Pazopanib for the first-line treatment of advanced renal cell carcinoma

Evidence-based recommendations on pazopanib (Votrient) for previously untreated advanced renal cell carcinoma in adults.

# Guidance
This guidance has been re-issued after a change to the patient access scheme (August 2013). Part B of the patient access scheme will not be activated. Reference to part B of the patient access scheme has been removed from the recommendations. Reference to it elsewhere in the document should be considered obsolete.
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
if the manufacturer provides pazopanib with a 12.5% discount on the list price as agreed in the patient access scheme.
When using ECOG performance status, healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect ECOG performance status and make any adjustments they consider appropriate.
People who are currently being treated with pazopanib for advanced metastatic renal cell carcinoma but who do not meet the criteria in 1.1 should have the option to continue their therapy until they and their clinicians consider it appropriate to stop.# The technology 
Pazopanib (Votrient, GlaxoSmithKline) is an orally administered tyrosine kinase inhibitor. It inhibits vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptors on cancer cells, vascular endothelial cells and pericytes, stopping the proliferation of tumour cells and the development of tumour blood vessels. Pazopanib has a conditional marketing authorisation for 'the first-line treatment of advanced renal cell carcinoma and for patients who have received prior cytokine therapy for advanced disease'. The conditional marketing authorisation is linked to the provision of further data including the outcome of the ongoing head-to-head non-inferiority trial of pazopanib versus sunitinib in patients with advanced renal cell carcinoma (COMPARZ). Only the indication for pazopanib for the first-line treatment of advanced renal cell carcinoma is within the remit of the appraisal.
Pazopanib is contraindicated in people who have hypersensitivity to the active substance or to any of the excipients, and people with severe hepatic impairment. The summary of product characteristics lists the adverse events that may be associated with pazopanib treatment, the most common being diarrhoea, hair colour changes, hypertension, nausea, anorexia, vomiting, fatigue, taste disturbance or loss of taste, and abnormal liver function. For full details of side effects and contraindications, see the summary of product characteristics.
Pazopanib is administered orally. The recommended dosage is 800 mg once daily. The dose may be adjusted in steps of 200 mg according to tolerability in order to manage adverse reactions but should not exceed 800 mg. The price for a pack of 400 mg tablets (30 tablets per pack) is 1121.00 (MIMS, November 2010). The daily cost of pazopanib is 74.73 as stated by the manufacturer. The manufacturer of pazopanib has agreed a two-part patient access scheme with the Department of Health. Part A of the patient access scheme provides a 12.5% discount from the list price. Therefore the daily acquisition cost of pazopanib is 65.39. Part B of the patient access scheme, the details of which are 'commercial in confidence', offers a future rebate linked to the outcome of the head-to-head COMPARZ trial. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.# The manufacturer's submission
The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of pazopanib and a review of this submission by the Evidence Review Group (ERG; appendix B).
The manufacturer presented evidence on the clinical effectiveness of pazopanib used in line with the conditional marketing authorisation and the appraisal scope. The main clinical-effectiveness evidence came from patients in the treatment-naive subgroup of a phase III randomised controlled trial (RCT). The RCT, VEG105192, compared the effect of a once-daily dose of pazopanib plus best supportive care (155 patients) with placebo plus best supportive care (78 patients). Best supportive care was defined as the monitoring of progression, symptom control and palliative care without active treatment. The trial was conducted in patients with advanced renal cell carcinoma with predominantly clear cell histology. All patients had a good performance status (ECOG performance status 0 or 1) at the start of the trial. Baseline characteristics of the patients in the two treatment arms were equally balanced.
The primary outcome in the study was progression-free survival, which was defined as time from randomisation to disease progression or death. Tumour assessments were performed using RECIST (Response Evaluation Criteria in Solid Tumours) and were confirmed by an independent review committee. Once disease progression was confirmed, patients who previously received placebo plus best supportive care could be offered open-label pazopanib plus best supportive care in the open-label extension study (VEG107769) if the treating clinician thought this was in the best interests of the patient. At disease progression, only patients with an ECOG performance status of less than or equal to 2 were permitted to cross over to receive pazopanib. The median progression-free survival was statistically significantly longer in patients receiving pazopanib (p < 0.001). The median progression-free survival was 11.1 months (95% confidence interval  7.4 to 14.8) for patients receiving pazopanib plus best supportive care and 2.8 months (95% CI 1.9 to 5.6) for patients receiving placebo plus best supportive care (hazard ratio  0.40, 95% CI 0.27 to 0.60) based on blinded imaging assessment by the Independent Review Committee. This meant there was a 60% reduction in risk of disease progression for patients receiving pazopanib plus best supportive care compared with those receiving placebo plus best supportive care at the final analysis. The manufacturer performed sensitivity analyses of progression-free survival based on actual scan dates and investigators' assessment to confirm the robustness of the findings. The median progression-free survival based on actual scan dates was 10.8 months (95% CI 7.4 to 14.8) for patients receiving pazopanib plus best supportive care and 2.9 months (95% CI 1.9 to 5.4) for patients receiving placebo plus best supportive care (HR 0.36, 95% CI 0.24 to 0.55). These latter estimates were used in the indirect comparison.
