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# **NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE** 

## **Final appraisal determination** 

## **Vinflunine for the second-line chemotherapy of advanced or metastatic transitional cell carcinoma of the urothelial tract** 

This guidance was developed using the single technology appraisal (STA) process. 

## **1 Guidance** 

1.1 Vinflunine is not recommended for the treatment of advanced or metastatic transitional cell carcinoma of the urothelial tract that has progressed after treatment with platinum-based chemotherapy. 

- 1.2 People currently receiving vinflunine for the treatment of advanced or metastatic transitional cell carcinoma of the urothelial tract should have the option to continue treatment until they and their clinicians consider it appropriate to stop. 

## **2 The technology** 

2.1 Vinflunine (Javlor, Pierre Fabre) is a chemotherapeutic agent belonging to the vinca-alkaloid class of drugs. Vinflunine has a marketing authorisation for use as ‘monotherapy for the treatment of adult patients with advanced or metastatic transitional cell carcinoma of the urothelial tract after failure of a prior platinumcontaining regimen’. The summary of product characteristics (SPC) notes that vinflunine has not been studied in patients with a performance status of 2 or more. 

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2.2 According to the SPC, common undesirable effects associated with vinflunine include haematological disorders (neutropenia and anaemia), gastrointestinal disorders (constipation, nausea, stomatitis, vomiting, abdominal pain and diarrhoea), and general disorders (asthenia/fatigue). For full details of side effects and contraindications, see the SPC. 

2.3 The SPC states that the recommended dosage of vinflunine is 320 mg/m[2] as a 20-minute intravenous infusion every 3 weeks. The SPC also states that in patients with an Eastern Cooperative Oncology Group (ECOG) performance status of 1 or of 0 who have had pelvic irradiation, treatment should be started at a dose of 280 mg/m[2] ; in the absence of any haematological toxicity during the first cycle causing treatment delay or dose reduction, the dosage can be increased to 320 mg/m[2] every 3 weeks for the subsequent cycles. The SPC states that monitoring of complete blood counts should be conducted before each treatment cycle, and that oral hydration and laxatives should be given during each cycle. Vinflunine is available in 50 mg and 250 mg vials, costing £212.50 and £1062.50 respectively (excluding VAT; ‘British National Formulary’ edition 60). The acquisition cost of vinflunine for an entire course of treatment is about £9817.50, assuming an average of 4.2 cycles, a dose of 287 mg/m[2] and a body surface area of 1.85 m[2] (see section 3.10). Costs may vary in different settings because of negotiated procurement discounts. 

## **3 The manufacturer’s submission** 

The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of vinflunine and a review of this submission by the Evidence Review Group (ERG; appendix B). 

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3.1 The main evidence for the clinical effectiveness of vinflunine was from one open-label, phase III, randomised controlled trial (study 302, the registration trial) that compared vinflunine plus best supportive care with best supportive care alone in patients with advanced or metastatic transitional cell carcinoma of the urothelial tract whose disease had progressed after platinum-based chemotherapy. Results from two open-label, single-arm, phase II studies (study 202 and CA001) were also provided. The manufacturer’s submission highlighted issues around using best supportive care alone as the control arm in study 302. In particular, patients had to be fit enough to receive chemotherapy but willing to accept randomisation to best supportive care. As a result, many patients in the trial were likely to be closer to the end of their lives than some of those patients in the UK whose disease has progressed after platinum-based chemotherapy and who receive further chemotherapy because their previous response to platinumbased treatment makes another response to therapy more likely. Also, there is currently no standard chemotherapy regimen for patients with advanced transitional cell carcinoma of the urothelial tract whose disease has progressed after a prior platinumcontaining chemotherapy, and there is a lack of trial evidence of survival advantage from chemotherapy in this clinical situation. Therefore no standard active treatments were available to use as a control, and best supportive care was considered the most appropriate comparator for vinflunine. 

3.2 Patients were included in study 302 if they had progressive disease after at least two cycles of platinum-based first-line chemotherapy (or after one cycle if there was clear evidence of disease progression at this point), an ECOG performance status of 0 or 1, and an estimated life expectancy of at least 12 weeks. Previous systemic chemotherapy must have been stopped at least 30 days 

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before randomisation. Patients were excluded if they had received more than one previous systemic chemotherapy for advanced or metastatic disease, or if they had been treated with neoadjuvant or adjuvant chemotherapy. Patients were randomised on a 2:1 basis to vinflunine plus best supportive care (hereafter called the vinflunine arm) or best supportive care alone (hereafter called the best supportive care arm). Patients in the vinflunine arm initially received 320 mg/m[2] every 21 days via infusion, but the protocol was subsequently amended to allow a lower starting dose (280 mg/m[2] ) in patients at greater risk of haematological toxicity. Best supportive care included palliative radiotherapy, antibiotics, analgesics, corticosteroids and blood transfusions. 

## 3.3 

A total of 370 patients were enrolled into the study (253 in the vinflunine arm and 117 in the best supportive care arm). The median age of study participants was 64 years, and 79% were male. Most baseline characteristics were similar across the two treatment arms. However, a greater proportion of patients in the vinflunine arm had an ECOG performance status of 1 compared with the best supportive care arm (72% and 62% respectively) although this difference was not statistically significant. Cisplatin was the most common first-line platinum treatment and had been received by more patients in the best supportive care arm than in the vinflunine arm (73% and 65% respectively), although this difference was not statistically significant. More patients in the vinflunine arm than in the best supportive care arm had received carboplatin as first-line platinum treatment (30% and 20% respectively; p = 0.044). 

