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

First-line treatment for people suitable for immunotherapy

4.1.2 One randomised controlled trial (RCT) of 649 people assessed the effect of bevacizumab plus IFN-α (n = 327) compared with IFN-α plus placebo (n = 322). In this study, the primary outcome was overall survival. The study was unblinded after a pre-planned interim analysis based on approximately 250 deaths, and participants in the IFN-α arm who had not progressed were offered bevacizumab plus IFN-α. IFN-α was given for a maximum of 1 year. The study included predominantly people with clear cell RCC who had risk factors suggestive of a favourable or intermediate prognosis. All participants had undergone a previous nephrectomy.

4.1.3 Median overall survival had not been reached in the bevacizumab plus IFN-α treatment arm at the time of data analysis and was 19.8 months in the IFN-α plus placebo arm. There was no statistically significant difference in overall survival between bevacizumab plus IFN-α compared with IFN-α plus placebo (hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.62 to 1.02, p = 0.0670).

4.1.4 Progression-free survival was defined as the time between randomisation and first documented disease progression or death from any cause. There was a statistically significant difference in median progression-free survival for bevacizumab plus IFN-α (10.2 months) compared with IFN-α plus placebo (5.4 months); HR 0.63, 95% CI 0.52 to 0.75.

4.1.5 Tumour response rate was measured as a partial or complete reduction in tumour size. The overall tumour response rate in the bevacizumab plus IFN-α arm was 31% compared with 13% in the IFN-α plus placebo arm (p = 0.0001). Approximately half of all the trial participants achieved stable disease.

4.1.6 Adverse events were taken from the 'safety population' (that is, people were assigned to treatments in the analysis based on what they actually received, for example patients in the IFN-α plus placebo arm receiving one or more doses of bevacizumab were assigned to the bevacizumab arm). No significant differences between the treatment and control arms were reported. A total of 28% of participants discontinued treatment in the bevacizumab plus IFN-α arm because of adverse events compared with 12% in the IFN-α plus placebo arm. Health-related quality of life was not measured in the study.

First-line treatment for people suitable for immunotherapy with at least three of six factors indicating poor prognosis

4.1.7 One RCT with 626 participants investigated the effectiveness of temsirolimus (n = 209), temsirolimus plus IFN-α (n = 210) and IFN-α alone (n = 207) as first-line treatments of RCC in people who were suitable for immunotherapy and had at least three of six factors indicating poor prognosis. The combination of temsirolimus plus IFN-α does not have a UK marketing authorisation and so data from this group were not considered. The primary outcome in this temsirolimus study was overall survival. Approximately 80% of participants had a Karnofsky performance status of 70 or less and clear cell carcinoma. Approximately 66% of participants had undergone prior nephrectomy. Interim and final analyses were presented.

4.1.8 In the temsirolimus study, there were statistically significant differences in median overall survival with temsirolimus (10.9 months) compared with IFN-α (7.3 months), in both the interim (HR 0.73, 95% CI 0.58 to 0.92; p = 0.008) and final analyses (HR 0.78, 95% CI 0.63 to 0.97; p = 0.0252). Some participants had not undergone prior nephrectomy and some had non-clear cell carcinoma. Subgroup analyses suggested that temsirolimus compared with IFN-α significantly improved overall survival for those who had not undergone prior nephrectomy (HR 0.61, 95% CI 0.41 to 0.91) and for those with non-clear-cell carcinoma (HR 0.55, 95% CI 0.33 to 0.90). No significant improvements in overall survival were observed for those who had undergone prior nephrectomy (HR 0.84, 95% CI 0.63 to 1.11) and those who had clear cell carcinoma (HR 0.85, 95% CI 0.64 to 1.08).

4.1.9 In the interim analyses, median progression-free survival was assessed by both site investigators and blinded independent assessment. For those receiving temsirolimus, the median progression-free survival was 3.8 months and 5.5 months as assessed by site investigators and blinded independent assessment, respectively. For those receiving IFN-α, the median progression-free survival was 1.9 months and 3.1 months, respectively. No statistical analysis was reported for the interim analyses. In the final analyses, the median progression-free survival was 3.8 months and 5.6 months as assessed by site investigators and blinded independent assessment, respectively. For those receiving IFN-α, median progression-free survival was 1.9 months and 3.2 months, respectively. There was a statistically significant difference in median progression-free survival with temsirolimus compared with IFN-α according to the independent assessment (HR 0.74, 95% CI 0.60 to 0.91; p = 0.0042) and the investigators' assessment (HR 0.74, 95% CI 0.60 to 0.90; p = 0.0028). Compared with IFN-α, temsirolimus improved progression-free survival for those who had not undergone prior nephrectomy (HR 0.62, 95% CI 0.43 to 0.88) and for those who had undergone prior nephrectomy (HR 0.72, 95% CI 0.55 to 0.93). Compared with IFN-α, temsirolimus improved progression-free survival for those who had non-clear-cell carcinoma (HR 0.36, 95% CI 0.22 to 0.59), and there was a non-statistically significant difference for those who had clear cell carcinoma (HR 0.84, 95% CI 0.67 to 1.05).

