Presentation on theme: "NOTE FOR HEALTHCARE PROFESSIONAL"— Presentation transcript:
1NOTE FOR HEALTHCARE PROFESSIONAL This presentation has been provided to you uponrequest. If presenting this to other healthcareprofessionals, GSK advises that you use thepresentation in full to ensure a fair balance ofInformation.Please delete this slide before presenting
2COMPARZ Results COMParing the efficacy, sAfety and toleRability of paZopanib vs. sunitinib in first-line advanced and/or metastatic renal cell carcinoma VEG108844Insert: Presenter nameInsert: Job role and place of workInsert: Date of presentationGSK has been involved in the preparation of this presentationPrescribing information can be found at the end of the main presentationUK/PAZ/0029/13 February 2013
3High-dose interleukin-2 Treatment options for advanced RCC have been revolutionised in a short period of time…Bevacizumab + IFN-αTimelines based on EMA approvalSorafenibPazopanibTemsirolimusHigh-dose interleukin-2AxitinibSunitinibEverolimusIFN-αEMA = European Medicines Agency
4Pazopanib indicationPazopanib 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 disease1Pazopanib’s licence is conditional pending further clinical data from GSK, including the outcome of COMPARZ1. Votrient Summary of Product Characteristics. January 2013.
5Pazopanib NICE Technology Appraisal Guidance (TA 215)1 Pazopanib is recommended as a first-line treatment option for people with advanced renal cell carcinomawho have not received prior cytokine therapy and have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1andunder 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 trial1. NICE. Pazopanib for the first-line treatment of advanced renal cell carcinoma. Final appraisal guidance no February 2011.
6Pazopanib 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
8Rationale COMPARZ was initiated in 2008 Provide comparative data to inform and aid prescribers and payersIn 2010 pazopanib was granted a conditional approval in the EU based on the VEG data (pazopanib vs. placebo)1As COMPARZ was already underway it became part of the obligation of the conditional approvalSternberg CN et al. J Clin Oncol 2010;28:
9Primary endpoint obligations Protocol-defined primary endpointNon inferiority in PFS at a margin of 1.25 (upper 95% CI)EMA-defined primary endpointNon inferiority in PFS at a margin of 1.22 (upper 95% CI)Linked to pazopanib’s conditional marketing authorisationSubsequently linked to pazopanib’s NICE and SMC guidanceEMA, NICE and SMC have been informed of the results and GSK await to hear from them
12Study design1 Pazopanib 800 mg OD Continuous dosing Sunitinib 50 mg OD Key Eligibility CriteriaAdvanced/metastatic RCCClear-cell histologyNo prior systemic therapyMeasurable disease (RECIST 1.0)KPS ≥ 70Adequate organ functionN=1110Randomised1:1Sunitinib 50 mg OD4 wk on/2 wk offStratification factors:Karnofksy Performance Status (KPS; vs )Prior nephrectomy (yes vs. no)Baseline lactate dehydrogenase (LDH; >1.5 vs. ≤1.5 x ULN)Motzer R, et al. ESMO 2012 oral presentation; abstract LBA8_PR.
13EndpointsPrimaryNon-inferiority in progression free survival (PFS) between pazopanib and sunitinibSecondaryOverall survival (OS)Objective response rate (ORR)Duration of responseTime to responseSafetyQuality of Life (QoL)Medical resource utilisationMotzer R, et al. ESMO 2012 oral presentation; abstract LBA8_PR.
14Why did GSK use a non-inferiority trial design? To establish that the efficacy of pazopanib is non inferior to sunitinibA 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 amount1This amount is known as the non-inferiority marginTo 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)CHMP. Guideline on the choice of the non-inferiority margin. EMEA 2005.