3.4 Study results were provided for four study populations, only two of which are presented here: the intention-to-treat (ITT) population, which included all randomised patients, and the ‘eligible ITT 

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population’. The latter excluded 13 patients who were found, upon retrospective review of the patient inclusion criteria, not to have progressive disease at the time of entry into the study, and who therefore should not have been randomised (4 patients in the vinflunine arm and 9 in the best supportive care arm; 3 of the 4 excluded patients in the vinflunine arm and 6 of the 9 excluded patients in the best supportive care arm were also ineligible because they had received neoadjuvant or adjuvant 

chemotherapy). The primary outcome of study 302 was median overall survival. For the ITT population, this was 6.9 months in the vinflunine arm compared with 4.6 months in the best supportive care arm (hazard ratio [HR] 0.88, 95% confidence interval [CI] 0.69 to 1.12, p = 0.2868). A pre-planned multivariate analysis, adjusting for a number of prognostic factors (performance status, visceral invasion, alkaline phosphatase, haemoglobin and prior pelvic irradiation), showed a statistically significant overall survival benefit for vinflunine (HR 0.77, 95% CI 0.61 to 0.98, p = 0.036). For the eligible ITT population, median overall survival was 6.9 months in the vinflunine arm and 4.3 months in the best supportive care arm (HR 0.78, 95% CI 0.61 to 0.99, p = 0.0403). An extended multivariate analysis was also done, adjusting for the same prognostic factors outlined above plus additional baseline characteristics such as age, sex and disease stage at diagnosis. This analysis also showed a statistically significant overall survival benefit for vinflunine (HR 0.68, 95% CI 0.52 to 0.88, p = 0.0035). 

3.5 Progression-free survival for the ITT population was 3.0 months in the vinflunine arm compared with 1.5 months in the best supportive care arm (HR 0.68, 95% CI 0.54 to 0.86, p = 0.0012). In the vinflunine arm, 46.5% of patients had stable disease after secondline treatment, 44.9% had progressive disease, and 8.6% had a partial or complete response. In the best supportive care arm, 27% 

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of patients had stable disease, 73% had progressive disease, and none had a partial or complete response. These outcomes were not reported for the eligible ITT population. After disease progression, 29% of patients in the vinflunine arm and 34% of patients in the best supportive care arm received palliative chemotherapy; 60% of these re-treated patients received multiagent chemotherapy. 

3.6 Quality of life was assessed using the cancer-specific European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire. This was done at study entry and at the end of cycles 1, 2, 4 and 6 for both arms. There were no statistically significant differences in overall EORTC QLQ-C30 global health status score between the two arms (p = 0.658). 

- 3.7 In the two phase II, single-arm trials (study 202 and CA001), vinflunine was given every 21 days at a dose of 320 or 280 mg/m[2] . In study 202 (n = 58), the overall response rate (partial or complete response) was 18%, median progression-free survival was 3 months (95% CI 2.4 to 3.8 months) and median overall survival was 6.6 months (95% CI 4.8 to 7.6 months). In CA001 (n = 151), the overall response rate was 14.6% (95% CI 9.4% to 21.2%), median progression-free survival was 2.8 months (95% CI 2.6 to 3.8 months) and median overall survival was 7.9 months (95% CI 6.7 to 9.7 months). 

- 3.8 The most common adverse events (any grade) associated with vinflunine across the three phase II and phase III studies (n = 450) were constipation (55%), nausea (41%), infusion-site reactions (28%), stomatitis/mucositis (27%) and vomiting (27%). Overall, there were six deaths related to treatment (1.3%), of which four were a result of myelotoxicity. Four treatment-related deaths occurred in the vinflunine arm of study 302. Grade 3 or 4 toxicities 

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relating to neutropenia, anaemia and constipation occurred in 50%, 19% and 16% respectively of patients in the vinflunine arm of study 302, compared with 1%, 8% and 1% of patients respectively in the best supportive care arm. Febrile neutropenia occurred in 6% of patients receiving vinflunine (none in the best supportive care arm). 

3.9 The manufacturer submitted an economic analysis comparing vinflunine plus best supportive care with best supportive care alone. The manufacturer’s model was similar to a Markov cohort model in that it included three health states: pre-progression, postprogression and dead. The model calculated the proportion of patients expected to be in each health state, based on the estimated survival curves for the eligible ITT population from study 302. The model assumed that treatment is administered in cycles of 21 days until disease progression, major toxicity or other reason for treatment discontinuation, or death (if occurring before progression). All patients are assumed to be in a pre-progression health state at model entry (baseline). Patients who experience disease progression are assumed to stop treatment with vinflunine and remain in the post-progression state until death. The cycle length of the model was 1 day and the time horizon was 5 years. 

- 3.10 Costs of vinflunine were based on the mean dose (287 mg/m[2] ), the mean body surface area (1.85 m[2] ) and the mean number of treatment cycles (4.2) in study 302. Other treatment costs included administration for intravenous infusion every 21 days in an outpatient setting, complete blood count before drug administration and constipation prophylaxis. Drug wastage was assumed to be zero in the base-case analysis. The total per-patient cost of treatment with vinflunine included in the model was £10,207. Costs for three common adverse events were included in the model: constipation (£39; based on one GP consultation and one pack of 

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laxatives), febrile neutropenia resulting in hospitalisation (£3538; NHS HRG [healthcare resource group] costs) and abdominal pain resulting in hospitalisation (£557; NHS HRG costs). 3.11 Costs for best supportive care were calculated for the preprogression and post-progression health states. For the preprogression health state, best supportive care included: home visits by a GP, community nurse, health home visitor and dietician, an oncologist follow-up visit (assumed to be the same for each treatment group) and palliative radiation therapy (which differed by treatment group). For the post-progression health state, best supportive care included home visits by a GP, community nurse, health home visitor and dietician, a non-consultant oncologist follow-up visit, hospice care, pain medication (assumed to be the same for each treatment group), and palliative radiation therapy and palliative chemotherapy (which differed by treatment group). 

