Sunitinib for the first-line treatment of advanced and/or metastatic renal cell carcinoma

One randomised controlled trial (RCT) of 750 people assessed the effect of sunitinib (n=375) compared with IFN-α alone (n=375). The primary outcome was progression-free survival. Three interim analyses were scheduled and after the second analysis the study was unblinded and participants in the IFN-α group with progressive disease were allowed to cross over into the sunitinib group. This is at variance with the study protocol which stated that all treatment would be stopped when there was evidence of disease progression. The study was conducted in participants with a good performance status (Eastern Cooperative Oncology Group [ECOG] status 0 or 1) with clear cell RCC. Most had undergone prior nephrectomy.

Median overall survival had not been reached in either treatment arm at the time of the interim data analyses. The manufacturer of sunitinib (Pfizer) submitted updated data on the final intention-to-treat (ITT) population. The median final overall survival was 26.4 months in the sunitinib arm and 21.8 months in the IFN-α arm (hazard ratio [HR] 0.821, 95% confidence interval [CI] 0.673 to 1.001, p=0.051). There were 25 participants in the IFN-α arm who, during the course of the study, crossed over to receive sunitinib treatment after disease progression. Censoring the data for these 25 participants (that is, the data for these 25 people were only included up to the point at which they crossed over) gave a median overall survival of 26.4 months in the sunitinib arm and 20.0 months in the IFN-α arm (HR 0.808, 95% CI 0.661 to 0.987, p=0.0362).

The manufacturer of sunitinib also provided post hoc data pertaining to a group of participants who did not receive any systemic post-study treatments. In this analysis, the median overall survival was 28.1 months for the 193 participants in the sunitinib arm and 14.1 months for the 162 participants in the IFN-α arm (HR 0.647, 95% CI 0.483 to 0.870, p=0.0033).

Progression-free survival was defined as the time between randomisation and first documented disease progression or death from any cause. Pre-planned interim results (at 13 months) and unplanned updated results (at 25 months) were presented, but the latter contained crossover between treatment arms. Again, the manufacturer submitted final results based on the ITT population and the median final progression-free survival was 48 weeks (11 months) in the sunitinib arm and 22.3 weeks (5.1 months) in the IFN-α arm (HR 0.488, 95% CI 0.406 to 0.586, p<0.000001). Analysis of the group of participants who received no systemic post-study treatments gave median progression-free survival of 50.1 weeks (11.5 months) in the sunitinib arm and 22.3 weeks (5.1 months) in the IFN-α arm (HR 0.52, 95% CI 0.39, 0.70).

A few participants were included who had not had a prior nephrectomy: 9% in the sunitinib arm and 11% in the IFN-α arm. The subgroup analyses, based only on the interim study results, suggested that sunitinib significantly improved progression-free survival for those who had undergone prior nephrectomy compared with IFN-α (HR 0.38, 95% CI 0.30 to 0.53). The improvement in progression-free survival for those who had not undergone prior nephrectomy was less and the difference between groups not statistically significant (HR 0.58, 95% CI 0.24 to 1.03).

Tumour response rate was measured as a partial or complete reduction in tumour size. Results for the interim analyses only showed that the partial tumour response rate in the sunitinib arm was 31% compared with 6% in the IFN-α arm (p<0.001). No participant had a complete tumour response.

Adverse events were taken from the 'safety population' (that is, people were assigned to treatments in the analysis based on what they actually received). Results for the period up to the interim analyses only showed no significant differences between the treatment and control arms. However, the Assessment Group stated that there are emerging concerns in the published literature about the frequency of cardiovascular events associated with sunitinib. In the trial, the most commonly reported 'any grade' adverse events for participants receiving sunitinib were hypertension, fatigue, diarrhoea and hand–foot syndrome. For the participants receiving IFN-α, these were fatigue and asthenia. A total of 8% of participants receiving sunitinib discontinued treatment because of adverse events compared with 13% in the IFN-α arm. At the time of the interim analyses, overall results for health-related quality of life (total score and all subscales using the functional assessment of cancer therapy – general [FACT-G] and functional assessment of cancer therapy – kidney symptom index [FKSI] tools) were significantly better in the sunitinib arm compared with the IFN-α arm.