15Why did GSK use a non-inferiority trial design? Non-inferiority shownInferiority shownNew agent better1New agent worseTreatment difference Hazard Ratio (HR)1.25With a margin of 1.25, at least 631 PFS events (independently reviewed) were required to provide 80% powerGSK took the risk to evaluate pazopanib vs. the standard of care
16Study assessments1 Disease assessments (CT/MRI) performed at: BaselineEvery 6 weeks to week 24Every 12 weeks thereafter until disease progression, death or unacceptable toxicityOther assessments performed in 6-week cyclesSafetyBaseline, day 28 & day 42 of every cycle through to cycle 9, day 42 of every cycle from cycle 10Patient-reported outcomesBaseline (except for CTSQ), day 28 every cycle through to cycle 9, day 42 of every cycle from cycle 10FACIT-FatigueFunctional Kidney Symptom Index (FKSI-19)Cancer Therapy Satisfaction Questionnaire (CTSQ)Supplementary Quality of Life Questionnaire (SQLQ)Motzer R, et al. ESMO 2012 oral presentation; abstract LBA8_PR
23No significant difference in OS between pazopanib and sunitinib (interim analysis) OS HR (95% CI ): ( ); p=0.275NMedian months OS (95% CI)Pazopanib55728.4 ( )Sunitinib55329.3 ( )PazopanibSunitinibBased on 502death events(May 2012)Motzer R, et al. ESMO 2012 oral presentation; abstract LBA8_PR.
24Most common adverse events ≥30%1 (treatment-emergent) Pazopanib (n = 554) %Sunitinib (n = 548) %All GrsGr 3/4Any event a>9959/1557/17Diarrhea639/0577/<1Fatigue5510/<117/<1Hypertension4615/<141Nausea452/0Decreased appetite371/03/0ALT increased3110/2182/<1Hair colour changes300/010<1/0Hand-foot syndrome296/05011/<1Taste Alteration2636Thrombocytopenia3412/4a 2% of patients in pazopanib arm and 3% of patients in sunitinib arm had grade 5 adverse events.Motzer R, et al. ESMO 2012 oral presentation; abstract LBA8_PR.24
25Most common adverse events ≥30%1 (treatment-emergent) Pazopanib(n = 554) %Sunitinib(n = 548) %All GradesAny event a>99Diarrhea6357Fatigue55Hypertension4641Nausea45Decreased appetite37ALT increased3118Hair colour changes3010Hand-foot syndrome2950Taste alteration2636Thrombocytopenia34a 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 1Motzer R, et al. ESMO 2012 oral presentation; abstract LBA8_PR.25
27Laboratory abnormalities (≥35%)1 Chemistry labsPazopanib (n = 554), %Sunitinib (n = 548),%All GradesALT6043AST61Hypoalbuminaemia3342Bilirubin3627Creatinine3246Hyperglycaemia5457Hyponatraemia35Hypophosphataemia52Haematology labsLeukopenia78Neutropenia3768Thrombocytopenia41Lymphopenia3855Anaemia31Blue 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 1Motzer R, et al. ESMO 2012 oral presentation; abstract LBA8_PR.
28Relative Risk in Adverse Events AE occurrence ≥10% in either arm; 95% CI for RR does not cross 1 1Adverse eventRelative risk (95% CI)Hair colour changeWeight decreasedSerum ALT increasedAlopeciaUpper abdominal painSerum AST increasedFatigueRashPain in extremityConstipationTaste alterationLDH increasedSerum creatinine increasedPeripheral oedemaHand-foot syndromeDyspepsiaPyrexiaLeukopeniaHypothyroidismEpistaxisSerum TSH increasedMucositisNeutropeniaAnaemiaThrombocytopeniaNote: AEs >10% where there was nostatistical difference in incidencebetween the arms are not included onthe graph:Diarrhoea / hypertension / nausea /decreased appetite / bilirubin / albumin /hyperglycaemiaForest plotTo 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 1Favours pazopanibFavours sunitinibLog scaleMotzer R, et al. ESMO 2012 oral presentation; abstract LBA8_PR.
29Treatment 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, %4451Discontinuations due to AEsa, %2419a. Most common reason: pazopanib arm (liver event, 6%); sunitinib arm (cytopenia, 3%)Motzer R, et al. ESMO 2012 oral presentation; abstract LBA8_PR.