3.12 The pre-progression utility values used in the manufacturer’s submission were based on responses to one item from the EORTC QLQ-C30 questionnaire used in study 302, which asked patients to rate their overall quality of life in the previous week. Responses were transformed to health-state utilities using a published regression model relating this measure to utility values from a timetrade-off analysis in a sample of US cancer patients and their relatives. Post-progression utility values were taken from a study reporting EQ-5D values in 1270 terminally ill cancer patients with painful bone metastases or poor-prognosis non-small-cell lung cancer. Disutility values associated with treatment-related adverse events were not included in the model. 

- 3.13 In the manufacturer’s base case, the incremental cost-effectiveness ratio (ICER) for vinflunine plus best supportive care compared with best supportive care alone was £100,144 per quality-adjusted life 

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year (QALY) gained (incremental cost of £13,071 and incremental benefit of 0.131 QALYs). The manufacturer’s deterministic sensitivity analyses showed that vial price and pre-progression utility values had the greatest impact on the base-case ICER. When a vial price of £0 was used, the ICER was £27,478 per QALY gained. When a pre-progression utility of 0.4 was used (instead of 0.65), the ICER was £133,094 per QALY gained. The ICER was also sensitive to assumptions about the number of vinflunine treatment cycles (£70,233 per QALY gained when three cycles were costed) and vial wastage (£121,095 per QALY gained when wastage was accounted for). The manufacturer’s probabilistic sensitivity analysis suggested that vinflunine had a 6% probability of being cost effective at a threshold of £30,000 per QALY gained when compared with best supportive care alone. 

3.14 The ERG considered the modelling approach and model structure used by the manufacturer to be appropriate and reasonable; however, it commented on a number of areas of uncertainty. The ERG stated that the modelled population reflected that of the pivotal trial (study 302) but may not be representative of the majority of patients whose disease progresses after first-line therapy. This was because patients who had received prior neoadjuvant or adjuvant platinum-based chemotherapy had been excluded from the trial. The ERG commented that best supportive care may not be the most appropriate comparator because alternative second-line treatments are available in UK clinical practice. However, the ERG noted that best supportive care was the comparator specified in the scope for the appraisal, and that there are no randomised controlled trials of relevant comparators for the population of interest. The ERG stated that data from the ITT population of study 302 may have been a more appropriate basis for the economic model than the data from the eligible ITT 

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population that were used by the manufacturer. It also stated that the utility values used did not fit with the preferred NICE reference case, and that there is considerable uncertainty around these estimates because standard methods were not used. The ERG also compared the overall survival curve for vinflunine used in the manufacturer’s economic model with that obtained using Kaplan– Meier estimates. It concluded that the most realistic results were those obtained using the Kaplan–Meier estimates, although it noted that the choice of survival curve did not have a significant impact on the cost effectiveness of vinflunine in the manufacturer’s sensitivity analysis. 

- 3.15 The ERG conducted an exploratory analysis using the confidence intervals around the modelled estimates of overall survival and progression-free survival. This resulted in ICERs ranging from £87,871 to £117,938 per QALY gained. In a separate exploratory analysis the ERG used estimates of progression-free survival and overall survival from the ITT population of study 302 (rather than the eligible ITT population) and corrected an error in the manufacturer’s model in which the vinflunine vial cost was entered incorrectly. The resulting ICER was £99,792 per QALY gained when the manufacturer’s method of estimating survival was used, and £126,422 per QALY gained when Kaplan–Meier estimates based on the ITT trial data were used. 

- 3.16 Full details of all the evidence are in the manufacturer’s submission and the ERG report, which are available from www.nice.org.uk/guidance/TAXXX 

## **4 Consideration of the evidence** 

4.1 The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of vinflunine, having considered 

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evidence on the nature of transitional cell carcinoma of the urothelial tract and the value placed on the benefits of vinflunine by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources. 

4.2 The Committee considered current UK practice for the treatment of patients with advanced or metastatic transitional cell carcinoma of the urothelial tract. It heard from clinical specialists that patients with localised muscle-invasive disease who are fit enough usually undergo either radical surgery (frequently preceded by neoadjuvant chemotherapy) or radical radiotherapy with concurrent chemotherapy. For patients whose disease progresses after radical treatment, platinum-based chemotherapy may be given to improve survival and quality of life. The clinical specialists stated that there is currently no standard treatment for patients whose disease relapses after first-line chemotherapy for advanced disease and who are fit enough to receive further treatment, although a number of agents may be used. They commented that there is general agreement that this patient group can benefit from second-line treatment, particularly if their disease has shown a good response to previous chemotherapy, and therefore would not usually receive palliative care alone. The clinical specialists stated that there was no comparative evidence on the use of any agents for the secondline chemotherapy of advanced or metastatic transitional cell carcinoma of the urothelial tract and that studies in this setting would be welcomed. The Committee was aware that the lack of research on second-line treatments for advanced or metastatic transitional cell carcinoma of the urothelial tract meant there was a significant unmet need for evidence on the treatment of patients whose disease has progressed after platinum-based 

chemotherapy. It welcomed study 302 as the first randomised 

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controlled trial of a second-line treatment for advanced or metastatic transitional cell carcinoma of the urothelial tract. 