In the RCT described above (see section 4.1.2), 6.1% of participants receiving sunitinib and 6.7% of participants receiving IFN-α were classified as having a poor prognosis according to the Memorial Sloan-Kettering Cancer Centre risk classification. However, outcome data were not reported separately for this subgroup.

The Assessment Group did not identify any full reports of RCTs assessing sunitinib as first-line treatment for people with advanced and/or metastatic RCC who were unsuitable for immunotherapy.

The Assessment Group did not identify any data on the clinical effectiveness of sunitinib as first-line treatment for people with advanced and/or metastatic RCC who had a poor prognosis and were unsuitable for immunotherapy.

The Assessment Group concluded that for people who are suitable for immunotherapy sunitinib appears to offer benefits compared with IFN-α alone in terms of overall survival, progression-free survival and tumour response. For people with a poor prognosis and people who are unsuitable for immunotherapy, limited evidence was identified and thus no conclusions about the clinical effectiveness of sunitinib as a first-line treatment in these groups could be made. The frequency of adverse events associated with sunitinib is comparable to that associated with IFN-α monotherapy.

The manufacturer of sunitinib (Pfizer) submitted a simple state-transition model with 3 health states: progression-free survival (PFS), progressed disease (PD) and death. The model compared sunitinib with IFN-α as a first-line treatment for people suitable for immunotherapy. Patient-level data were taken from the sunitinib trial described in section 4.1.2. Weibull survival curves were fitted to the overall and progression-free survival data from the IFN-α arm in the trial. Hazard ratios for sunitinib were then used to extrapolate overall and progression-free survival for sunitinib treatment. The following treatment and health-state specific utility data from the sunitinib trial were applied: sunitinib, PFS 0.77; IFN-α, PFS 0.79; sunitinib, PD 0.72; IFN-α, PD 0.69. Drug costs were adjusted according to RCT data on dose intensity; the first-line drug cost for sunitinib was weighted by 86.4%. A pricing strategy with the first cycle of sunitinib being free of charge to the NHS was applied.

The original base cases submitted by the manufacturer of sunitinib used the interim effectiveness data which were superseded by the final ITT results. With discounting at 3.5% per annum, the comparison of sunitinib with IFN-α produced an ICER of £72,003 per QALY gained using the final ITT population and £71,760 per QALY gained using the final ITT population censored for crossover. One-way sensitivity analyses applied to the original base case demonstrated that the ICERs were most sensitive to the extrapolation method and choice of utility value for progressed disease.

The manufacturer of sunitinib also submitted cost-effectiveness analyses using the data from the group of participants who received no systemic post-study treatments. The progression-free and overall survival curves for IFN-α were modelled using Weibull curves and the hazard ratios for sunitinib were then applied, as in the ITT analyses. Without any curve adjustments, the ICER for sunitinib compared with IFN-α was £41,472 per QALY gained. However, the manufacturer stated that the modelled IFN-α progression-free survival curve did not fit the observed progression-free survival data well, and adjusted the curve using fewer data points. Application of the trial hazard ratio to this curve then resulted in a progression-free survival curve that did not fit the empirical data from the sunitinib arm of the trial well. Therefore, the progression-free survival curve for sunitinib was also fitted independently. These adjustments resulted in an ICER of £35,245 per QALY gained for sunitinib compared with IFN-α.

The manufacturer of sunitinib then adjusted the overall survival curve for the IFN-α arm using the same principles as for adjustments for the progression-free survival curve. However, unlike the curve fitting for progression-free survival, for overall survival the trial hazard ratio was applied to the fitted IFN-α curve to derive an overall survival curve for the sunitinib arm. These adjustments resulted in an extrapolated mean overall survival of 46.6 months for participants in the sunitinib arm and 27.5 months for participants in the IFN-α arm. These adjustments were associated with an ICER of £29,440 per QALY gained for sunitinib compared with IFN-α. Probabilistic sensitivity analyses of the final cost-effectiveness estimate demonstrated that at a willingness to pay threshold of £30,000 per QALY gained, sunitinib has a 51% probability of being a cost-effective treatment compared with IFN-α.

