4 Consideration of the evidence
4.1 The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of sunitinib for the treatment of GIST, having considered evidence on the nature of the condition and the value placed on the benefits of sunitinib by people with unresectable and/or metastatic malignant GIST, those who represent them, and clinical specialists. It was also mindful of the need to take account of the effective use of NHS resources.
4.2 The Committee first considered the clinical-effectiveness data presented by the manufacturer. It noted that there were statistically significant improvements in time to tumour progression and progression-free survival for people taking sunitinib plus best supportive care compared with people taking placebo plus best supportive care. The Committee noted that the estimates of time to tumour progression and progression-free survival were obtained at the first interim analysis and so were not confounded by any crossover. The Committee heard from clinical specialists and patient experts that the observed benefits in time to tumour progression and progression-free survival were clinically meaningful. The Committee was aware that, after the interim analysis, people were offered open-label sunitinib and that the ITT analysis was confounded by the crossover. The Committee accepted that the benefits seen in time to tumour progression and progression-free survival were such that a substantial improvement in overall survival with sunitinib treatment was probable. The Committee therefore concluded that sunitinib was a clinically effective treatment for unresectable and/or metastatic malignant GIST which is resistant or intolerant to imatinib. Additionally, the Committee understood that the use of sunitinib should be supervised by cancer specialists with experience in treating people with unresectable and/or metastatic malignant gastrointestinal stromal tumours after failure of imatinib treatment because of resistance or intolerance.
4.3 The Committee then discussed the cost-effectiveness estimate of sunitinib compared with best supportive care submitted by the manufacturer. The Committee considered the ERG comments that the model structure was appropriate for the decision problem. It also noted the concern raised by the ERG that the utility data supplied by the manufacturer in clarification could not be reconciled with data originally submitted. However, the Committee agreed that the cost-effectiveness estimate was relatively insensitive to variations in the utility values and therefore the utility values used in the base case were appropriate.
4.4 The Committee discussed the best supportive care effectiveness data that were used in the economic model. It agreed that the high level of crossover in the RCT confounded the ITT data for the best supportive care arm. The Committee therefore agreed that it was appropriate to adjust the best supportive care effectiveness data for the crossover that had occurred. The Committee considered that as censoring of the participants at the point at which they crossed over was based on very early data, the results would be unreliable. The Committee discussed the RPSFT method used by the manufacturer and the clarification provided after the first Appraisal Committee meeting and agreed that it was an acceptable approach. The Committee then discussed the best supportive care costs that were included in the economic model. The Committee noted that the base-case estimate did not include imatinib as part of best supportive care. The Committee heard from clinical specialists that in practice it may be possible that a person would benefit from imatinib as part of best supportive care because there may be newly formed tumour cells or metastases that could respond to further imatinib therapy. However, the Committee was aware that in the RCT, from which the effectiveness data were derived, no further imatinib therapy was given. The Committee therefore concluded that it was appropriate not to include imatinib as part of best supportive care and that the best supportive care costs in the base case were appropriate.
4.5 The Committee next discussed the source of the sunitinib effectiveness data and costs. The Committee noted that the median progression-free survival in the sunitinib arm of the RCT was shorter than that of the EAP. The Committee acknowledged the manufacturer's response that the EAP results should be viewed principally as confirmation of the safety and efficacy of sunitinib. The Committee agreed that the source of the sunitinib effectiveness data and costs should, if possible, be consistent with the effectiveness data and concluded that the sunitinib effectiveness data and costs should come from the RCT.
4.6 The Committee then considered the difference between sunitinib costs that were included in the economic model and those that could be inferred from the RCT. The Committee noted that 22% of people assigned to sunitinib continued to receive it after disease progression. The costs of this continued treatment were not included in the original economic model, which assumed sunitinib was given only until disease progression. The Committee acknowledged that the effectiveness data came from the RCT and that it was possible that people who received sunitinib after disease progression could have experienced additional benefits. It also heard from clinical specialists that, in practice, sunitinib could be given after disease progression because it was possible that some of the tumour might still respond to sunitinib. Also, many people might experience 'tumour flare' if sunitinib treatment was completely withdrawn. Therefore the Committee agreed that it was important to incorporate the costs of sunitinib given after disease progression, as in the RCT, into the cost-effectiveness estimate. It therefore concluded that the most plausible ICER for sunitinib compared with best supportive care was £31,800 per QALY gained.
4.7 The Committee next discussed the uncertainty surrounding the cost-effectiveness estimates. The Committee acknowledged the revised probabilistic sensitivity analysis presented by the manufacturer after the first Committee meeting. The Committee noted that at a willingness-to-pay threshold of £30,000 per QALY gained, then the most plausible ICER (£31,800) had around 42% probability of being cost effective.
4.8 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 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.
No alternative treatment with comparable benefits is available through the NHS.
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 that the assumptions used in the reference case economic modelling are plausible, objective and robust.
4.9 The Committee then discussed whether sunitinib for unresectable and/or metastatic malignant GIST, given after intolerance or resistance to imatinib, fulfilled the criteria for consideration as a life-extending, end-of-life treatment. It was aware that in England and Wales the total number of people concerned was between 90 and 150, which clearly did not materially influence the numbers of people who might be eligible for sunitinib treatment across all indications. The Committee noted from the clinical trial that the life expectancy for unresectable and/or metastatic malignant GIST, following intolerance or resistance to imatinib, with best supportive care alone was unlikely to be greater than 24 months and was potentially as low as 9 months. The Committee also noted that the evidence from the RPSFT analysis of the trial suggested that sunitinib increased survival by more than 3 months compared with best supportive care. It was further persuaded that sunitinib provided a marked change in the treatment of unresectable and/or metastatic malignant GIST that is intolerant or resistant to imatinib. In addition, the Committee noted the comments from patient experts and clinical specialists highlighting the important benefits of sunitinib. In summary, the Committee was satisfied that sunitinib met the criteria for being a life-extending, end-of-life treatment, and that the evidence presented for this consideration was sufficiently robust.
4.10 The Committee then considered the most plausible cost-effectiveness estimate of £31,800 per QALY gained in light of the appraisal of a life-extending, end-of-life treatment, although this would probably be somewhat higher if the treatment entry criteria widened beyond ECOG performance status 0–1. 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. The Committee also considered 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 the QALY weighting needed would be acceptable even accommodating the small minority of patients with poorer performance status than were entered (before crossover) into the pivotal trial. The Committee concluded that sunitinib as a treatment for unresectable and/or metastatic GIST that is resistant or intolerant to imatinib could be recommended as a cost-effective use of NHS resources.
4.11 In summary, the Committee concluded that sunitinib could be recommended, within its licensed indication, as a treatment option for people with unresectable and/or metastatic malignant GIST after failure of imatinib treatment because of resistance or intolerance. Additionally, the Committee concluded that the use of sunitinib should be supervised by cancer specialists with experience in treating people with unresectable and/or metastatic malignant gastrointestinal stromal tumours after failure of imatinib treatment because of resistance or intolerance.