## _**Clinical effectiveness**_ 

4.3 The Committee considered the clinical evidence on the use of vinflunine for the second-line chemotherapy of patients with advanced or metastatic transitional cell carcinoma of the urothelial tract. It noted there was only one randomised clinical trial (study 302), and that this compared vinflunine with best supportive care alone, and not with other agents that might be used in a secondline setting. 

4.4 The Committee discussed whether the population in study 302 was representative of patients with advanced or metastatic transitional cell carcinoma of the urothelial tract who would receive vinflunine in UK clinical practice. It heard from the clinical specialists that the study population was younger, fitter and had better renal function than the general population of UK patients with advanced or metastatic transitional cell carcinoma of the urothelial tract. The Committee was also aware that neoadjuvant or adjuvant chemotherapy and concurrent chemoradiotherapy are used as part of radical treatment for localised muscle-invasive transitional cell carcinoma of the urothelial tract. The Committee noted that patients treated in this way had been excluded from study 302. The Committee heard from the clinical specialists that many patients in the UK who are eligible to receive second-line palliative chemotherapy will already have received two lines of treatment (that is, neoadjuvant or adjuvant chemotherapy or concurrent chemoradiotherapy plus first-line palliative chemotherapy). The Committee concluded that there was uncertainty about whether the results of study 302 are generalisable to the use of vinflunine as second-line chemotherapy in UK clinical practice. 

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4.5 The Committee discussed the appropriate comparators for vinflunine. It noted that best supportive care was the only comparator used in study 302. It was aware that this was the only comparator listed in the scope for the appraisal. The Committee considered comments from the clinical specialists that a number of agents are used for the second-line chemotherapy of advanced or metastatic transitional cell carcinoma of the urothelial tract. It understood that the evidence base for these agents consisted of small, often single-institution, phase II studies of selected patients and that considerable publication bias was likely to exist. The Committee was also aware that although patients in study 302 were randomised to receive vinflunine plus best supportive care or best supportive care alone, the patient population was fit and many of the participants could have been eligible for chemotherapy according to current UK practice. Nevertheless, patients were prepared to pursue a policy of best supportive care in consultation with their clinicians. In addition, the committee noted that 30% of the patients in the study went on to receive chemotherapy after disease progression. On considering the treatment options available for this patient population, the Committee thought it possible that best supportive care could be a comparator for patients presenting with advanced or metastatic disease who may not benefit from currently used second-line chemotherapy regimens because they failed to respond or only had a short-lived response to first-line chemotherapy. The Committee also heard from the clinical specialists that, in UK practice, vinflunine might be used more commonly as a third-line rather than a second-line chemotherapy for advanced or metastatic transitional cell carcinoma of the urothelial tract. This is because patients whose disease relapses after a good response to first-line platinum-based chemotherapy would usually receive a further platinum-based or 

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taxane-based treatment before an alternative agent was tried. The Committee therefore considered that best supportive care was the appropriate comparator for patients presenting with advanced or metastatic disease who may not benefit from other currently used second-line chemotherapy regimens. 

4.6 The Committee discussed the results of study 302. It noted that vinflunine was associated with improved progression-free survival and a higher disease control rate (defined as the percentage of patients with a complete response, a partial response or stable disease) compared with best supportive care alone. The Committee also noted that the difference in overall survival between the study arms was not statistically significant for the ITT population, but was significant for the eligible ITT population. The Committee was aware that the difference between the two analyses resulted from the exclusion of 13 patients from the eligible ITT analysis because they had not been shown to have progressive disease after prior therapy. A greater proportion of ineligible patients came from the best supportive care arm than from the vinflunine arm (8% versus 2%) and this lowered the overall survival in the best supportive care arm in the eligible ITT analysis. The Committee considered that the results from the ITT population were the most appropriate basis for its deliberations because randomisation had not been broken and because inclusion of the 13 patients was more likely to reflect what happens in daily clinical practice. It also noted that there were no significant differences in health-related quality of life between patients receiving vinflunine and those receiving best supportive care alone. The Committee concluded that the extent of the clinical effectiveness of vinflunine compared with best supportive care had not been conclusively demonstrated because of the uncertainty in the overall survival results. 

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4.7 The Committee discussed the most common adverse events associated with vinflunine, namely constipation, anaemia, stomatitis and infusion-site reactions. It noted that grade 3 or 4 constipation occurred in 16% of patients receiving vinflunine and considered this to be a significant adverse event. It was aware that grade 4 constipation can lead to intestinal obstruction or acute abdominal distension requiring hospitalisation. The Committee also noted the 6% incidence of febrile neutropenia in the vinflunine arm of the study. It considered comments from the clinical specialists that a number of the other agents used for the second-line chemotherapy of advanced or metastatic transitional cell carcinoma of the urothelial tract are reasonably well tolerated and considered to offer a potentially better side-effect profile than vinflunine. The clinical specialists stated that the safety profile of second-line 

chemotherapy in this setting needed to be predictable, acceptable to patients and manageable, and that they had concerns about vinflunine in this regard. In addition they stated that, anecdotally, vinflunine was thought to be less effective and more toxic than other chemotherapy regimens that are currently used for secondline treatment. The Committee concluded that there were concerns about the tolerability of vinflunine. 

## _**Cost effectiveness**_ 

4.8 The Committee reviewed the economic model submitted by the manufacturer and the ERG’s critique of the model. The Committee was aware that the costs for the intravenous administration of vinflunine included in the manufacturer’s model were based on outof-date NHS HRG figures which were lower than current estimates. The Committee considered the manufacturer’s lack of inclusion of vial wastage in the model to be inappropriate because of the small number of patients who would be treated with vinflunine at any one 

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centre and time. The Committee concluded that the costs of treatment with vinflunine had been underestimated in the manufacturer’s model. 