At the time of the interim overall survival analysis (23 May 2008), 31 of 78 (40%) treatment-naive patients randomised to receive placebo in the VEG105192 trial had crossed over to receive pazopanib. At the final analysis (15 March 2010), a total of 40 (51%) treatment-naive patients randomised to placebo had crossed over to receive pazopanib. Overall survival for the treatment-naive, intention-to-treat population, unadjusted for crossover, was 22.9 months (95% CI 17.6 to 25.4 months) for patients randomised to pazopanib plus best supportive care and 23.5 months (95% CI 12.0 to 34.3 months) for patients randomised to placebo plus best supportive care. The hazard ratio for overall survival was 1.01 (95% CI 0.72 to 1.42, p = 0.525). The manufacturer presented a variety of methods to adjust for crossover when estimating median overall survival, including the inverse probability censoring weighted (IPCW) and rank preserved structural failure time (RPSFT) methods. The manufacturer considered the RPSFT weighted method to be the most appropriate because it was considered an acceptable approach for NICE technology appraisal guidance 179 ('Sunitinib for the treatment of gastrointestinal stromal tumours') and the ongoing technology appraisal 'Everolimus for the second-line treatment of advanced renal cell carcinoma'. The RPSFT weighted method estimated the overall survival of patients randomised to receive placebo assuming that they had not crossed over, that is, as if they had remained on placebo for the duration of the trial. The method proportionally 'shrunk' the estimated amount of additional survival given to patients who crossed over to receive pazopanib. The RPSFT analysis suggested that treatment with pazopanib was consistently associated with survival benefit compared with placebo (HR 0.501, 95% CI 0.136 to 2.348). The manufacturer also noted that the 0.501 hazard ratio lies within the range of estimates obtained from the different methods used to adjust for crossover. This hazard ratio was subsequently used for the indirect comparison.
No head-to-head trials analysing the efficacy of pazopanib compared with other active treatment options were available. Therefore, the manufacturer undertook a search for trials of comparator interventions and carried out an indirect comparison to estimate the relative effect of pazopanib versus the comparators (sunitinib, interferon- and best supportive care). Seven studies were included in the indirect comparison, including one study of pazopanib compared with placebo (VEG105192), one study of sunitinib compared with interferon- (Motzer et al. 2009) and five studies that directly compared interferon- with a non-interferon control therapy (medroxyprogesterone acetate and vinblastine). The populations in the pazopanib (VEG105192) and sunitinib (Motzer et al. 2009) studies were comparable, but with the exception that a higher proportion of patients with a baseline ECOG performance status of 0 were recruited to the sunitinib study than to the VEG105192 trial (approximately 60% versus 40%). Both studies restricted entry to patients with renal cell carcinoma with either clear cell or predominantly clear cell histology. The average age of patients in both studies was 60 years and 8391% of patients had prior nephrectomy. The patient populations in the five interferon- studies were generally similar. All patients had renal cell carcinoma, the age range was 6066 years and 57100% of patients had prior nephrectomy. Three of the interferon- studies included some patients with a baseline ECOG performance status of 2.
Hazard ratios for progression free survival and overall survival from all seven studies were used in the indirect comparison to obtain hazard ratios for pazopanib versus interferon- and pazopanib versus sunitinib. The hazard ratios for progression-free survival used in the indirect comparison for pazopanib versus placebo plus best supportive care, sunitinib versus interferon- and interferon- versus best supportive care were 0.36 (95% CI 0.24 to 0.55), 0.539 (95% CI 0.451 to 0.643) and 0.704 (95% CI 0.0.580 to 0.854). Median progression-free survival estimates derived from the indirect comparison for pazopanib, sunitinib, interferon- and placebo plus best supportive care were 11.3 months (95% CI 5.1 to 17.5), 10.7 months (95% CI 7.9 to 13.4), 5.4 months (95% CI 5.4 to 5.4) and 5.6 months (95% CI 4.0 to 7.3) respectively.
The pazopanib overall survival value was estimated using the RPSFT weighted method. The manufacturer used hazard ratios derived from all seven studies in a Weibull survival model to estimate the median overall survival values for pazopanib versus interferon- and pazopanib versus sunitinib. In the base-case scenario, derived using the RPSFT weighted method, the median overall survival estimates for pazopanib, sunitinib, interferon- and placebo plus best supportive care were 27.8, 26.8, 15.8 and 12.1 months, respectively. These results indicated that pazopanib was associated with a decreased risk of death (37% reduction) compared with interferon-, and that pazopanib appeared to have comparable efficacy with sunitinib in terms of overall survival. The manufacturer highlighted that the 95% confidence intervals around the hazard ratios were wide, indicating a level of uncertainty with the estimates. Sensitivity analyses were performed that included varying the hazard ratio for overall survival in the VEG105192 trial by using different methods for adjusting for crossover and varying the interferon- studies included. The manufacturer concluded that the results of these sensitivity analyses of the indirect comparison were similar to those of the base-case analysis.
Only the VEG105192 trial, which compared pazopanib and placebo, and the study by Motzer et al. (2009), which compared sunitinib with interferon-, reported health-related quality of life data. For the VEG105192 trial, there were no statistically significant differences between pazopanib and placebo for any of the instruments used (European Organisation for Research and Treatment of Cancer  quality of life questionnaire  Core 30, EQ-5D, EQ-5D-VAS). For the comparison of sunitinib with interferon-, patients receiving sunitinib had a statistically significantly better quality of life than patients receiving interferon-, as measured by the EQ-5D, EQ-5D-VAS and the Functional Assessment of Cancer Therapy (FACT) Kidney Symptom Index Disease-related Symptom (FKSI-DRS) Index, FACT-Kidney Symptom Index  15-item scale (FKSI-15 Index) and the FACT-General Scale (FACT-G). No indirect comparison was made for this outcome.
