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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…

EMA = European Medicines Agency

High-dose interleukin-2

Sorafenib

IFN-α

1992-2005 2005 2006 2007 2008 2009 2010 2011 2012

Sunitinib

Bevacizumab + IFN-α

Temsirolimus

Pazopanib

EverolimusAxitinib

Timelines based on EMA approval

Pazopanib indication

1. Votrient Summary of Product Characteristics. January 2013.

• 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

Pazopanib NICE Technology Appraisal Guidance (TA 215)1

1. NICE. Pazopanib for the first-line treatment of advanced renal cell carcinoma. Final appraisal guidance no. 215. February 2011.

• 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

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

1. Sternberg CN et al. J Clin Oncol 2010;28:1061-1068.

• 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

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

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1. Motzer R, et al. ESMO 2012 oral presentation; abstract LBA8_PR.

Randomised 1:1

N=1110

Sunitinib50 mg OD

4 wk on/2 wk off

Pazopanib800 mg OD

Continuous dosing

Study design1

• 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)

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

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

Endpoints


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?

• 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

Non-inferiority shown

Inferiority shown

New agentbetter

1 New agentworse

Treatment difference Hazard Ratio (HR)

1.25

• 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

Study assessments1

Results

Key baseline characteristics1

Pazopanib (n=557) Sunitinib (n=553)

Age, median years (range) 61 (18-88) 62 (23-86)

Male, % 71 75

Prior nephrectomy, %* 82 84

KPS, %*

90-100% 75 76

70-80% 25 24

LDH,%*

≤1.5 x ULN 93 95

>1.5 x ULN 7 5

MSKCC risk category, %

Favourable 27 27

Intermediate 58 59

Poor 12 9

Unknown 3 4

* Stratification factor


Key baseline characteristics (cont’d)1

Pazopanib (n=557) Sunitinib (n=553)

Number of organs involved, %

1 or 2 58 56

≥3 42 44

Most common metastatic site, %

Lung 76 77

Lymph node 40 45

Bone 20 15

Liver 15 20


N Median months PFS (95% CI)

Pazopanib 557 8.4 (8.3-10.9)

Sunitinib 553 9.5 (8.3-11.1)


Primary endpoint: Pazopanib is non-inferior to sunitinib (independent review)

PazopanibSunitinib

PFS HR (95% CI): 1.047 (0.898-1.220)

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)

PazopanibSunitinib


Pazopanib (n=557) Sunitinib (n=553)0

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60

80

100

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p=0.032

Response rate (independent review)


Best overall response, %

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

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)

PazopanibSunitinib


Based on 502death events (May 2012)

Most common adverse events ≥30%1 (treatment-emergent)

Adverse Event

Pazopanib (n = 554) % 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.


Most common adverse events ≥30%1 (treatment-emergent)

Adverse Event

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 34a 2% of patients in pazopanib arm and 3% of patients in sunitinib arm had grade 5 adverse eventsBlue Highlight: Risk greater for sunitinib and 95% CI for relative risk does not cross 1Yellow highlight: Risk greater for pazopanib and 95% CI for relative risk does not cross 1


Laboratory abnormalities (≥35%)1

Chemistry labs (≥35%)

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

Haematology labs

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


Laboratory abnormalities (≥35%)1

Chemistry labs

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

Haematology labs

Leukopenia 43 78

Neutropenia 37 68

Thrombocytopenia 41 78

Lymphopenia 38 55

Anaemia 31 60

Blue Highlight: Risk greater for sunitinib and 95% CI for relative risk does not cross 1Yellow highlight: Risk greater for pazopanib and 95% CI for relative risk does not cross 1


Hair colour changeWeight decreasedSerum ALT increasedAlopeciaUpper abdominal painSerum AST increasedFatigueRashPain in extremityConstipationTaste alterationLDH increasedSerum creatinine increasedPeripheral oedemaHand-foot syndromeDyspepsiaPyrexiaLeukopeniaHypothyroidismEpistaxisSerum TSH increasedMucositisNeutropeniaAnaemiaThrombocytopenia

Relative Risk in Adverse EventsAE occurrence ≥10% in either arm; 95% CI for RR does not cross 1 1

Favours pazopanib Favours sunitinib


Note: AEs >10% where there was no statistical difference in incidence between the arms are not included onthe graph:Diarrhoea / hypertension / nausea / decreased appetite / bilirubin / albumin / hyperglycaemia

Relative risk (95% CI)Adverse event

Log scale

Treatment duration and dose adjustments1

Pazopanib (n = 554)

Sunitinib(n = 548)

Median duration of treatment (months, range)

8.0 (0−40) 7.6 (0−38)

Dose reductions, % 44 51

Discontinuations due to AEsa, % 24 19

a. Most common reason: pazopanib arm (liver event, 6%); sunitinib arm (cytopenia, 3%)


Quality of Life Results (first 6 monthsa)1

Instrument Domain Description Treatment difference: mean change from baseline b

Reported MIDs P-value

FACIT-F Fatigue/Total score 2.32 3 <0.001

FKSI-19

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

Cancer Treatment SatisfactionQuestionnaire (CTSQ)

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

Supplementary Quality of Life Questionnaire (SQLQ)*

Worst mouth/throat soreness 0.505 N/A <0.0001

Worst foot soreness 0.204 N/A 0.0016

Worst hand soreness 0.267 N/A 0.0008

Limitations due to mouth/throat soreness

0.94 N/A <0.001

Limitations due to foot soreness 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 81


Measured day 28 every cycle (end of sunitinib 4-week on cycle)

Health-related quality of life in PISCES1

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

Instrument Domain name Scale Results (cross-over analyses)1,2 P-value

FACIT-F Fatigue/Total score0-3

Favoured pazopanib by 2.5 pointsMID = 3.0

(mean: 38.1 paz / 35.6 sun)0.002

SQLQ

Three items on Mouth and Throat Soreness (MTS), Hand soreness (H) and Foot soreness (F)

0-3 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

Two items on limitations due to MTS and F

0-15 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

A randomised, double-blind, cross-over patient preference study of pazopanib vs.sunitinib in treatment-naïve locally advanced or metastatic renal cell carcinoma

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

Treatment-naïve (n=233)

PFS: 11.1m vs. 2.8m HR 0.40 (0.27-0.60) p<0.0001

All patients (n=435)

PFS: 9.2m vs. 4.2mHR 0.46 (0.34-0.62) p<0.0001

ORR (independent)pazopanib vs. placebo1

32% vs. 4% p<0.001

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


The COMPARZ results complement the PISCES data – continued1

Preferred pazopanib Preferred sunitinib No preference0

10

20

30

40

50

60

70

80

90

100

Patie

nts

(%)

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

70%(n=80)

22%(n=25)

8%(n=9)

*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)


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%


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.


• 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



• 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



• 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



• 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


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 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. 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, 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 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 treatment-

related 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 EventsAE 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 PISCES1

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

• 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

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