4.9 The Committee discussed the utility values used in the manufacturer’s model. It noted that different methods of estimating utilities were used for the post-progression and pre-progression health states. It noted that the utility for the post-progression health state was taken from a study of patients with lung cancer. The preprogression utility was based on answers to one of the 30 questions in the EORTC questionnaire, which asked patients to rate their overall quality of life during the past week. The questionnaire was administered at the end of each treatment cycle. The Committee noted clinical specialist opinion that quality of life varies considerably between two consecutive clinic visits. It therefore considered that this question may have been misleading because a patient’s quality of life in the last week of a treatment cycle may not reflect their quality of life for the whole period before disease progression. It also noted that established algorithms for mapping EORTC responses to EQ-5D exist but were not used by the manufacturer. The Committee noted that neither utility used in the economic model conformed to the preferred NICE reference case and concluded that the lack of appropriate utility data contributed to uncertainty in the model. 

4.10 The Committee discussed the data on clinical effectiveness used in the model. It was aware that various hazard ratios of overall survival had been reported depending on the population analysed and the type of analysis used (multivariate analysis or extended multivariate analysis). The Committee noted that the modelled hazard ratios were based on the multivariate analysis of the results for the eligible ITT population and that these results were more 

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favourable for vinflunine than those obtained from the ITT population. The Committee had previously concluded (see section 4.6) that the results from the ITT population were the most appropriate for this appraisal. It therefore concluded that the survival benefit of vinflunine compared with best supportive care alone was likely to be overestimated in the manufacturer’s model. 

- 4.11 The Committee discussed the inclusion of adverse events in the model and noted that although the costs of adverse events were included, the disutility associated with them was not. It discussed the costs for grade 3 and 4 constipation, and considered that these were likely to be significantly higher than the cost for constipation used in the model (£39). 

- 4.12 The Committee discussed the manufacturer’s base-case ICER of £100,100 per QALY gained (incremental cost of £13,100 and incremental QALYs of 0.131). It noted that in the manufacturer’s sensitivity analyses the inclusion of vial wastage and the use of a lower pre-progression utility value increased the ICER significantly from the base case (to £121,100 and £133,100 per QALY gained respectively). It also noted that in the ERG’s exploratory analysis, based on Kaplan–Meier estimates of survival from the ITT population rather than the eligible ITT population, the ICER was £126,400 per QALY gained. The Committee considered the most plausible ICER to be above £120,000 per QALY gained. It further considered that additional uncertainties around the costs of adverse events and the modelling of survival data would increase the ICER. 

- 4.13 The Committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with a short life expectancy and that are licensed for indications that affect small numbers of people with 

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incurable illnesses. For this advice 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. 

In addition, when taking these criteria into account, the Committee must be persuaded that the estimates of the extension to life are robust and the assumptions used in the reference case of the economic modelling are plausible, objective and robust. 

4.14 The Committee considered that the life expectancy of patients with advanced or metastatic transitional cell carcinoma of the urothelial tract whose disease has progressed after first-line chemotherapy is usually less than 6 months. It discussed the number of UK patients for whom vinflunine is licensed, estimated by the manufacturer to be about 800–1500, and concluded that this could be considered a small patient population. The Committee discussed the extension to life offered by vinflunine in the study populations. In the manufacturer’s model, the overall survival benefit of vinflunine was 3.2 months. However, the overall survival benefit based on the trial results was 2.3 months in the ITT population (not statistically significant) and 2.6 months in the eligible ITT population. The Committee was not persuaded that an extension to life of at least 3 months had been proven, and therefore concluded that the endof-life advice did not apply to this appraisal. The Committee further noted that even if the end-of-life considerations were taken into 

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account, the most plausible ICER for vinflunine compared with best supportive care was substantially higher than would normally be considered cost effective. Therefore the Committee concluded that vinflunine could not be considered a cost-effective use of NHS resources for the treatment of advanced or metastatic transitional cell carcinoma of the urothelial tract that has progressed after treatment with platinum-based chemotherapy. 


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## _**Summary of Appraisal Committee’s key conclusions**_ 