4.1.10 The temsirolimus study measured objective tumour response rate. The manufacturer of temsirolimus (Wyeth Pharmaceuticals) stated that no statistically significant differences were observed; the objective partial tumour response rate was 8.6% (18 participants) for those who received temsirolimus compared with 4.8% (10 participants) for those who received IFN-α. There was a statistically significant difference in the number of participants that achieved stable disease for at least 8 weeks with temsirolimus (131 participants, 62.7%) compared with IFN-α (80 participants, 38.6%).

4.1.11 In the temsirolimus study, time without symptoms and toxicity (TWiST) and quality-adjusted survival and toxicity (Q-TWiST) were reported as pre-defined endpoints. The reported results included some participants from the third treatment arm (temsirolimus plus IFN-α). Participants receiving temsirolimus had a significantly longer time in both TWiST and Q-TWiST health states (6.5 months and 7.0 months, respectively) compared with participants receiving IFN-α alone (4.7 months and 5.7 months, respectively). In the temsirolimus study, 67% of participants receiving temsirolimus and 78% of those receiving IFN-α alone reported a grade 3 or 4 adverse event (p = 0.02). Anaemia was the most commonly reported grade 3 or 4 adverse event in the temsirolimus arm (20%) and asthenia (loss of strength) in the IFN-α alone arm (26%). A total of 7% (n = 15) of participants in the temsirolimus arm discontinued treatment because of adverse events compared with 14% (n = 29) in the IFN-α alone arm. According to the Memorial Sloan-Kettering Cancer Center (MSKCC) risk classification, 31% of participants in the temsirolimus arm and 24% in the IFN-α alone arm had an intermediate rather than a poor prognosis.

4.1.12 In the bevacizumab study (see section 4.1.2), 9% of participants receiving bevacizumab plus IFN-α and 8% of those receiving IFN-α plus placebo were defined as having a poor prognosis. Only progression-free survival was reported according to this subgroup. There was no statistically significant difference in median progression-free survival between bevacizumab plus IFN-α (2.2 months) and IFN-α alone (2.1 months) for participants with at least three MSKCC risk factors for poor prognosis (HR 0.81, 95% CI 0.46 to 1.42).

First-line treatment for people unsuitable for immunotherapy

4.1.13 The Assessment Group did not identify any full reports of RCTs assessing sorafenib as first-line treatment for people with advanced and/or metastatic RCC who were unsuitable for immunotherapy. One RCT was identified with a small population subgroup (17% of the total number of participants) that was unsuitable for immunotherapy. However, these participants did not receive sorafenib as a first-line treatment because the RCT only included people who had received at least one prior systemic therapy. Further details of the sorafenib RCT are given in section 4.1.15. The manufacturer of sorafenib (Bayer) submitted data on first-line treatment of people unsuitable for immunotherapy from two expanded access programmes conducted in Europe (318 participants unsuitable for immunotherapy) and North America (224 participants unsuitable for immunotherapy). Both were in effect single-arm studies and the results were reported only in abstract form. The expanded access studies reported median progression-free survival of 6.0 months and 8.1 months, respectively.

First-line treatment for people with poor prognosis unsuitable for immunotherapy

4.1.14 The Assessment Group did not identify any data on the clinical effectiveness of sorafenib or temsirolimus as first-line treatment for people with advanced and/or metastatic RCC who had a poor prognosis and were unsuitable for immunotherapy. In order to inform a cost-effectiveness estimate for this population, the manufacturer of temsirolimus (Wyeth Pharmaceuticals) performed an indirect comparison of temsirolimus with best supportive care. Data were taken from the temsirolimus RCT and an RCT that compared IFN-α with medroxyprogresterone (MPA). No further details on clinical effectiveness were presented.