In the VEG105192 trial, 91% of patients receiving pazopanib experienced an adverse event. In 87% of patients the adverse events were related to study medication. In the placebo group 74% of patients experienced an adverse event and in 37% of patients these were related to study medication. The most frequent adverse events related to pazopanib treatment were diarrhoea, hair colour change, hypertension, nausea, anorexia and increased liver enzymes. The manufacturer conducted an indirect comparison using one of the interferon- studies to estimate the adverse event rates of pazopanib compared with sunitinb. The adverse event rates for pazopanib were generally lower than for sunitinib, in particular for dyspepsia, mucositis/stomatitis, fatigue, hand-foot syndrome, skin discolouration, hypophosphataemia, anaemia and altered taste. However, only the difference in fatigue was statistically significant (HR 0.21, 95% CI 0.06 to 0.77).
The manufacturer submitted an economic model to assess the cost effectiveness of pazopanib in treatment-naive patients. The model compared pazopanib with interferon-, sunitinib and best supportive care. The manufacturer described the model as a 'partitioned survival' model, characterised by three mutually exclusive health states: alive pre-progression, alive post-progression and dead. Unlike a Markov model, which models transitions between health states explicitly using transition probabilities, the partitioned survival model calculated the proportion of patients in each treatment arm at any time after starting treatment, using parametric survival curves fitted to empirical data on overall survival and progression-free survival over time. The proportion of patients in the 'alive post-progression' health state at any given time was calculated as the difference between overall survival and progression-free survival. In the model, pazopanib was assumed to be given until disease progression or death (if occurring before progression). After starting treatment, patients were assumed to be in an 'alive pre-progression' health state, and to be at risk of disease progression and/or death over time. Patients who experienced disease progression were assumed to discontinue treatment with pazopanib (and receive only best supportive care) and to transition to an 'alive post-progression' health state and to stay in that state until death.
For the model, a utility value of 0.70 was assumed for patients who had no disease progression and no adverse events, based on the mean EQ-5D utility value among patients without adverse events in the VEG105192 trial. Disease progression was assumed to be associated with a decrement in utility of 15% (that is, a post-progression utility value of 0.59). These values were used for all the interventions in the model. Utility decrements for adverse events were also obtained from the VEG105192 trial. As a result of the lack of published utility data in this patient population, the manufacturer commissioned a health state preference study to generate utility values for progression-free survival and post-progression survival and disutilities for treatment-related adverse events such as anaemia, diarrhoea, fatigue, hand-foot syndrome, nausea, mucositis and hypertension. The utility decrements for adverse events were used in a sensitivity analysis.
The manufacturer agreed a two-part patient access scheme with the Department of Health. Part A of the patient access scheme provides a 12.5% discount to the list price of pazopanib. Part B of the patient access scheme, the details of which are 'commercial-in-confidence', offers a future rebate linked to the outcome of the head-to-head COMPARZ trial. The manufacturer assumed that there would be no additional costs to the NHS associated with administering the patient access scheme. The costs considered in the economic model included acquisition costs for study medications, drug administration costs for infusions, costs of treating grade 3 or higher adverse events, routine follow-up costs, costs of progression and supportive care costs. In order to account for dose reductions and dose interruptions, the manufacturer adjusted the cost of study medication by using relative dose intensities reported in RCTs of the study treatments. In the model, the manufacturer used a dose intensity for pazopanib of 86%, equivalent to 688 mg per patient per day. Similar dose intensities were used for sunitinib (86%) and interferon- (84%). Only the costs of treating adverse events that were grade 3 or higher with an incidence of at least 5% were considered for any treatment based on the indirect comparison. The cost per event was assumed to be independent of treatment.
For part A of the patient access scheme, which provides a 12.5% discount to the pazopanib list price, sunitinib was extendedly dominated by a combination of pazopanib and interferon-. An option is 'extendedly dominated' when its ICER is higher than that of the next, more effective, option when compared with a common baseline (that is, it is dominated by a combination of two other alternatives). As a result, using the RPSFT weighted method of adjusting for crossover, the ICERs for pazopanib versus sunitinib, interferon- and best supportive care were 1790, 38,925 and 32,898 per QALY gained respectively. These ICERs were derived from incremental costs of 122, 27,921 and 32,216, and incremental QALYs of 0.068, 0.717 and 0.979 respectively. The manufacturer provided additional cost-effectiveness analyses using alternative methods of adjusting for crossover. The ICERs for pazopanib versus sunitinib, interferon- and best supportive care ranged from 1790 to 5327, 21,625 to 72,274 and 20,824 to 48,877 per QALY gained respectively. One-way sensitivity analyses showed that the ICER was most sensitive to the efficacy estimates for pazopanib versus interferon-, which contribute to the relative efficacy of pazopanib and sunitinib. Specifically, the model is sensitive to the method used for adjusting for crossover for overall survival data from the VEG105192 trial. The manufacturer also provided cost-effectiveness estimates based on part B of the patient access scheme. However, these data are 'commercial-in-confidence' and therefore no details can be reported.