30Quality of Life Results (first 6 monthsa)1 InstrumentDomain DescriptionTreatment difference: mean change from baseline bReported MIDsP-valueFACIT-FFatigue/Total score2.323<0.001FKSI-19Kidney Symptom Index/Total score1.4150.018Physical0.780.027Emotional0.05N/A0.409Treatment Side Effects0.310.033Functional Well Being0.098Cancer Treatment SatisfactionQuestionnaire (CTSQ)Expectations of Therapy8.30.284Feelings about Side Effects8.5010.3Satisfaction with Therapy3.215.9Supplementary Quality of Life Questionnaire (SQLQ)*Worst mouth/throat soreness0.505<0.0001Worst foot soreness0.2040.0016Worst hand soreness0.2670.0008Limitations due to mouth/throat soreness0.94Limitations due to foot soreness0.650.014a 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.Motzer R, et al. ESMO 2012 oral presentation; abstract LBA8_PR.
31FACIT-Fatigue results up to cycle 81 Quality of Life:FACIT-Fatigue results up to cycle 81Measured day 28 every cycle (end of sunitinib 4-week on cycle)Motzer R, et al. ESMO 2012 oral presentation; abstract LBA8_PR.
32Health-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 carcinomaInstrumentDomain nameScaleResults (cross-over analyses)1,2P-valueFACIT-FFatigue/Total score0-3Favoured pazopanib by 2.5 pointsMID = 3.0(mean: 38.1 paz / 35.6 sun)0.002SQLQThree items on Mouth and Throat Soreness (MTS), Hand soreness (H) and Foot soreness (F)MTS - Favoured pazopanib by 0.38(mean: 0.40 paz / 0.78 sun)<0.001H - Favoured pazopanib by 0.08(mean: 0.21 paz / 0.29 sun)0.026F - Favoured pazopanib by 0.16(mean: 0.36 paz / 0.52 sun)0.005Two items on limitations due to MTS and F0-15MTS - Favoured pazopanib by 0.60(mean: paz / sun)F - Favoured pazopanib by 0.58(mean: paz / sun)0.003QoL assessments in PISCES were measured every 2 weeksEscudier BJ, Porta C, Bono P, et al. Abstract and oral presentation at the American Society of Clinical Oncology Annual Congress J Clin Oncol 2012; 30 (suppl.): Abstract CRA4502.Clinical results summary for VEG GSK clinical trials register:B49&compound=pazopanib
34ConclusionsLargest head-to-head study in advanced RCC, demonstrates non-inferiority of pazopanib relative to sunitinib for progression-free survival(HR: 1.047; 95% CI: ) (independent review)Both the protocol-defined and EMA-defined primary endpoints have been metPazopanib efficacy is further supported by similar overall survival and higher response ratesPazopanib and sunitinib achieved more than 2 years median interim OS (28.4 months vs 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 mucositisLower incidence of haematological toxicitiesHigher incidence of liver function test abnormalitiesQoL assessment favours pazopanib over sunitinib on the majority (11/14) of the QoL scales for patients receiving pazopanib
35The COMPARZ results complement the data from the registrational trial PFS (Independent)pazopanib vs. placebo1Treatment-naïve (n=233)PFS: 11.1m vs. 2.8mHR 0.40 ( ) p<0.0001All patients (n=435)PFS: 9.2m vs. 4.2mHR 0.46 ( ) p<0.0001ORR (independent)pazopanib vs. placebo132% vs. 4%p<0.00130% vs. 3%Pazopanib has a well characterised and manageable safety profile in advanced RCC1,2Most adverse events in the pazopanib group were grade 1 or 21,2Low incidence of grade 3 or 4 fatigue, hand-foot syndrome and mucositis/stomatitis1,2The most common grade 3/4 laboratory abnormalities were ALT and AST elevations1,2Low incidence of grade 3/4 haematological adverse events1,2Pazopanib maintained health-related quality of life compared with placebo1Sternberg CN, Davis ID, Mardiak J, et al. J Clin Oncol 2010; 28: 1061–1068.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.
36The COMPARZ results complement the PISCES data1 PazopanIb versus Sunitinib patient preferenCE Study intreatment naïve locally advanced or metastatic renal cell carcinoma1Randomised, double-blind, cross-over study over a 22 week periodTotal 168 patients randomised; 114 patients in primary analysis populationPatients completed the patient preference questionnaire at the end of the study before unblinding1. Escudier BJ, Porta C, Bono P, et al. Abstract and oral presentation at the American Society of Clinical Oncology Annual Congress J Clin Oncol 2012; 30 (suppl.): Abstract CRA4502.