Second-line treatment for people in whom immunotherapy has failed

4.1.15 One RCT with 903 participants investigated the effectiveness of sorafenib (n = 451) compared with placebo, which was considered equivalent to best supportive care (n = 452). The RCT included people who had experienced disease progression after one systemic treatment within the previous 8 months. All participants in the RCT had clear cell carcinoma with an ECOG performance status of 0 or 1 and a favourable or intermediate MSKCC prognostic score. A total of 83% of participants had received previous immunotherapy and the remaining 17% of participants were unsuitable for immunotherapy so had received other first-line therapies. The primary outcome of the RCT was overall survival. The RCT was terminated early, on ethical grounds, after an independent review decided that sorafenib should be offered to participants who were receiving placebo.

4.1.16 For the whole trial population, at the time of the first interim analyses, the median overall survival in the sorafenib RCT had not been reached in the sorafenib arm, and was 14.7 months in the placebo arm (HR 0.72, 95% CI 0.54 to 0.94; p = 0.02). The difference was not considered statistically significant because it did not reach the pre-specified O'Brien–Fleming threshold of less than or equal to 0.0005.

4.1.17 From the whole trial population of the sorafenib RCT, results were reported of a pre-planned interim analysis and an unplanned updated analysis (at the point of crossover) for progression-free survival. For the pre-planned analyses, both the independent and investigator assessments resulted in statistically significant differences in median progression-free survival. The independent assessment of median progression-free survival was 5.5 months in the sorafenib arm compared with 2.8 months in the placebo arm (HR 0.44, 95% CI 0.35 to 0.55). The investigator assessment of median progression-free survival was 5.9 months in the sorafenib arm compared with 2.8 months in the placebo arm (p < 0.001). The unplanned investigator assessment of median progression-free survival at the time of crossover was 5.5 months in the sorafenib arm compared with 2.8 months in the placebo arm (HR 0.51, 95% CI 0.43 to 0.60).

4.1.18 The sorafenib RCT measured tumour response rate. Out of the whole trial population, one participant who received sorafenib achieved a complete tumour response compared with none who received placebo. A total of 43 (10%) participants receiving sorafenib and 8 (2%) receiving placebo achieved a partial response, and 333 (74%) participants receiving sorafenib and 239 (53%) receiving placebo achieved stable disease. This difference was statistically significant (p < 0.001).

4.1.19 Health-related quality of life was measured in the whole trial population of the sorafenib RCT using the FACT-G and FKSI indices. There was no significant difference between the placebo and sorafenib groups in mean FACT-G physical well-being score nor was there any statistically significant difference in mean FKSI-10 total score between groups over the first 32 weeks of treatment (p = 0.83 and p = 0.98, respectively). However, median time to health status deterioration, as defined by a four-point or more drop in FKSI-10 total score, was significantly greater for those receiving sorafenib compared with those receiving placebo (p < 0.0001). On the following items of the FKSI-15 index, those people who had received sorafenib scored significantly better than those who had received placebo: coughing (p < 0.0001); fever (p = 0.0015); worry about their disease (p = 0.0004); ability to enjoy life (p = 0.0119). However, a significantly greater number of people receiving sorafenib reported 'bothersome side effects of treatment' than those receiving placebo (p < 0.0001). Skin rashes, hypertension, diarrhoea and hand–foot syndrome were more common in the sorafenib arm.

4.1.20 One randomised discontinuation trial was also identified that compared sorafenib with best supportive care. The randomised discontinuation trial included 65 people with advanced and/or metastatic RCC. In most participants immunotherapy had failed. Most participants in this trial had an ECOG performance status of 0 or 1 and had undergone prior nephrectomy. The median progression-free survival in the sorafenib randomised discontinuation trial was significantly longer for participants receiving sorafenib (24 weeks) compared with those receiving placebo (6 weeks); p = 0.0087. At 24 weeks, a greater proportion of participants who had received sorafenib had no evidence of disease progression compared with those who had received placebo (50% and 18%, respectively; p = 0.0077). Overall survival, health-related quality of life and adverse events were not assessed in the randomised discontinuation trial.

4.1.21 Two single-arm phase II studies, of 63 and 106 participants, investigated the effectiveness of sunitinib as second-line treatment following prior nephrectomy and at least one course of cytokine-based therapy. A total of 57% of the pooled population had an ECOG performance status of 0. In both studies, sunitinib was given until disease progression, and dose reductions were allowed if adverse effects were observed. In both studies, the primary outcome was objective tumour response.