|**TAXXX**|**Appraisal title: **Vinflunine for the second-line<br>chemotherapy of advanced or metastatic<br>transitional cell carcinoma of the urothelial<br>tract|**Section**|
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|**Key conclusion**|||
|Vinflunine is not recommended for the treatment of advanced or metastatic transitional<br>cell carcinoma of the urothelial tract that has progressed after treatment with platinum-<br>based chemotherapy.<br>The Committee considered that the clinical effectiveness of vinflunine compared with<br>best supportive care had not been conclusively demonstrated and that the most plausible<br>ICER was above £120,000 per QALY gained. The Committee considered whether<br>vinflunine met the criteria that should be taken into account when appraising treatments<br>that may extend the life of patients with a short life expectancy and that are licensed for<br>indications that affect small numbers of people with incurable illnesses. It was not<br>persuaded that an extension to life of at least 3 months had been proven, and therefore<br>concluded that the end-of-life advice did not apply to this appraisal. The Committee<br>concluded that vinflunine could not be considered a cost-effective use of NHS resources.|||
|**Current practice**|||
|Clinical need of patients,<br>including the availability of<br>alternative treatments|The Committee heard from the clinical<br>specialists that a number of agents are used<br>for the second-line chemotherapy of advanced<br>or metastatic transitional cell carcinoma of the<br>urothelial tract. It understood that the evidence<br>base for these agents consisted of small, often<br>single-institution, phase II studies of selected<br>patients and that considerable publication bias<br>was likely to exist.|4.5|
|**The technology**|||
|Proposed benefits of the<br>technology<br>How innovative is the<br>technology in its potential<br>to make a significant and<br>substantial impact on<br>health-related benefits?|The clinical specialists stated that there is<br>currently no standard treatment for patients<br>whose disease relapses after first-line<br>chemotherapy and who are fit enough to<br>receive further treatment, although a number<br>of agents may be used.<br>The clinical specialists stated that there was<br>no comparative evidence on the use of any<br>agents for the second-line chemotherapy of<br>advanced or metastatic transitional cell<br>carcinoma of the urothelial tract and that<br>studies in this setting would be welcomed.|4.2|
|What is the position of the<br>treatment in the pathway|The Committee heard from the clinical<br>specialists that, in UK practice, vinflunine|4.5|
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|of care for the condition?|might be used more commonly as a third-line<br>rather than a second-line chemotherapy for<br>advanced or metastatic transitional cell<br>carcinoma of the urothelial tract. This is<br>because patients whose disease relapses<br>after a response to first-line platinum-based<br>chemotherapy would usually receive a further<br>platinum-based or taxane-based treatment<br>before an alternative agent was tried.||
|---|---|---|
|Adverse effects|The Committee discussed the most common<br>adverse events associated with vinflunine,<br>namely constipation, anaemia, stomatitis and<br>infusion-site reactions. It noted that grade 3 or<br>4 constipation occurred in 16% of patients<br>receiving vinflunine and considered this to be<br>a significant adverse event. The Committee<br>concluded that there were concerns about the<br>tolerability of vinflunine.|4.7|
|**Evidence for clinical effectiveness**|||
|Availability, nature and<br>quality of evidence|The Committee noted there was only one<br>randomised clinical trial (study 302), and that<br>this compared vinflunine with best supportive<br>care alone, and not with other agents that<br>might be used in a second-line setting.<br>The Committee discussed the results of study<br>302. It noted that the difference in overall<br>survival between the study arms was not<br>statistically significant for the ITT population,<br>but was significant for the eligible ITT<br>population.<br>It concluded that the extent of the clinical<br>effectiveness of vinflunine compared with best<br>supportive care had not been conclusively<br>demonstrated.|4.3<br>4.6|
|Relevance to general<br>clinical practice in the NHS|The Committee heard from the clinical<br>specialists that the study population was<br>younger, fitter and had better renal function<br>than the general population of UK patients with<br>advanced or metastatic transitional cell<br>carcinoma of the urothelial tract.<br>The Committee heard from the clinical<br>specialists that many patients in the UK who<br>are eligible to receive second-line palliative<br>chemotherapy will already have received two<br>lines of treatment (that is, neoadjuvant or<br>adjuvant chemotherapy or concurrent|4.4|



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||chemoradiotherapy plus first-line palliative<br>chemotherapy). Study 302 excluded patients<br>who had had adjuvant or neoadjuvant<br>chemotherapy. .<br>The Committee concluded that there was<br>uncertainty about whether the patient<br>population of study 302 was representative of<br>patients with advanced or metastatic<br>transitional cell carcinoma of the urothelial<br>tract who would receive vinflunine in UK<br>clinical practice.||
|---|---|---|
|Uncertainties generated<br>by the evidence|The Committee noted that the difference in<br>overall survival between the study arms was<br>not statistically significant for the ITT<br>population, but was significant for the eligible<br>ITT population.<br>The Committee concluded that the extent of<br>the clinical effectiveness of vinflunine<br>compared with best supportive care had not<br>been conclusively demonstrated|4.6|
|Are there any clinically<br>relevant subgroups for<br>which there is evidence of<br>differential effectiveness?|No relevant subgroups were identified in this<br>appraisal.||
|Estimate of the size of the<br>clinical effectiveness<br>including strength of<br>supporting evidence|The Committee concluded that the extent of<br>the clinical effectiveness of vinflunine<br>compared with best supportive care had not<br>been conclusively demonstrated.|4.6|
|**Evidence for cost effectiveness**|||
|Availability and nature of<br>evidence|The Committee considered evidence on the<br>cost effectiveness of vinflunine compared with<br>best supportive care, including quality-of-life<br>estimates, costs and ICERs presented by the<br>manufacturer.|4.8 to 4.12|
|Uncertainties around and<br>plausibility of assumptions<br>and inputs in the economic<br>model|The Committee was aware that the costs for<br>the intravenous administration of vinflunine<br>included in the manufacturer’s model were<br>based on out-of-date NHS HRG figures which<br>were lower than current estimates.<br>The Committee considered the manufacturer’s<br>lack of inclusion of vial wastage in the model<br>to be inappropriate because of the small<br>number of patients who would be treated with<br>vinflunine at any one centre and time.|4.8<br>4.8|