37The COMPARZ results complement the PISCES data – continued1 Patients (%)90% CI (for difference): 37.0%-61.5%; p<0.00170%(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)1. Escudier BJ, Porta C, Bono P, et al. Abstract and oral presentation at the American Society of Clinical Oncology Annual Congress J Clin Oncol 2012; 30 (suppl.): Abstract CRA4502.
38The COMPARZ results complement the PISCES data – continued1 The most important symptom which influenced this preferencePazopanib: 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 J Clin Oncol 2012; 30 (suppl.): Abstract CRA4502.
39Posology and special warnings (1)1 Please refer to full SmPC before prescribingVotrient tablets should be taken800mg dailyWhole (not broken or crushed)Without food - at least 1 hour before or 2 hours after a mealDose modificationsShould be in 200mg decrements/incrementsDrug interactionsThe 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 monitoringRenal impairmentNo dose adjustment is required in patients with creatinine clearance >30 ml/minCaution is advised in patients with creatinine clearance <30 ml/min1. Pazopanib Summary of Product Characteristics. January 2013.
40Posology and special warnings (2)1 Hepatic impairment & hepatic effectsCases of hepatic failure have been reported during Votrient useVotrient is not recommended in patients with severe hepatic impairmentUse with caution and close monitoring in patients with mild or moderate hepatic impairmentPatients with mild hepatic impairment should be treated with 800mg once dailyA reduced dose of 200 mg once daily is recommended in moderate hepatic impairmentSerum 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.HypertensionBlood pressure should be well controlled prior to initiating VotrientPatients should be monitored for hypertension within 1 week of starting treatment and frequently thereafter to ensure blood pressure controlHypertension 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 reduction1. Pazopanib Summary of Product Characteristics. January 2013.
41Posology and special warnings (3)1 PRES / RPLSPosterior 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 fatalPatients developing PRES/RPLS should permanently discontinue pazopanibCardiac dysfunction/heart failureThe 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 studiedIn 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 dysfunctionBaseline & periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunctionPatients should be carefully monitored for clinical signs or symptoms of congestive heart failureInterruption of Votrient and/or dose reduction should be combined with treatment of hypertension in patients with significant reductions in LVEF, as clinically indicatedThrombotic microangiopathy (TMA)Thrombotic microangiopathy (TMA) has been reported in clinical trials of pazopanib as monotherapy, in combination with bevacizumab, and in combination with topotecanPatients developing TMA should permanently discontinue pazopanib; reversal of effects of TMA has been observed after pazopanib treatment was discontinued1. Pazopanib Summary of Product Characteristics. January 2013.
42Posology and special warnings (4)1 Other warningsEvents 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 pneumothoraxVenous 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 surgeryHypothyroidism 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 proteinuriaCases of serious infection (with/without neutropenia) have been reportedCombination with other systemic anti-cancer therapies: Safe and effective dose in combination with pemetrexed or lapatinib has not been established1. Pazopanib Summary of Product Characteristics. January 2013.
43Posology 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 reductionIn patients with wound dehiscenceIn patients with grade 4 proteinuriaIn patients developing PRES/RPLS or TMASerious adverse events have been associated with Votrient, with the most important events each being reported in <1% of treated patients1. Pazopanib Summary of Product Characteristics. January 2013.
44Prescribing Information (Please refer to full SmPC before prescribing) 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 £ mg x 30 tablet pack £ Marketing authorisation (MA) nos. EU/1/10/628/ MA holder Glaxo Group Limited, Berkeley Avenue, Greenford, Middlesex UB6 ONN. Legal category POM. UK/PAZ/0012/13. January 2013.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 adequateAdverse events should be reported. Reporting forms and information can be found at:Adverse events should also be reported to GlaxoSmithKline onFurther information is available from Customer Contact Centre, GlaxoSmithKline, Stockley Park West, Uxbridge, Middlesex UB11 1BT; Freephone: Votrient is a trademark of the GlaxoSmithKline group of companies.