4.1.22 The median overall survival in the smaller sunitinib study was 16.4 months (95% CI 10.8 to 'not reached') and 23.9 months (95% CI 14.1 to 30.7) in the larger sunitinib study. The median progression-free survival in the smaller sunitinib study was 8.7 months (95% CI 5.5 to 10.7) and 8.8 months (95% CI 7.8 to 13.5) in the larger sunitinib study. No participants achieved a complete tumour response in either of the sunitinib studies. A total of 40% in the smaller sunitinib study and 33% in the larger sunitinib study achieved partial tumour responses. Approximately equal proportions of the remaining participants in both studies experienced stable disease or progressive disease. Informal analysis comparing the pooled sunitinib studies with the best supportive care arm of the sorafenib RCT suggests that sunitinib may be clinically effective compared with best supportive care.

Second-line treatment for people unsuitable for immunotherapy

4.1.23 The Assessment Group did not identify any full reports of RCTs assessing sorafenib as a second-line treatment for people with advanced and/or metastatic RCC who were unsuitable for immunotherapy. The manufacturer of sorafenib (Bayer) submitted data from an RCT with a small population subgroup (17% of the total number of participants) who were unsuitable for immunotherapy but had received other first-line treatments. This was a trial of sorafenib compared with placebo, which was assumed to be equivalent to best supportive care. Further details of the sorafenib RCT are given in section 4.1.15. The Assessment Group did not consider the results from this subgroup because it was unclear whether the subgroups were defined at the start of the study and the size of the subgroup was small. The results of the trial for this subgroup were marked as academic in confidence. Therefore they are not presented in this document.

Summary of clinical effectiveness

4.1.24 The Assessment Group concluded from a summary of the data on the clinical effectiveness of first-line treatments for people who are suitable for immunotherapy, that bevacizumab plus IFN-α appears to have significant benefits compared with IFN-α alone in terms of progression-free survival and tumour response. For people with poor prognosis, temsirolimus appears to have significant benefits compared with IFN-α in terms of overall survival, progression-free survival and tumour response rate. There is some evidence to suggest that temsirolimus may have a differential effect on people who have non-clear-cell carcinoma and who have not undergone nephrectomy. The frequency of adverse events associated with bevacizumab and temsirolimus is comparable to that associated with IFN-α monotherapy, but the adverse event profiles differ between treatments.

4.1.25 The Assessment Group concluded that for second-line treatment for people in whom immunotherapy had failed, sorafenib demonstrated clinically and statistically significant benefits compared with best supportive care in terms of progression-free survival and tumour response rate. Sorafenib was associated with more adverse events than best supportive care, particularly hand–foot skin reactions and hypertension. The Assessment Group also stated that although an informal comparison suggests that sunitinib may be beneficial compared with best supportive care, no definitive conclusions could be drawn because of the absence of any comparator in the studies.

Manufacturers' models

Assessment Group model

First-line treatment for people suitable for immunotherapy

4.3.5 The Committee reviewed the evidence of clinical effectiveness from the bevacizumab study. The Committee noted that bevacizumab plus IFN-α demonstrated a statistically significant gain in terms of progression-free survival compared with IFN-α plus placebo. The Committee was aware that the data presented on overall survival were immature because median overall survival had not been reached. The Committee was persuaded that bevacizumab plus IFN-α is a clinically effective first-line treatment. However, the Committee heard testimony from clinical specialists and people with RCC that IFN-α is associated with high toxicity, is poorly tolerated and is administered by subcutaneous injection. Therefore the Committee was mindful of the concerns highlighted by patient experts and clinical specialists associated with the combination of bevacizumab and IFN-α.

4.3.6 The Committee considered the estimates of cost effectiveness of bevacizumab plus IFN-α. It noted that the models from the manufacturer and the Assessment Group were similar in terms of structure and data sources; the models differed chiefly in the drug acquisition costs. These differences resulted in different estimates of cost effectiveness between the manufacturer and the Assessment Group of £75,000 and £171,000 per QALY gained, respectively. The Committee noted that when the original patient access scheme was applied to the Assessment Group cost-effectiveness estimate, the Assessment Group base-case ICER was reduced from £171,000 to £90,500 per QALY gained. The Committee noted that the original patient access scheme was not agreed by the Department of Health and that the final agreed patient access scheme had an additional component which would further reduce these ICERs.