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||The Committee noted that the modelled<br>hazard ratios of overall survival were based on<br>the multivariate analysis of the results for the<br>eligible ITT population and that these results<br>were more favourable for vinflunine than those<br>obtained from the ITT population.|4.10|
|---|---|---|
|Incorporation of health-<br>related quality-of-life<br>benefits and utility values<br>Have any potential<br>significant and substantial<br>health-related benefits<br>been identified that were<br>not included in the<br>economic model, and how<br>have they been<br>considered?|The Committee noted that the pre-progression<br>utility was based on answers to one of the 30<br>questions in the EORTC questionnaire, which<br>asked patients to rate their overall quality of<br>life during the past week.<br>The Committee considered that this question<br>may have been misleading because a<br>patient’s quality of life in the last week of a<br>treatment cycle may not reflect their quality of<br>life for the whole period before disease<br>progression.<br>It also noted that established algorithms for<br>mapping EORTC responses to EQ-5D exist<br>but were not used by the manufacturer.|4.9|
|Are there specific groups<br>of people for whom the<br>technology is particularly<br>cost effective?|No relevant subgroups were identified in this<br>appraisal.||
|What are the key drivers<br>of cost effectiveness?|The Committee noted that in the<br>manufacturer’s sensitivity analyses the<br>inclusion of vial wastage and the use of a<br>lower pre-progression utility value increased<br>the ICER significantly from the base case (to<br>£121,100 and £133,100 per QALY gained<br>respectively).<br>It also noted that in the ERG’s exploratory<br>analysis, based on Kaplan–Meier estimates of<br>survival from the ITT population rather than<br>the eligible ITT population, the ICER was<br>£126,400 per QALY gained.|4.12|
|Most likely cost-<br>effectiveness estimate<br>(given as an ICER)|The Committee agreed that the most plausible<br>estimate of the ICER for vinflunine plus best<br>supportive care compared with best supportive<br>care alone was above £120,000 per QALY<br>gained.|4.12|
|**Additional factors taken into account**|||
|Patient access schemes|Not applicable to this appraisal.|–|




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|(PPRS)|||
|---|---|---|
|End-of-life considerations|The Committee considered that the life<br>expectancy of patients with advanced or<br>metastatic transitional cell carcinoma of the<br>urothelial tract whose disease has progressed<br>after first-line chemotherapy is usually less<br>than 6 months.<br>It discussed the number of UK patients for<br>whom vinflunine is licensed and concluded<br>that this could be considered a small patient<br>population.<br>However, the Committee was not persuaded<br>that an extension to life of at least 3 months<br>had been proven, and therefore concluded<br>that the end-of-life advice did not apply to this<br>appraisal.|4.14|
|Equalities considerations<br>and social value<br>judgements|No equality issues were raised during the<br>scoping exercise or through the course of this<br>appraisal.|–|



## **5 Implementation** 

5.1 The Secretary of State and the Welsh Assembly Minister for Health and Social Services have issued directions to the NHS in England and Wales on implementing NICE technology appraisal guidance. When a NICE technology appraisal recommends use of a drug or treatment, or other technology, the NHS must usually provide funding and resources for it within 3 months of the guidance being published. If the Department of Health issues a variation to the 3- month funding direction, details will be available on the NICE website. When there is no NICE technology appraisal guidance on a drug, treatment or other technology, decisions on funding should be made locally. 

5.2 NICE has developed tools to help organisations put this guidance into practice (listed below). These are available on our website 

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(www.nice.org.uk/guidance/TAXXX). [NICE to amend list as needed at time of publication] 

- Slides highlighting key messages for local discussion. 

- Costing template and report to estimate the national and local savings and costs associated with implementation. 

- Implementation advice on how to put the guidance into practice and national initiatives that support this locally. 

- A costing statement explaining the resource impact of this guidance. 

- Audit support for monitoring local practice. 

## **6 Recommendations for further research** 

6.1 The Committee noted the need for research on second-line treatments for transitional cell carcinoma of the urothelial tract. It noted that the vinflunine studies were the only studies in patients with transitional cell carcinoma of the urothelial tract whose disease had progressed after platinum-based chemotherapy. The Committee noted the lack of evidence for the relative effectiveness of treatment options at this stage in the pathway of care. It 

recommended that studies be undertaken to investigate the relative safety and efficacy of second-line treatments for transitional cell carcinoma of the urothelial tract, particularly randomised controlled trials. 

## **7 Related NICE guidance** 

## **Published** 

- Laparoscopic cystectomy. NICE interventional procedure guidance 287 (2009). Available from www.nice.org.uk/guidance/IPG287 

- Improving outcomes in urological cancers. NICE cancer service guidance (2002). Available from www.nice.org.uk/guidance/csguc 

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## **8 Review of guidance** 

- 8.1 The guidance on this technology will be considered for review by the Guidance Executive in October 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. 

Peter Clark 

Chair, Appraisal Committee November 2010 


National Institute for Health and Clinical Excellence 

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## **Appendix A: Appraisal Committee members and NICE project team** 

## _**A Appraisal Committee members**_ 

The Appraisal Committees are standing advisory committees of NICE. Members are appointed for a 3-year term. A list of the Committee members who took part in the discussions for this appraisal appears below. There are four Appraisal Committees, each with a chair and vice chair. Each Appraisal Committee meets once a month, except in December when there are no meetings. Each Committee considers its own list of technologies, and ongoing topics are not moved between Committees. 

Committee members are asked to declare any interests in the technology to be appraised. If it is considered there is a conflict of interest, the member is excluded from participating further in that appraisal. 

The minutes of each Appraisal Committee meeting, which include the names of the members who attended and their declarations of interests, are posted on the NICE website. 