The ERG stated that the evidence base was not ideal for this appraisal as there were no data available from head-to-head comparisons of pazopanib with sunitinib or interferon-. However, the ERG commented on the substantial amount of evidence on the efficacy and safety of pazopanib and on the considerable effort that had gone into providing these data, and the methods were generally well reported.
The ERG commented that the choice of model appeared to be appropriate given the decision problem and the data available. The time horizon appeared to be appropriate, although there were concerns that it may overestimate survival because the median age of diagnosis is 6065 years and constant all-cause mortality was assumed, rather than taking data from life tables, which would have the impact of mortality increasing over time. The ERG stated that the results appeared valid with the methods used. Most of the model analyses performed could be replicated, although this was not true for all sensitivity analyses.
The ERG noted that in the manufacturer's original submission the base-case analysis was based on estimates from the model using the unweighted unadjusted RPSFT method to adjust for crossover and pooled interferon- studies. In the updated analysis, provided as an addendum to the original submission, the method used for adjusting for crossover was the RPSFT weighted method, unadjusted. The ERG acknowledged that the manufacturer had presented a set of analyses that comprehensively covered the range of methods available for crossover. The ERG stated that the RPSFT weighted method advocated by the manufacturer was weakened by the lack of an adequately developed method to analyse relatively immature data robustly. The RPSFT weighted method provided a higher hazard ratio than the unweighted method, and although this did affect the results, the change in method had not necessarily been favourable to pazopanib.
The ERG also highlighted a concern about the manufacturer's assumption that as soon as a patient's disease progressed they stopped treatment. The ERG considered that, in practice, it is unlikely this will happen immediately because patients will only know the status of their disease when they have their next review, which may not be at the exact time the disease progresses. This assumption may create a small bias in favour of the more costly treatments such as pazopanib.
The ERG also stated that there was some uncertainty around the utility value estimate used. The manufacturer used an estimate that was based on the EQ-5D utility value among all patients without adverse events in the VEG105192 trial. The manufacturer also assumed this value to be similar for all interventions. The ERG noted, however, that given the minimal impact adverse events had on the model (in terms of QALYs and costs) this was not likely to be a major issue.
The ERG conducted an exploratory analysis to address concerns about the weighted unadjusted RPSFT results for overall survival being used for the base-case analysis. It assessed the potential impact of a robust weighted analysis on the results, particularly with a model adjusted for baseline covariates, for which methods are still in development. The ERG considered the impact of weighting by comparing the unweighted analyses with the weighted analyses when the models were unadjusted for baseline. The ERG concluded that, overall, weighting does have an impact on the hazard ratio, but it is difficult to establish the direction and magnitude of this effect. The ERG performed multivariate sensitivity analyses around utility value estimates for progression-free survival, utility decrement for progression and duration of utility with adverse events. The results of these analyses indicated that they are sensitive to some combinations of changes and that the ICER associated with pazopanib could increase to more than 50,000 per QALY gained. However, the confidence interval around the hazard ratio for overall survival was very wide. The ERG noted that the manufacturer only reported pair-wise probabilistic sensitivity analysis, therefore the ERG used the base case to compare all four treatment options. The ERG concluded that pazopanib is most likely to be the most cost effective option at willingness to pay thresholds between 35,000 and 50,000. However, the ERG stated that such analyses take the base case at face value and that it was not possible to explore the uncertainty of the various methods used to adjust for crossover or the point estimates used in the economic model due to limited data available for some parameters.
Full details of all the evidence are in the manufacturer's submission and the ERG report.# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of pazopanib, having considered evidence on the nature of advanced renal cell carcinoma and the value placed on the benefits of pazopanib by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.

# Clinical effectiveness
The Committee heard from the patient experts and clinical specialists that advanced renal cell carcinoma is a relatively rare cancer and noted the views of patient experts and clinical specialists on the severity of the disease. The Committee noted that there are limited treatment options for patients with advanced renal cell carcinoma and that currently sunitinib is the only first-line treatment recommended by NICE (Sunitinib for the first-line treatment of advanced and/or metastatic renal cell carcinoma. NICE technology appraisal guidance 169). The Committee heard from the patient experts that, while sunitinib is considered an effective treatment, it is associated with a number of side effects as a result of its toxicity. These include hypertension, fatigue, diarrhoea and hand-foot syndrome. The patient experts highlighted that hand-foot syndrome is frequently intolerable. The clinical specialists stated that patients receiving treatment with sunitinib require a 2-week rest period as part of the treatment cycle, because patients are not able to tolerate sunitinib after 4 weeks. In addition, for a number of patients the dose of sunitinib has to be adjusted to maintain tolerability. The clinical specialists considered that the 2-week rest period and dose adjustment may reduce the benefits gained from sunitinib. The clinical specialists and patient experts were of the opinion that pazopanib is a useful option because it has a more favourable toxicity profile than sunitinib.
The Committee considered the evidence on the clinical effectiveness of pazopanib presented in the manufacturer's submission and the ERG report. The Committee noted that the VEG105192 trial compared pazopanib with placebo and the trial was generally of acceptable quality. It was aware of the ERG's concerns that the trial included only a small number of patients from the UK. The Committee accepted advice from clinical specialists that the data were relevant to clinical practice in England and Wales. The Committee considered the evidence from the VEG105192 trial. It noted that pazopanib, when compared with placebo, produced a statistically significant improvement in median progression-free survival of approximately 8 months (10.8 versus 2.9 months ).