4.3.7 The Committee considered the parameter changes suggested by the manufacturer of bevacizumab for insertion into the Assessment Group's model (see section 4.2.27). Although the first suggestion to censor participants once second-line treatments were received was appropriate in principle, the Committee noted that its application produced some anomalous findings: there were more participants in the bevacizumab arm than the IFN-α arm that were censored. Although the Committee noted that, on average, the participants in the bevacizumab plus IFN-α arm had received treatment for almost twice as long as those in the IFN-α plus placebo arm, the Committee considered that the cause of the greater censoring was likely to be the withdrawal of more participants from bevacizumab plus IFN-α treatment than IFN-α plus placebo treatment because of the adverse effects of bevacizumab plus IFN-α. It also noted that the revised hazard ratio for overall survival was now lower than the original hazard ratio for progression-free survival. The Committee considered that a reduced hazard ratio for overall survival was plausible, but that it would not be expected to be lower than the hazard ratio for progression-free survival. The Committee then reviewed the bevacizumab dosages and quantity and cost of bevacizumab administrations applied in the economic model. The Committee accepted that it was plausible that in the trial participants may have stopped treatment before 12 months, but considered that the trial protocol and exact interpretation of treatment duration was unclear. The Committee also considered that lower costs of bevacizumab administration were plausible, although noted that the costs of administration were unlikely to be halved. The Committee noted and accepted the revised dose intensity estimate of 92% and bevacizumab administration cost of £170 as provided by the manufacturer of bevacizumab.

4.3.8 The Committee then discussed the fact that bevacizumab was licensed to be given to people with advanced and/or metastatic RCC in combination with IFN-α. It noted that the health-state utilities used in calculating the cost-effectiveness estimate of bevacizumab plus IFN-α compared with IFN-α plus placebo were obtained from an RCT of sunitinib compared with IFN-α (see section 4.2.2), and that the health-state utilities were not treatment specific. The Committee was aware that the costs of adverse effects had been included in the economic model, although these were negligible. It considered that there would be disutility associated with the high toxicity, poor tolerance and issues with the administration of bevacizumab plus IFN-α, that had been highlighted by clinical specialists and patient experts, and that this disutility had not been incorporated into the cost-effectiveness estimate of bevacizumab plus IFN-α compared with IFN-α. Taking these concerns that had been highlighted into account the Committee agreed that the ICER was likely to be an underestimate and therefore the Committee concluded that the lowest plausible ICER estimate was £53,800 per QALY gained.

4.3.9 The Committee next discussed whether bevacizumab plus IFN-α for the treatment of advanced and/or metastatic RCC fulfilled the criteria for a life-extending, end-of-life treatment. The Committee noted from the clinical trials that life expectancy with IFN-α treatment alone was unlikely to be greater than 24 months and was potentially as low as 12 months. The Committee agreed that it was likely that bevacizumab plus IFN-α would increase overall survival by more than 3 months in comparison with IFN-α alone. It had heard that RCC does not respond well to IFN-α alone, but considered that bevacizumab plus IFN-α does represent a marked change in the treatment of advanced and/or metastatic RCC. The Committee was aware that the total number of people with advanced and/or metastatic RCC in England and Wales was approximately 4000. However, the Committee understood that it should take into account the cumulative population for each product in considering the strength of any case, for justifying decisions which employ, in whole or part, the supplementary criteria for appraising life-extending, end-of-life treatments. It noted that bevacizumab was licensed for a number of other indications involving much larger patient groups. The Committee noted that the manufacturer argued that the use of bevacizumab was restricted in the UK and that, in effect, the valid patient population for bevacizumab is small. However the Committee considered that this point did not override its view that bevacizumab is licensed for a relatively large population across its range of indications. In summary, the Committee was not persuaded that bevacizumab plus IFN-α meets all the criteria for a life-extending end-of-life treatment, given the size of the patient populations (in RCC and other cancers) for whom it is licensed.

4.3.10 The Committee considered the lowest plausible cost-effectiveness estimate of bevacizumab plus IFN-α of £53,800 per QALY gained and concluded that bevacizumab plus IFN-α as a first-line treatment for people with advanced and/or metastatic RCC would not be a cost-effective use of NHS resources.

First-line treatment for people suitable for immunotherapy with three of six factors indicating poor prognosis

4.3.11 The Committee reviewed the evidence of clinical effectiveness from the temsirolimus study. The Committee was mindful that the criteria used for defining poor prognosis in the temsirolimus trial were different from those commonly used in clinical practice. It noted that temsirolimus demonstrated a statistically significant gain in terms of overall survival, progression-free survival and tumour response rate compared with IFN-α. The Committee discussed the available subgroup data, but had concerns as to whether the data were robust enough to distinguish particular subgroup responses. Some of the subgroups were very small, in particular one of the subgroups highlighted by the manufacturer, non-clear-cell carcinoma, was based on less than 20% (n=73) of the trial population. This subgroup was also defined imprecisely as 'non-clear-cell carcinoma and 'indeterminate histologies' in the trial. It was also unclear whether all of the subgroup analyses had been defined a priori. However, the Committee was persuaded that in general temsirolimus is a clinically effective first-line treatment for people with a poor prognosis, and was minded to consider the cost-effectiveness evidence, including the subgroups who might gain greater benefit.