The Committee reviewed the evidence of clinical effectiveness from the ITT population analyses of the sunitinib RCT. The Committee noted that 25 out of 375 participants in the IFN-α arm had crossed over and received sunitinib after disease progression. The Committee noted that the ITT censored population analyses accounted for the crossover by censoring the participants who had crossed over from the IFN-α arm to receive sunitinib. The Committee noted that, in these analyses, sunitinib demonstrated significant gains in terms of progression-free and overall survival compared with IFN-α. The Committee noted that the sunitinib trial was only conducted with participants that had a good ECOG performance status of 0 or 1. Therefore the Committee concluded that sunitinib is a clinically effective first-line treatment for advanced and/or metastatic RCC for patients with an ECOG performance status of 0 or 1.

The Committee then considered the estimates provided of the cost effectiveness of sunitinib. For the ITT population the manufacturer's and the Assessment Group's estimates were £72,000 and £105,000 per QALY, respectively. The Committee also noted the manufacturer's estimate of £71,800 per QALY gained for the ITT censored for crossover population. The Committee noted instructions from the Department of Health that all of the cost-effectiveness estimates should include the first cycle of sunitinib as free to the NHS.

The Committee understood that in the sunitinib RCT not only had there been crossover after disease progression, but also participants had had second-line treatment after the study had ended. This could be expected to exaggerate overall survival estimates for people in the UK receiving IFN-α in the future, as the Committee accepted testimony from clinical experts that current UK practice is likely to preclude treatment with second-line therapies. The Committee therefore considered that the investigation of outcomes in the participants who received no 'post-study treatment' was appropriate. However, the Committee was concerned about the data and approach used by the manufacturer. The Committee was mindful that this group was not pre-specified and represented approximately half of the original trial population. The Committee noted that even though the baseline demographics of the group appeared similar to those of the whole trial population the findings were suggestive of an unbalanced comparison. In the ITT analysis the differences in progression-free survival and overall survival between treatment groups had been 8.2 and 6.2 months, respectively. For the 'no post-study treatment' group they were 6.5 and 19.1 months, respectively. The Committee agreed that this divergence made the argument that these groups were matched implausible. It could indicate that the 'no post-study treatment' group receiving sunitinib comprised people who had not experienced disease progression and thus had not needed any second-line treatments, whereas the IFN-α group might have included more people who had died before other treatments could be considered. The Committee further considered that the divergence might have been exacerbated by the curve fitting techniques used in the manufacturer's model. For the group with 'no post-study treatment' the progression-free survival curves for IFN-α and sunitinib were fitted independently, but the overall survival curve for sunitinib was estimated by applying the study hazard ratio to the IFN-α overall survival curve.

The Committee then considered what cost-effectiveness inferences could be made from the 'no post-study treatment' data provided by the manufacturer. The Committee considered that it was reasonable to accept the reduced overall survival estimate that these data implied for the control (IFN-α) group. However, it agreed that it could not accept that not having a second-line treatment could increase the overall survival of participants receiving sunitinib. The Committee noted the decrease in survival in the sunitinib group when crossover was censored (but participants not excluded completely from the study). Furthermore, the Committee agreed that the best estimates for progression-free survival came from the whole-study ITT population rather than a population lacking over half of the trial participants. The Committee could not therefore accept the manufacturer's ICER of £29,400 for the 'no post-study treatment' group. The Committee proceeded to explore the cost-effectiveness estimates based on its preferred assumptions for the 'no post-study treatment' group.

The Committee noted the DSU and Assessment Group analyses based on the Committee's preferred assumptions (see sections 4.2.12 and 4.2.13). These analyses used estimates for progression-free survival derived from the ITT population for both groups (approximately 13 months and 21 months for the IFN-α and sunitinib arms, respectively) and estimates for overall survival of the sunitinib group from the ITT population (approximately 37 months), but overall survival estimates for the IFN-α group from those with 'no post-study treatment' (approximately 27 months) applied to the manufacturer's model (performed by the DSU) and the Assessment Group model (performed by the Assessment Group). The Committee noted the DSU's resulting cost-effectiveness estimate of £49,300 per QALY gained. The Committee noted the DSU's comments that this was likely to be an underestimate and also noted the cost-effectiveness estimate of £54,400 per QALY gained from the same preferred Committee assumptions in the Assessment Group model.