The Committee then discussed the estimates of overall survival gain obtained from the VEG105192 trial. The Committee acknowledged that the estimates of overall survival for pazopanib versus placebo according to the intention-to-treat analysis (22.9 versus 23.5 months; HR 1.01, 95% CI 0.72 to 1.42) had been confounded by crossover and that 51% of patients who had received placebo crossed over to receive pazopanib after disease progression. The Committee heard from the clinical specialists that an increase in progression-free survival would be expected to result in an increase in overall survival, and agreed that it was appropriate to adjust the results to control for the crossover using statistical modelling techniques.
The Committee discussed the manufacturer's approach to estimating overall survival, adjusting for crossover. It acknowledged that the manufacturer had presented a set of analyses that comprehensively covered the range of methods available to adjust for crossover, including an analysis of survival in patients who did not receive post-study cancer therapy. The Committee noted the hazard ratios for overall survival varied from 0.30, based on patients who did not receive post-study cancer therapy, to 0.642, based on the IPCW method, and that these had wide confidence intervals. The Committee acknowledged that the hazard ratio chosen by the manufacturer for the indirect comparison (HR 0.501, 95% CI 0.136 to 2.348) was estimated by the RPSFT weighted method. Although subject to uncertainty, the hazard ratio was in the middle of the range of estimates generated by the manufacturer. The Committee noted the ERG's comments suggesting that this approach was reasonable and it accepted the use of this hazard ratio in the indirect comparison. The Committee concluded that there was sufficient evidence that pazopanib increased progression-free and overall survival compared with placebo, although there was uncertainty about the precise magnitude of the overall survival gain. The Committee noted that the pazopanib trial was only conducted with patients who had a good ECOG performance status of 0 or 1. Therefore the Committee concluded that pazopanib is a clinically effective first-line treatment for advanced renal cell carcinoma for patients with an ECOG performance status of 0 or 1 when compared with placebo or best supportive care.
The Committee then discussed the manufacturer's indirect comparison, used to estimate progression-free survival and overall survival for pazopanib compared with sunitinib, interferon- and best supportive care. It noted that the results of the indirect comparison for median progression-free survival for pazopanib versus interferon- (11.3 versus 5.4 months; HR 0.512, 95% CI 0.326 to 0.802) were comparable with the corresponding results from the sunitinib study by Motzer et al. (2009) (11.0 versus 5.1 months; HR 0.539, 95% CI 0.451 to 0.643). The Committee noted the results of the indirect comparison that suggested pazopanib was associated with considerably improved overall survival compared with either interferon- or best supportive care, and was comparable with sunitinib, although the confidence intervals around the hazard ratios were wide. The Committee heard from the clinical specialists that, in their opinion, the estimates obtained for progression-free survival (with no need for adjustment for crossover) supported the overall survival estimates. The Committee noted that the results of a direct comparison would be available in 2012 when an ongoing head-to-head study of pazopanib versus sunitinib (the COMPARZ trial) was complete, but until then it was reasonable to consider that pazopanib was as clinically effective as sunitinib. The Committee concluded that pazopanib is likely to be more clinically effective than interferon- and is probably comparable in its effectiveness to sunitinib.
The Committee heard from the clinical specialists that the evidence presented by the manufacturer suggested that pazopanib has a more favourable toxicity profile than sunitinib, especially in relation to hand-foot syndrome. It noted that in the VEG105192 trial, 1.9% of patients receiving pazopanib had hand-foot syndrome (all grades) compared with 0% receiving placebo, while in the study by Motzer et al. (2009), 29% of patients receiving sunitinib) experienced hand-foot syndrome (all grades) compared with 3% of patients receiving interferon-. The Committee noted that grade 3 or 4 hand-foot syndrome occurred in 0% of patients receiving either pazopanib or placebo in the VEG105192 study, while 9% of patients receiving sunitinib in the study by Motzer et al. (2009) had grade 3 or 4 hand-foot syndrome compared with 1% of patients receiving interferon-. The Committee discussed the evidence provided by the manufacturer on the adverse events associated with pazopanib. The Committee noted that the numbers of grade 3 and 4 adverse events were similar between the pazopanib and placebo groups in the VEG105192 trial. The Committee noted that the evidence from the indirect comparison indicated that the number of adverse events was generally lower for pazopanib than for sunitinib, although only statistically significant for fatigue. The Committee noted that the results of the indirect comparison were not presented for hand-foot syndrome. The Committee was aware of the evidence from the patient experts about the debilitating adverse effects of treatment with sunitinib and the importance of an alternative treatment being available for patients experiencing such adverse effects. The Committee agreed that pazopanib would be a useful treatment option for patients with advanced renal cell carcinoma.

# Cost effectiveness
The Committee considered the manufacturer's economic model and the critique and exploratory sensitivity analyses performed by the ERG. It broadly accepted the model structure, but was aware of the points raised by the ERG about the uncertainties around the parameter values used in the economic model.