4.3.12 Therefore the Committee considered the estimates of cost effectiveness of temsirolimus. It noted that the original models from the manufacturer and the Assessment Group were similar in terms of structure and data sources; the models differed chiefly in the acquisition cost of temsirolimus and costs associated with the administration of IFN-α. However, the Committee heard from clinical specialists that most people would be able to self-administer IFN-α at home and that the proportion needing help with administration assumed by the Assessment Group was considered reasonable. The Committee acknowledged consultation responses from the manufacturer that highlighted that the duration of temsirolimus treatment had been overestimated in the Assessment Group economic model by the use of hazard ratios for deriving survival curves. Therefore the Committee considered that the most appropriate ICERs were those calculated by the manufacturer, but with the Assessment Group's costs for IFN-α administration incorporated and the manufacturer's initial cost for the acquisition of temsirolimus. These resulted in a base-case ICER of £102,000 per QALY gained and subgroup ICERs ranging from £63,100 ('non-clear-cell carcinoma and indeterminate histologies') to £121,300 (clear-cell carcinoma) per QALY gained. However, The Committee noted the recently published price of £620 for a vial of temsirolimus and was aware that these ICER estimates were derived using an underestimate of the price of a vial of temsirolimus of £515. Therefore it concluded that the ICERs were underestimates and would all increase if the recently published price of temsirolimus was incorporated into the cost-effectiveness analyses.

4.3.13 The Committee next discussed whether temsirolimus for the treatment of advanced and/or metastatic RCC fulfilled the criteria for a life-extending, end-of-life treatment. The Committee noted from the clinical trials that life expectancy with IFN-α treatment alone was unlikely to be greater than 24 months and was potentially as low as 7 months for patients with a poor prognosis. The Committee considered that evidence from the temsirolimus trial suggested that temsirolimus increased survival by more than 3 months compared with IFN-α alone and it considered temsirolimus to be an improvement in treatment for advanced and/or metastatic RCC. It was aware that the total number of people with advanced and/or metastatic RCC in England and Wales was approximately 4000 and that temsirolimus was licensed for people with a poor prognosis and so had a very small patient population. The Committee agreed that the criterion for the robustness of evidence was convincing for the overall trial data, but not for the subgroup data. In summary, the Committee was satisfied that temsirolimus met the criteria for being a life-extending, end-of-life treatment for the whole trial population.

4.3.14 The Committee then considered the cost-effectiveness estimate of temsirolimus of £102,000 per QALY gained (noting that this was an underestimate because of the underestimated price of temsirolimus), in light of the appraisal of a life-extending, end-of-life treatment. The Committee was aware that the patient population eligible for temsirolimus treatment was very small, but noted that NICE had not received direction from the Department of Health that 'ultra-orphan' conditions should be appraised differently from any other appraisal; including those that meet the end-of-life criteria. The Committee considered that the additional weight that would need to be assigned to the original QALY benefits in this patient group for the cost effectiveness of temsirolimus to fall within the current threshold range would be too great. The subgroup data were not considered to be robust enough to apply a consideration of additional weight that would need to be assigned to the original QALY benefits in these subgroups. Therefore the Committee concluded that temsirolimus as a first-line treatment for people with advanced RCC and a poor prognosis would not be a cost-effective use of NHS resources.

4.3.15 Very few data were presented to the Committee on the clinical effectiveness of bevacizumab plus IFN-α compared with IFN-α plus placebo as a first-line treatment for people with a poor prognosis, suitable for immunotherapy. The Committee noted that only a small subgroup of the bevacizumab RCT (see section 4.1.2) had a poor prognosis and the data available confirmed no benefit in terms of progression-free survival. The Committee concluded that with such limited evidence, it could not consider bevacizumab plus IFN-α as a clinically effective first-line treatment for people with poor prognosis, suitable for immunotherapy with advanced and/or metastatic RCC.