The Committee then considered the sensitivity analyses on utility values conducted by the Assessment Group. The Committee was aware that there was a paucity of data on quality of life and acknowledged consultation responses that the difference of 0.08 between the utility assigned to a progression-free health state and a progressed disease health state was too small. The Committee considered that the impact of sunitinib on quality of life may not have been adequately captured, particularly for the progressed disease state. Therefore, the Committee agreed that an increased utility difference between the 2 health states was plausible and noted the Assessment Group's utility sensitivity analyses which suggested a lowering of the final ICER as the utility difference widened. Taking this into account and reflecting back to the proven benefit in median progression-free survival in the ITT sensitivity analyses, the Committee was persuaded that the ICER for sunitinib 'no post-study treatment group' could be less than £50,000 per QALY gained.

The Committee next discussed whether sunitinib for advanced and/or metastatic RCC fulfilled the criteria for consideration as a life-extending, end-of-life treatment. It was aware that the total number of people with advanced and/or metastatic RCC in England and Wales was approximately 4,000. Although the Committee noted that sunitinib was to be aimed at more patient groups than just people with RCC, such as people with gastrointestinal stromal tumours, this was the first indication for which it was being appraised. It therefore considered that for this appraisal, sunitinib should be regarded as meeting this criterion for an end-of-life treatment. The Committee noted from the clinical trials that the normal 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 also noted that evidence from the sunitinib trial suggested that sunitinib increased survival by more than 3 months in comparison with IFN-α alone. It was further persuaded that sunitinib provided a step-change in the first-line treatment of advanced and/or metastatic RCC and noted that more than 20% of the public and patients that responded in consultation highlighted this impressive benefit from sunitinib. In summary, the Committee was satisfied that sunitinib currently meets the criteria for being a life-extending end-of-life treatment, and that the evidence presented for this consideration was sufficiently robust.

The Committee next considered the cost-effectiveness estimates of sunitinib, in light of the appraisal of a life-extending, end-of-life treatment. Firstly, it considered the ITT cost-effectiveness estimates (derived from the whole trial population) of £72,000 per QALY gained and £105,000 per QALY gained as calculated by the manufacturer of sunitinib and the DSU (using the Assessment Group model), respectively. 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.

The Committee then considered the most plausible cost-effectiveness estimate following the sensitivity analysis of the utility values of the group of people that had received no post-study treatments (see section 4.3.10), in light of the appraisal of a life-extending, end-of-life treatment. It considered the impact of giving a greater weight to QALYs achieved in the later stages of terminal diseases, using the assumption that the extended survival period is experienced at the full quality of life anticipated for a healthy person of the same age and 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. The Committee concluded that although it might be at the upper end of any plausible valuation of such benefits, in this case there was a significant step-change in treating a disease for which there is only 1 current standard first-line treatment option. The Committee concluded that sunitinib as a first-line treatment for advanced and/or metastatic RCC could be recommended as a cost-effective use of NHS resources, if a patient has an ECOG performance status of 0 or 1 and there are no further treatment options recommended by NICE after first-line sunitinib treatment. The Committee also considered that, because of the additional weight assigned to the original QALY benefit, rigorous data collection investigating the benefits of sunitinib in this group of people should be conducted.

Very few data were presented to the Committee on the clinical or cost effectiveness of sunitinib compared with IFN-α as first-line treatments for people with a poor prognosis, suitable for immunotherapy. In the absence of robust data, the Committee concluded that sunitinib could not be considered a clinically effective first-line treatment for people with poor prognosis, suitable for immunotherapy with advanced and/or metastatic RCC.

No data were presented to the Committee on the clinical or cost effectiveness of sunitinib compared with best supportive care as a first-line treatment for people who were unsuitable for immunotherapy. In the absence of robust data, the Committee concluded that sunitinib could not be considered a clinically effective first-line treatment for those unsuitable for immunotherapy with advanced and/or metastatic RCC.

No data were presented to the Committee on the clinical or cost effectiveness of sunitinib compared with best supportive care as a first-line treatment for people with a poor prognosis who were unsuitable for immunotherapy. In the absence of robust data, the Committee concluded that sunitinib could not be considered a clinically effective first-line treatment for people with a poor prognosis who are unsuitable for immunotherapy.