The Committee discussed the cost-effectiveness data submitted by the manufacturer for pazopanib compared with sunitinib, interferon- and best supportive care. The Committee discussed the key parameters used in the model. It agreed that the cost-effectiveness estimates derived from the hazard ratio estimate for overall survival for pazopanib versus placebo, obtained using the unadjusted weighted RPSFT analysis (hazard ratio 0.501), were reasonable (see section 4.6). The Committee then considered the utility values used in the model (0.70 for patients who had no disease progression and no adverse events and 0.59 for post progression). It was aware of the issues raised by the ERG about the methods used by the manufacturer to derive the values but also noted that these issues were not considered to be major. The Committee noted that these utility values were lower than those used in NICE technology appraisal 169 but that the difference of 0.11 between these values was greater. The Committee agreed that this difference in utility values between the health states was reasonable and therefore accepted the utility values modelled by the manufacturer.
The Committee was aware that a two-part patient access scheme has been agreed by the Department of Health (see section 2.3). The Committee agreed that when considering the cost effectiveness of pazopanib it was appropriate to consider both parts of the patient access scheme. The Committee noted that when the manufacturer had presented cost-effectiveness estimates for part A of the patient access scheme, it had also provided additional cost-effectiveness results that used alternative methods of adjusting for crossover in the VEG105192 trial. It acknowledged that the ICERs were highly sensitive to the method used for adjusting for crossover, with ICERs ranging from 21,600 to 72,300 per QALY gained for pazopanib versus interferon-, and from 1790 to 5330 per QALY gained for pazopanib versus sunitinib. Given that the Committee accepted the RPSFT-derived hazard ratio of 0.501 used for the indirect comparison, it agreed that the base-case ICERs for pazopanib compared with best supportive care, interferon- and sunitinib of 33,000, 38,900 and 1790 per QALY gained (based on incremental costs of 32,200, 27,900, 122 and incremental QALYs of 0.979, 0.717 and 0.068 respectively) were reasonable estimates.
The Committee then discussed how to apply these ICERs given that a treatment such as sunitinib, recommended using the supplementary advice on appraising life extending, end-of-life treatments, should not, in view of the same supplementary advice, automatically be considered a standard comparator when a new treatment for the same indication is appraised. The Committee agreed that for this reason, and because sunitinib and pazopanib were developed at the same time, it was appropriate that pazopanib also be considered against interferon- when applying the supplementary advice on appraising life extending, end of life treatments. The Committee was aware that only the ICERs for pazopanib compared with best supportive care and interferon- in relation to part A of the patient access scheme were higher than the range normally considered a cost-effective use of NHS resources.
The Committee next considered whether pazopanib fulfilled the criteria for an end of life treatment in the context of the supplementary advice from NICE that should be taken into account when appraising treatments which may extend the life of people with a short life expectancy and which are licensed for indications that affect small numbers of people with incurable illnesses. For this to be applied, all the following criteria must be met:
The treatment is indicated for patients with a short life expectancy, normally less than 24 months.
There is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3 months, compared with current NHS treatment.
The treatment is licensed or otherwise indicated for small patient populations.When taking these criteria into account, the Committee must be persuaded that the estimates of the extension to life are robust and that the assumptions used in the reference case of the economic modelling are plausible, objective and robust.
The Committee was aware from discussion with the clinical specialists that in England and Wales the total number of people that would be eligible for treatment with pazopanib was less than 4000. The Committee heard from the clinical specialist that the life expectancy for people with advanced renal cell carcinoma receiving best supportive care alone was unlikely to be greater than 24 months and was potentially as low as 5 months. The Committee also noted that the evidence from the RPSFT analysis suggested that pazopanib increased overall survival by more than 3 months compared with placebo, and from the indirect comparison by more than 3 months compared with interferon-. In summary, the Committee was satisfied that pazopanib met the criteria for being a life-extending, end-of-life treatment, and that the evidence presented for this consideration was sufficiently robust.
The Committee considered the central estimate of the ICER (38,900 per QALY gained) and the robustness and uncertainty of the ICER. The Committee was aware of exploratory net benefit analyses carried out by the ERG which indicated that pazopanib would be considered cost effective at willingness to pay thresholds between 35,000 and 50,000 per QALY gained. The Committee considered that the magnitude of additional weight that would need to be assigned to the original QALY benefits in this patient group was within the range considered acceptable for an end of life treatment. Therefore, the Committee concluded that pazopanib should be recommended as a first-line treatment option for patients with advanced renal cell carcinoma who have not received prior cytokine therapy and have an ECOG performance status of 0 or 1, and if the manufacturer provides pazopanib with a 12.5% discount on the list price.
The Committee considered part B of the patient access scheme which linked a specific future rebate to the outcome of the COMPARZ trial. The Committee accepted that the approach taken in part B of the patient access scheme, the details of which are provided 'commercially in confidence', was reasonable and that the ICERs were acceptable. The Committee concluded that pazopanib should be recommended as indicated above (see section 4.14) and if the manufacturer provides a future rebate linked to the outcome of the COMPARZ trial, as agreed under the terms of the patient access scheme and to be confirmed when the COMPARZ trial data are made available.
The Committee considered whether its recommendation was associated with any potential issues related to equality. The Committee concluded that healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect ECOG performance status and make any adjustments they consider appropriate.

# Summary of Appraisal Committee's key conclusions
TA215
Appraisal title: Pazopanib for the first-line treatment of advanced renal cell carcinoma
Section
Key conclusion
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 ECOG performance status of 0 or 1
and
if the manufacturer provides pazopanib with a 12.5% discount on the list price as agreed in the patient access scheme.