First-line treatment for people unsuitable for immunotherapy

4.3.16 The only data presented to the Committee for the first-line treatment of people unsuitable for immunotherapy came from two single-arm studies of sorafenib which were presented in abstract form only. The Committee concluded that, with such weak evidence, it could not consider sorafenib as a clinically effective first-line treatment for people with advanced RCC who were unsuitable for immunotherapy.

First-line treatment for people unsuitable for immunotherapy with three of six factors indicating poor prognosis

4.3.17 The Committee reviewed the evidence of clinical and cost effectiveness for temsirolimus compared with best supportive care as presented by the manufacturer (Wyeth Pharmaceuticals). The Committee was aware that the data informing the comparisons came from an indirect comparison. Limited information on the trial used in the comparison was presented and the Committee heard that the best supportive care in the trial was unlikely to be offered as current clinical practice. The Committee concluded that temsirolimus had not been shown to be a clinically effective first-line treatment for people with advanced RCC and a poor prognosis and who were unsuitable for immunotherapy.

4.3.18 No data were presented to the Committee on the clinical or cost effectiveness of sorafenib compared with best supportive care as a first-line treatment for people with a poor prognosis who were unsuitable for immunotherapy. The Committee noted that the sorafenib RCT included only people with an ECOG performance status of 0 or 1 and therefore did not include people with a poor performance. The Committee concluded that, in the absence of evidence, sorafenib had not been shown to be a clinically effective first-line treatment for people with advanced RCC and a poor prognosis and who were unsuitable for immunotherapy.

Second-line treatment for people in whom immunotherapy has failed

4.3.19 The Committee reviewed the clinical effectiveness of sorafenib for people in whom immunotherapy has failed. The Committee noted that sorafenib demonstrated a clinically relevant and statistically significant advantage over best supportive care in terms of progression-free survival and tumour response for the 83% of the trial participants in whom immunotherapy had failed. The Committee was persuaded that sorafenib is a clinically effective therapy for second-line treatment of RCC for people in whom immunotherapy has failed.

4.3.20 The Committee then reviewed the cost-effectiveness estimates for the subgroup in whom immunotherapy had failed. The Committee noted that the trial was not stratified according to prior treatments, but acknowledged responses from consultation that the subgroup was pre-specified, and considered that the subgroup represented most of the trial participants and was relatively large. The Committee noted comments from the DSU that the reduced ICERs, presented by the manufacturer of sorafenib in the revised analyses, were derived using appropriate modelling techniques, similar to that used by the Assessment Group. However, the Committee agreed that due to the concerns raised by the DSU about the change in direction of the subgroup ICER as presented by the manufacturer of sorafenib that the most reasonable subgroup estimate came from the DSU revised analysis using the Assessment Group's economic model. The Committee, noting instructions from the Department of Health that all of the cost-effectiveness estimates should include the first pack of sorafenib as free to the NHS and the new increased price of sorafenib, accepted that the most plausible ICER for sorafenib compared with best supportive care for people in whom immunotherapy had failed was £65,900 per QALY gained.

4.3.21 The Committee next discussed whether sorafenib for the treatment of advanced RCC fulfilled the criteria for consideration as a life-extending, end-of-life treatment. The Committee noted from the clinical trials that life expectancy with best supportive care alone was unlikely to be greater than 24 months and was potentially as low as 6 months. The Committee considered that even though the sorafenib trial was terminated early, this was done after a report of increased progression-free survival in the sorafenib arm. The Committee considered that it was likely that sorafenib would increase overall survival by more than 3 months in comparison with best supportive care. It also agreed that sorafenib provided an improvement in the treatment of advanced RCC. It was aware that the total number of people with advanced and/or metastatic RCC in England and Wales was approximately 4000. Therefore the Committee was satisfied that sorafenib meets the criteria for being a life-extending, end-of-life treatment and that the trial evidence presented for this consideration was robust.

4.3.22 The Committee then considered the most plausible cost effectiveness of sorafenib for people in whom immunotherapy had failed, of £65,900 per QALY gained, in light of the appraisal of a life-extending, end-of-life treatment. It considered that the magnitude of additional weight that would need to be assigned to the original QALY benefits in this patient group for the cost effectiveness of the drug to fall within the current threshold range would be too great. Therefore the Committee concluded that sorafenib as a second-line treatment for people with advanced RCC in whom immunotherapy has failed would not be a cost-effective use of NHS resources.

