) p<0.0001

ORR (independent) pazopanib vs. placebo

32% vs. 4% p<0.001

30% vs. 3% p<0.001

1

• Pazopanib has a well characterised and manageable safety profile in advanced RCC 1,2 • Most adverse events in the pazopanib group were grade 1 or 2 1,2 • Low incidence of grade 3 or 4 fatigue, hand-foot syndrome and mucositis/stomatitis 1,2 • The most common grade 3/4 laboratory abnormalities were ALT and AST elevations 1,2 • Low incidence of grade 3/4 haematological adverse events 1,2 • Pazopanib maintained health-related quality of life compared with placebo 1 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 data

1 P azopan I b versus S unitinib patient preferen CE S tudy in treatment naïve locally advanced or metastatic renal cell carcinoma 1

• 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.

50 40 30 20 10 0 100 90 80 70 60

The COMPARZ results complement the PISCES data – continued

1 90% CI (for difference): 37.0%-61.5%; p<0.001

70% (n=80)

Preferred pazopanib

22% (n=25)

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 – continued

1

• 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.

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

Each tablet contains 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 mild/moderate impairment. Mild impairment - 800mg once daily; Moderate impairment 200mg once daily.

Contra-indications

Elderly

with caution and close monitoring in : Limited data in patients ≥ 65 yrs.

Paediatrics

children <2 yrs. Safety & efficacy not established in children 2-18 yrs; no data available.

Hypersensitivity to active substance or excipients.

: Not to be used in

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 ≤Grade 1. If transaminases >8xULN, interrupt pazopanib until they return to ≤Grade 1. If transaminases ≤8xULN, continue pazopanib with weekly monitoring until they return to >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.

Posterior reversible encephalopathy Hypertension:

hypertensive crisis, have occurred in pazopanib studies. Control BP prior to initiating pazopanib. Monitor for hypertension early Events of hypertension, including (≤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.

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 pre existing 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.

dysfunction and manage as per standard medical practice.

Grade 4 proteinuria develops.

Pneumothorax Proteinuria 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 : Baseline and periodic urinalysis recommended. Monitor patients for worsening proteinuria. Discontinue pazopanib if : Observe patients closely for signs and symptoms of pneumothorax.

reported.

Interactions

Infection

s: Cases of serious infection (with/without neutropenia) Avoid concomitant use with strong inhibitors of CYP3A4, p glycoprotein (P-gp) or breast cancer resistance protein (BCRP) and CYP3A4 inducers.

Hyperglycaemia observed during concomitant administration with ketoconazole. Avoid co administration with medicines that increase gastric pH (e.g. PPIs and H caution. Avoid grapefruit juice during pazopanib treatment.

2 receptor antagonists) unless medically necessary. Undertake concomitant administration with uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1) substrates and simvastatin (and other statins) with

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.

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

Undesirable effects

to pazopanib Most important serious ADRs associated with 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:

Common

Very common: Decreased appetite; Dysgeusia; Hypertension; Diarrhoea, nausea, vomiting, abdominal pain; Hair colour changes; Fatigue; Increased ALT and AST.

: 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, failure, Increased hepatitis; creatinine/bilirubin/lipase/BP/TSH/GGT.

jaundice; Photosensitivity 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

reaction,

Uncommon

skin

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 exfoliation; Menorrhagia, No specific antidote. Treatment should consist of general supportive measures.

400mg x 30 tablet pack £1121.00.

Basic NHS Cost

200mg x 30 tablet pack

Marketing authorisation (MA) nos.

£560.50.

EU/1/10/628/001-4

.

MA holder

Glaxo Group Limited, Berkeley Avenue, Greenford, Middlesex UB6 ONN.

category

POM. UK/PAZ/0012/13. January 2013.

Legal 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

Park West, Uxbridge, Middlesex UB11 1BT; [email protected]; Freephone: 0800 221 441. Customer Contact Centre, GlaxoSmithKline, Stockley 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 days 1 – Used previously to evaluate fatigue with anti-angiogenesis treatments, including assessments for sunitinib 2,3 •

FKSI-19 (validated)

– A disease-specific measure that measures disease and treatment related symptoms specifically in renal cancer patients 4,5,6 – 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 sub study

EQ5D data from PISCES

1 • 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