When using ECOG performance status, healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect ECOG performance status and make any adjustments they consider appropriate.
People who are currently being treated with pazopanib for advanced metastatic renal cell carcinoma but who do not meet the criteria in 1.1 should have the option to continue their therapy until they and their clinicians consider it appropriate to stop.
Current practice
Clinical need of patients, including the availability of alternative treatments
The Committee noted that there are limited treatment options for patients with advanced renal cell carcinoma and that currently sunitinib is the only first-line treatment recommended by NICE.
The Committee heard from the patient experts that, while sunitinib is considered an effective treatment, it is associated with a number of side effects as a result of its toxicity, including hypertension, fatigue, diarrhoea and hand-foot syndrome.
The clinical specialists and patient experts were of the opinion that pazopanib is a useful option because it has a more favourable toxicity profile than sunitinib and is expected to be as effective.
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?
The Committee heard from the clinical specialists that the evidence from the indirect comparison suggested that pazopanib has a more favourable toxicity profile than sunitinib, especially in relation to hand-foot syndrome, and is expected to be as effective.
The Committee agreed that pazopanib would be a useful treatment option for patients with advanced renal cell carcinoma.
What is the position of the treatment in the pathway of care for the condition?
Pazopanib has a conditional marketing authorisation for 'the first-line treatment of advanced renal cell carcinoma and for patients who have received prior cytokine therapy for advanced disease'. Only the indication for pazopanib for the first-line treatment of advanced renal cell carcinoma is within the remit of the appraisal.
Adverse effects
The most frequent adverse events related to pazopanib treatment were diarrhoea, hair colour change, hypertension, nausea, anorexia and increased liver enzymes.
The Committee noted that the evidence from the indirect comparison indicated that the number of adverse events was generally lower for pazopanib than for sunitinib, although only statistically significant for fatigue. The Committee noted that the results of the indirect comparison were not presented for hand-foot syndrome. The Committee was aware of the evidence from the patient experts about the debilitating adverse effects of treatment with sunitinib and the importance of an alternative treatment being available for patients experiencing such adverse effects.
The Committee agreed that pazopanib would be a useful treatment option for patients with advanced renal cell carcinoma.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The Committee considered the evidence from the VEG105192 trial. It noted that pazopanib, when compared with placebo, produced a statistically significant improvement in median progression-free survival of approximately 8 months (10.8 versus 2.9 months ).
The Committee noted that the results of the indirect comparison for median progression-free survival for pazopanib versus interferon- (11.3 versus 5.4 months; HR 0.512, 95% CI 0.326 to 0.802) were comparable with the corresponding results from the sunitinib study by Motzer et al. (2009) (11.0 versus 5.1 months; HR 0.539, 95% CI 0.451 to 0.643).
The Committee heard from the clinical specialists that an increase in progression-free survival would be expected to result in an increase in overall survival, and agreed that it was appropriate to adjust the results to control for the crossover using statistical modelling techniques.
The Committee concluded that there was sufficient evidence that pazopanib increased progression-free and overall survival compared with placebo, although there was uncertainty about the precise magnitude of the overall survival gain.
Therefore the Committee concluded that pazopanib is a clinically effective first-line treatment for advanced renal cell carcinoma for patients with an ECOG performance status of 0 or 1 when compared with placebo or best supportive care.
Relevance to general clinical practice in the NHS
The Committee was aware of the ERG's concerns that the VEG105192 trial included only a small number of patients from the UK. The Committee accepted advice from clinical specialists that the data were relevant to clinical practice in England and Wales.
Uncertainties generated by the evidence
The Committee acknowledged that the hazard ratio chosen by the manufacturer for the indirect comparison (HR 0.501, 95% CI 0.136 to 2.348) was estimated by the RPSFT weighted method. Although subject to uncertainty, the hazard ratio was in the middle of the range of estimates generated by the manufacturer. The Committee concluded that there was sufficient evidence that pazopanib increased progression-free and overall survival compared with placebo, although there was uncertainty about the precise magnitude of the overall survival gain.
The Committee noted the results of the indirect comparison that suggested pazopanib was associated with considerably improved overall survival compared with either interferon- or best supportive care, and was comparable with sunitinib, although the confidence intervals around the hazard ratios were wide.
The Committee concluded that pazopanib was more clinically effective than interferon- and was probably comparable in its effectiveness to sunitinib.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
None
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The Committee noted that the results of the indirect comparison for median progression-free survival for pazopanib versus interferon- (11.3 versus 5.4 months; HR 0.512, 95% CI 0.326 to 0.802) were comparable with the corresponding results from the sunitinib study by Motzer et al. (2009) (11.0 versus 5.1 months; HR 0.539, 95% CI 0.451 to 0.643).
The Committee concluded that there was sufficient evidence that pazopanib increased progression-free and overall survival compared with placebo, although there was uncertainty about the precise magnitude of the overall survival gain.
Evidence for cost effectiveness
Availability and nature of evidence
The Committee considered the manufacturer's economic model and the critique and exploratory sensitivity analyses performed by the ERG. It broadly accepted the model structure, but was aware of the points raised by the ERG about the uncertainties around the parameter values used in the economic model.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The Committee acknowledged that the ICERs were highly sensitive to the method used for adjusting for crossover, with ICERs ranging from 21,600 to 72,300 per QALY gained for pazopanib versus interferon-, and from 1790 to 5330 per QALY gained for pazopanib versus sunitinib.