4.3.23 The Committee then reviewed the clinical and cost effectiveness for sunitinib as a second-line treatment compared with best supportive care for people in whom immunotherapy had failed. The Committee was concerned that the data informing the comparisons came from two small single-arm trials. The Committee acknowledged that the comparison with best supportive care suggested that sunitinib may be clinically effective compared with best supportive care. However, in the absence of further robust data, the Committee concluded that sunitinib could not be considered a clinically effective second-line treatment for people with advanced and/or metastatic RCC in whom immunotherapy had failed.

Second-line treatment for people in whom non-immunotherapy first-line treatment has failed and who are unsuitable for immunotherapy

4.3.24 The Committee reviewed the academic-in-confidence evidence on the clinical effectiveness of sorafenib compared with best supportive care for people unsuitable for immunotherapy as presented by the manufacturer (Bayer). The Committee noted that the subgroup constituted a small proportion (17%) of the sorafenib RCT, but that the overall trial population was relatively large. Following consultation, the Committee heard that the data informing the comparison came from a pre-planned subgroup from the sorafenib RCT, although it was unclear what prior therapies the subgroup had received. The Committee concluded that, although the data were limited, sorafenib could be considered as a clinically effective second-line treatment for those unsuitable for immunotherapy with advanced RCC.

4.3.25 The Committee then reviewed the estimates of cost effectiveness of sorafenib as a second-line treatment for people unsuitable for immunotherapy. The Committee noted that the manufacturer of sorafenib (Bayer) had not provided revised ICERs for this subgroup. The Committee noted that, overall, the revised models submitted by the manufacturer and the Assessment Group were generally similar in terms of structure, data sources and assumptions. The resulting estimates of cost effectiveness were broadly similar with a revised manufacturer base-case ICER for the whole trial population of £72,500, per QALY gained and a DSU revised Assessment Group base-case ICER of £74,900 per QALY gained. The Committee noted that the subgroup ICER for the 83% of trial participants in whom immunotherapy had failed was lower than these ICERs for the whole trial population. The Committee therefore agreed that the most plausible subgroup ICER for the 17% of trial participants who were unsuitable for immunotherapy must be higher than the ICER for the whole trial population of £72,500 or £74,900 per QALY gained.

4.3.26 The Committee agreed that the criterion for the robustness of evidence for this subgroup was not convincing therefore the Committee did not discuss whether sorafenib for the second-line treatment of people with advanced RCC who are unsuitable for immunotherapy fulfilled the criteria for consideration as a life-extending, end-of-life treatment. This was because it was not clear what prior therapies the people in the subgroup had received and no cost-effectiveness estimates were provided. The Committee considered the most plausible ICERs that were higher than £72,500 and £74,900 per QALY gained and concluded that sorafenib as second-line treatment for people in whom non-immunotherapy first-line treatment has failed and who are unsuitable for immunotherapy with advanced RCC would not be a cost-effective use of NHS resources.

Second-line treatment for people in whom sunitinib has failed

4.3.27 The Committee noted the suggestion made by the manufacturer of sorafenib that consideration should be given to the sequencing of treatments (particularly sunitinib as a first-line treatment followed by sorafenib as second-line treatment). It also noted that the marketing authorisation of sorafenib was for people in whom immunotherapy had failed or who were unsuitable for immunotherapy. Therefore the Committee considered that the use of sorafenib after sunitinib would be relevant only for people who had received sunitinib as a first-line treatment and were unsuitable for immunotherapy. The Committee noted that the evidence base for this treatment pathway was absent, because participants were excluded from the sorafenib RCT if they had received sunitinib as a first-line treatment and the sunitinib RCT only included people who were suitable for immunotherapy. In the absence of robust data, the Committee could not reach any conclusions on whether sorafenib could be considered a clinically effective second-line treatment for people with advanced RCC who had received sunitinib as a first-line treatment.

The Institute's duties under the equalities legislation

4.3.28 In carrying out its consideration of the evidence and reaching its conclusions, the Committee was aware of the Institute's duties under the equalities legislation and considered whether those duties required the Committee to alter or to add to its recommendations in any way. However, the Committee did not identify any way in which its guidance would have a particular impact on any of the groups whose interests are protected by the equalities legislation. It noted that in relation to first-line treatment for people who are unsuitable for immunotherapy and second-line treatment for people who are unsuitable for immunotherapy its recommendations are based on the view that there is limited or no evidence of clinical effectiveness for any patient group. For the other patient populations the Committee's conclusions are based on the view that the treatments are not cost effective for any patient group. The guidance does not recommend the availability of the treatments to some patients and not to others. The recommendations apply to all patients with renal cell carcinomas and all such patients are affected by the guidance in the same way.