46Patient reported outcome tools FACIT-Fatigue (validated)Measures severity and impact of fatigue on functioning and HRQoL experienced in past seven days1Used previously to evaluate fatigue with anti-angiogenesis treatments, including assessments for sunitinib2,3FKSI-19 (validated)A disease-specific measure that measures disease and treatment-related symptoms specifically in renal cancer patients4,5,6Includes 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.Cella D, Lai J, Chang C, et al. Fatigue in cancer patients compared with fatigue in general United States population. Cancer; 2002;94:Motzer RJ et al. Sunitinib malate shows anti-tumor activity in patients with metastatic renal cell carcinoma; updated results from phase II trials. European Cancer Conference, Abstract 797. Paris, France. Oct. 30-Nov. 3, 2005Beaumont J, et al. Efficacy and patient reported outcomes of sunitinib malate in 3 phase II trials in advanced RCC, GIST, and NET. International Congress on Anti-Cancer Treatment, Jan. 2006, Paris.Rosenbloom S.K, Beaumont J, Diaz P, et al. (). Patient-centered validation of 11 symptom indices to evaluate response to chemotherapy for advanced cancer. J. Clin. Oncol., ASCO Annual Meeting Proceedings (Post-Meeting Edition). 2007; 25, No 18S (June 20 Supplement): 6524.Rosenbloom SK, Yount SE, Yost, KJ, et al. Development and Validation of Eleven Symptom Indices to Evaluate Response to Chemotherapy for Advanced Cancer: Measurement Compliance with Regulatory Demands. In, The Value of Innovation: Impacts on Health, Life Quality, and Regulatory Research. Farquhar I, Summers K, and Sorkin A (Eds.); Oxford: Elsevier (in press).Rao, D., Butt, Z., Rosenbloom, S., Robinson, D., Von Roenn, J., Kuzel, T., & Cella, D. A comparison of the Renal Cell Carcinoma Symptom Index (RCC-SI) and the Functional Assessment of Cancer Therapy - Kidney Symptom Index (FKSI) (manuscript in preparation).1. Cella, Motzer, Beaumont, Rosenbloom, Rosenbloom, Rao, 2008
47Patient 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.)1Supplementary 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 2-5One 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)6Abetz. Development of the cancer therapy satisfaction questionnaire: item generation and content validity testing. Value in Health, 2005:8:S41.Abrams SK, Hays RD. Health-related quality of life in cancer patients with oral mucositis. Presented at the 24th Annual Scientific Meeting of the American Pain Society, Boston, MA, March 30-April 2, 2005 (abstract).Stiff PJ, Emmanouilides C, Bensinger WI, et al. Palifermin reduces patient-reported mouth and throat soreness and improves patient functioning in the hematopoietic stem cell transplantation setting. J. Clin. Oncol. 2006a; 24:Stiff PJ, Erder H, Bensinger WI, et al: Reliability and validity of a patient self administered daily questionnaire to assess impact of oral mucositis (OM) on pain and daily functioning in patients undergoing autologous hematopietic stem cell transplantation (HSCT). Bone Marrow Transplant. 2006b; 37:Syrjala K, Hays RD, Kallich JD, et al: Impact of oral mucositis and its sequelae on quality of life. Blood 102:751a, 2003 (abstract 2771).National Center for Health Statistics, Hyattsville, MD. National Health and Nutrition Examination Survey (NHANES),1. Abetz, 2005; 2. Abrams, 2005 ; 3. Stiff, 2006a ; 4. Stiff, 2006b; 5. Syrjala, 2003 ; 6. National Center for Health Statistics,
48Relative Risk in Adverse Events AE occurrence ≥10% in either arm; 95% CI for RR does not cross 1Forest plotTo 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
49VEG Asian sub-studyCOMPARZ was originally designed with a non-inferiority margin (upper bound 95% CI) of 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 eventsThe trials were designed almost identically and therefore the studies could be combined for analysis without statistical concernAsian 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 groupsAdditional 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 progressionExclusion due to discordance between the independent review and investigator assessments of progressionThe analysis for COMPARZ is based on 927 patients plus 183 from the Asian sub- study
50EQ5D data from PISCES1The EQ-5D data presented at ESMO 2012 were inconclusiveEQ-5D assessment showed that utility scores deteriorated in pazopanib-treatedpatients in treatment period 1, but the deterioration in period 2 was numericallygreater in sunitinib-treated patients compared with those on pazopanibCella 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 Abstract no. 792PD