Given that the Committee accepted the RPSFT-derived hazard ratio of 0.501 used for the indirect comparison, it agreed that the base-case ICERs for pazopanib (including a 12.5% discount on the list price) compared with best supportive care, interferon- and sunitinib of 33,000, 38,900 and 1790 per QALY gained (based on incremental costs of 32,200, 27,900, 122 and incremental QALYs of 0.979, 0.717 and 0.068 respectively) were reasonable estimates.
Incorporation of health-related quality-of-life benefits and utility values
The Committee considered the utility values used in the model (0.70 for patients who had no disease progression and no adverse events and 0.59 for post progression). It was aware of the issues raised by the ERG about the methods used by the manufacturer to derive the values but also noted that these issues were not considered to be major. The Committee agreed that the difference in utility values between the health states was reasonable and therefore accepted the utility values modelled by the manufacturer.
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
No potential health-related benefits have been identified that were not included in the model.
Are there specific groups of people for whom the technology is particularly cost effective?
The Committee did not identify any specific groups of people for whom the technology was considered particularly cost effective.
What are the key drivers of cost effectiveness?
The Committee acknowledged that the ICERs were highly sensitive to the method used for adjusting for crossover, with ICERs ranging from 21,600 to 72,300 per QALY gained for pazopanib versus interferon-, and from 1790 to 5330 per QALY gained for pazopanib versus sunitinib.
The Committee agreed that the base-case ICERs for pazopanib (including a 12.5% discount on the list price) compared with best supportive care, interferon- and sunitinib of 33,000, 38,900 and 1790 per QALY gained (based on incremental costs of 32,200, 27,900, 122 and incremental QALYs of 0.979, 0.717 and 0.068 respectively) were reasonable estimates.
Most likely cost-effectiveness estimate (given as an ICER)
Given that the Committee accepted the RPSFT-derived hazard ratio of 0.501 used for the indirect comparison, it agreed that the base-case ICERs for pazopanib (including a 12.5% discount on the list price) compared with best supportive care, interferon- and sunitinib of 33,000, 38,900 and 1790 per QALY gained were reasonable.
Additional factors taken into account
Patient access schemes (PPRS)
The Committee was aware that a two-part patient access scheme has been agreed by the Department of Health (see section 2.3).
The Committee agreed that when considering the cost effectiveness of pazopanib it was appropriate to consider both parts of the patient access scheme.
It agreed that the base-case ICERs for pazopanib (including a 12.5% discount on the list price) compared with best supportive care, interferon- and sunitinib of 33,000, 38,900 and 1790 per QALY gained (based on incremental costs of 32,200, 27,900, 122 and incremental QALYs of 0.979, 0.717 and 0.068 respectively) were reasonable estimates.
The Committee accepted that the approach taken in part B of the patient access scheme, the details of which were provided 'commercially in confidence', was reasonable and that the ICERs were acceptable.
End-of-life considerations
The Committee then discussed how to apply these ICERs given that a treatment such as sunitinib, recommended using the supplementary advice on appraising life extending, end-of-life treatments, should not, in view of the same supplementary advice, automatically be considered a standard comparator when a new treatment for the same indication is appraised. The Committee agreed that for this reason, and because sunitinib and pazopanib were developed at the same time, it was appropriate that pazopanib also be considered against interferon- when applying the supplementary advice on appraising life extending, end of life treatments.
The Committee also noted that the evidence from the RPSFT analysis suggested that pazopanib increased survival by more than 3 months compared with placebo, and from the indirect comparison by more than 3 months compared with interferon-. In summary, the Committee was satisfied that pazopanib met the criteria for being a life-extending, end-of-life treatment, and that the evidence presented for this consideration was sufficiently robust.
Equalities considerations and social value judgements
The Committee considered whether its recommendations were associated with any potential issues related to equality. The Committee concluded that healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect ECOG performance status and make any adjustments they consider appropriate.

# Recommendations for further research 
An ongoing head-to-head study of pazopanib versus sunitinib (COMPARZ) is due to report in June 2012.# Related NICE guidance
Sunitinib for the first-line treatment of advanced and/or metastatic renal cell carcinoma. NICE technology appraisal guidance 169 (2009).
Bevacizumab (first-line), sorafenib (first- and second-line), sunitinib (second-line) and temsirolimus (first-line) for the treatment of advanced and/or metastatic renal cell carcinoma. NICE technology appraisal guidance 178 (2009).
Everolimus for the second-line treatment of advanced renal cell carcinoma.NICE technology appraisal guidance 219 (2011).# Review of guidance
The guidance on this technology will be considered for review when the COMPARZ data will be made available and at the latest in December 2013. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.
Andrew DillonChief ExecutiveFebruary 2011# Changes after publication
March 2012: Minor maintenance.
August 2013: Part B of the patient access scheme removed.
April 2017: The company changed from GlaxoSmithKline to Novartis. Contact details for the patient access scheme updated.# About this guidance
NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.
This guidance was developed using the NICE single technology appraisal process.
We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Your responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
ISBN: 978-1-4731-2483-7