## **Professor Darren Ashcroft** 

Professor of Pharmacoepidemiology, School of Pharmacy and Pharmaceutical Sciences, University of Manchester 

## **Dr Matthew Bradley** 

Value Demonstration Director, AstraZeneca 

## **Dr Brian Buckley** 

Lay member 

## **Professor Usha Chakravarthy** 

Professor of Ophthalmology and Vision Sciences, Queen’s University of Belfast 

## **Professor Peter Clark (Chair)** 

## Consultant Medical Oncologist, Clatterbridge Centre for Oncology 

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## **Dr Ian Davidson** 

Lecturer in Rehabilitation, University of Manchester 

## **Dr Martin Duerden** 

Assistant Medical Director, Betsi Cadwaladr University Health Board 

## **Dr Alexander Dyker** 

Consultant Physician, Wolfson Unit of Clinical Pharmacology, University of Newcastle 

## **Gillian Ells** 

Prescribing Advisor, NHS Sussex Downs and Weald 

## **Dr Jon Fear** 

Consultant in Public Health Medicine, Head of Healthcare Effectiveness NHS Leeds 

## **Paula Ghaneh** 

Senior Lecturer and Honorary Consultant, University of Liverpool 

## **Niru Goenka** 

Consultant Physician, Countess of Chester NHS Foundation Trust 

## **Dr Susan Griffin** 

Research Fellow, Centre for Health Economics, University of York 

## **Professor Carol Haigh** 

Professor in Nursing, Manchester Metropolitan University 

## **Alison Hawdale** 

Lay member 

## **Professor Peter Jones** 

Pro Vice Chancellor for Research & Enterprise, Keele University Professor of Statistics, Keele University 

## **Dr Vincent Kirkbride** 

Consultant Neonatologist, Regional Neonatal Intensive Care Unit, Sheffield 

## **Dr Rachel Lewis** 

Doctoral Researcher, Manchester Business School 

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## **Dr Anne McCune** 

Consultant Hepatologist, University Hospitals Bristol NHS Foundation Trust 

## **Professor Jonathan Michaels (Vice Chair)** 

Professor of Vascular Surgery, University of Sheffield 

## **Dr Neil Milner** 

General Medical Practitioner, Tramways Medical Centre 

## **Professor Femi Oyebode** 

Professor of Psychiatry & Consultant Psychiatrist, The National Centre for Mental Health 

## **Dr John Radford** 

Director of Public Health, Rotherham Primary Care Trust 

## **Dr Phillip Rutledge** 

GP and Consultant in Medicines Management, NHS Lothian 

## **Dr Brian Shine** 

Consultant Chemical Pathologist, John Radcliffe Hospital 

## **Dr Murray D. Smith** 

Associate Professor in Social Research in Medicines and Health, University of Nottingham 

## **Paddy Storrie** 

Lay member 

## **Dr Cathryn Thomas** 

GP and Associate Professor, University of Birmingham 

## **Charles Waddicor** 

Chief Executive, NHS Berkshire 

## **Mike Wallace** 

Health Economics & Reimbursement Director, Johnson & Johnson Medical Ltd 

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## _**B NICE project team**_ 

Each technology appraisal is assigned to a team consisting of one or more health technology analysts (who act as technical leads for the appraisal), a technical adviser and a project manager. 

## **Sally Gallaugher, Christian Griffiths and Raphael Yugi** 

Technical Leads 

## **Joanne Holden** 

Technical Adviser 

## **Kate Moore** 

Project Manager 


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## **Appendix B: Sources of evidence considered by the Committee** 

- A The Evidence Review Group (ERG) report for this appraisal was prepared by Southampton Technology Assessments Centre: 

      - Cooper K, Frampton G, Mendes D, Bryant J, Vinflunine for the second line treatment of transitional cell carcinoma of the urothelial tract, September 2010 

- B The following organisations accepted the invitation to participate in this appraisal as consultees and commentators. They were invited to comment on the draft scope, the ERG report and the appraisal consultation document (ACD). Organisations listed in I were also invited to make written submissions. Organisations listed in II and III had the opportunity to give their expert views. Organisations listed in I, II and III also have the opportunity to appeal against the final appraisal determination. 

   - I Manufacturer/sponsor: 

      - Pierre Fabre 

## II Professional/specialist and patient/carer groups: 

- Macmillan Cancer Support 

- British Uro-oncology Group (BUG) 

- Royal College of Nursing 

- Royal College of Pathologists 

- Royal College of Physicians, Medical Oncology Joint Special Committee 

- United Kingdom Oncology Nursing Society 

III Other consultees: 

- NHS Bury 

- Department of Health 

- NHS Norfolk 

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      - Welsh Assembly Government 

   - IV Commentator organisations (did not provide written evidence and without the right of appeal): 

      - British National Formulary 

      - Commissioning Support Appraisals Service 

      - Department of Health, Social Services and Public Safety for Northern Ireland 

      - NHS Quality Improvement Scotland 

      - Institute of Cancer Research 

      - Southampton Health Technology Assessment Centre 

      - National Institute for Health Research Health Technology Assessment Programme 

- C The following individuals were selected from clinical specialist 

nominations from the non-manufacturer consultees and commentators. 

They gave their expert personal view on vinflunine by attending the initial Committee discussion and providing written evidence to the Committee. They were also invited to comment on the ACD. 

      - Dr Alison Birtle, Consultant Clinical Oncologist, Royal Preston Hospital, nominated by British Uro-oncology Group – clinical specialist 

      - Dr John Chester, Honorary Consultant in Medical Oncology, Leeds Institute of Molecular Medicine, nominated by Royal College of Physicians – clinical specialist 

      - Dr Tony Elliott, Consultant Clinical Oncologist, The Christie Hospital, nominated by Royal College of Physicians – clinical specialist 

- D Representatives from the following manufacturer attended Committee 

   - meetings. They contributed only when asked by the Committee chair to 

   - clarify specific issues and comment on factual accuracy. 

      - Pierre Fabre 

National Institute for Health and Clinical Excellence 


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