Ipilimumab for previously treated advanced (unresectable or metastatic) melanoma

4 Consideration of the evidence

4.1 The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of ipilimumab, having considered evidence on the nature of advanced (unresectable or metastatic) melanoma and the value placed on the benefits of ipilimumab 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 heard from the clinical specialists that they considered ipilimumab to represent a 'step-change' in the treatment of advanced melanoma and that it is the first new treatment available in 30 years that may offer clinical benefit and possible long-term survival gain for people with advanced, unresectable disease that has progressed after first-line therapy. Other drugs are also in development. The Committee heard that the optimal place for ipilimumab treatment in the clinical pathway for advanced (unresectable or metastatic) melanoma was still being debated in the clinical community. However, the Committee understood that most clinicians in the UK would use ipilimumab as a second-line treatment in line with its UK marketing authorisation. The Committee heard from a patient expert that unresectable melanoma substantially worsens quality of life and, without effective new therapies, the prognosis for advanced disease is very poor. The Committee concluded that there was a significant unmet need for effective therapies in this patient population.

4.3 The Committee considered the evidence presented by the manufacturer on the clinical effectiveness of ipilimumab. It noted that the manufacturer derived efficacy data primarily from the MDX010-20 trial, which showed that treatment with ipilimumab led to a statistically significant median overall survival gain of approximately 3.7 months (HR 0.66; 95% CI 0.51 to 0.87; p=0.0026) compared with gp100 for people with progressive disease after first-line therapy. The Committee heard from the clinical specialists that people treated with ipilimumab will have some survival benefit, but only 10% of people may experience long-term benefits. The Committee was aware that the trial length was 56 months, and that survival benefit was demonstrated for the length of the trial, but that there was uncertainty about continuing benefit thereafter. The clinical specialists indicated that melanoma may have an unpredictable clinical course and that late recurrences are well recognised. The Committee noted that a curative treatment would be expected to result in the disappearance of all visible disease (complete response), but less than 1% of patients in the ipilimumab arms of the MDX010-20 trial showed a complete disease response. In addition, although there was trial evidence of some people whose disease remained stable after being treated with ipilimumab, it was not clear how prolonged that response might be. The clinical specialists agreed that it is too early to regard this as a curative treatment.

4.4 The Committee further considered the additional data presented by the manufacturer. These data were presented to provide further evidence of the survival benefit of ipilimumab over a period of 50 to 70 months' follow-up, and to supplement the evidence from the MDX010-20 trial. The Committee agreed that these additional data supported the findings in the MDX010-20 trial, but agreed with the ERG that the pooling of these additional data with data from the MDX010-20 trial was inappropriate and should not be included in the economic modelling. The Committee concluded that the evidence on the clinical effectiveness of ipilimumab was robust for a period of at least 5 years, and that a small proportion of patients were likely to benefit from ipilimumab in the long term.

4.5 The Committee considered the adverse reactions associated with treatment with ipilimumab. The Committee understood from the clinical specialists and patient experts that people being treated with ipilimumab can have immune-related adverse reactions, which have a substantial negative impact on their quality of life. The Committee noted that 12 deaths related to treatment with ipilimumab occurred in the MDX010-20 trial, but heard from the clinical specialists that subsequent trials of ipilimumab as first-line treatment have not reported any treatment-related deaths. The clinical specialists considered that this indicated that, as experience with ipilimumab grows, adverse reactions will be more quickly identified and treated. The Committee also heard from the patient experts that the possible survival benefits from adhering to treatment with ipilimumab outweigh the severe adverse reactions. The Committee concluded that although the adverse reactions and mortality associated with ipilimumab seen in the MDX010-20 trial were considerable, most adverse reactions, including those that led to hospital admission, were manageable and would be managed more effectively as clinicians become familiar with ipilimumab's toxicity profile. It also concluded that people may be willing to tolerate considerable toxicity if there are potential survival benefits.

4.6 The Committee noted that the UK marketing authorisation for ipilimumab stipulates that people should receive all 4 doses of treatment, even if the disease appears to progress during treatment. The Committee heard from the clinical specialists that late responses to treatment have been reported. It heard that people should therefore continue to be treated unless their disease progresses to a degree that a response is very unlikely, or the side effects become intolerable. The Committee also understood from the clinical specialists that, although it is not possible to predict how a person's condition might respond to ipilimumab, people who experience a substantial decrease in performance status while receiving treatment are likely to have rapidly progressive disease and will not benefit from continued use of ipilimumab. The clinical specialists indicated that despite guidance on the use of all 4 doses, normal clinical evaluation and discussion with patients would be carried out to determine whether or not it was reasonable to continue with treatment. The Committee noted that approximately 65% of people treated with ipilimumab in the MDX010-20 trial received all 4 doses of treatment. They also heard from the clinical specialists that it is likely that more than 65% of people treated with ipilimumab in clinical practice would receive all 4 doses. The Committee concluded that it was reasonable to assume that not all patients would receive 4 doses of ipilimumab in clinical practice despite the administration advice in the UK marketing authorisation.

4.7 The Committee discussed the cost-effectiveness estimates from the manufacturer's original and revised economic models, the assumptions on which these were based, and the ERG's critique and exploratory analyses. The Committee noted that the manufacturer assumed that the gp100 vaccine was clinically comparable to best supportive care and used the efficacy estimates from the gp100 arm in the MDX010-20 trial to inform model inputs. The Committee understood from the clinical specialists that, although studies of vaccines (other than gp100) in people with advanced and metastatic melanoma have shown a survival disadvantage, there is no evidence that this occurs for people treated with gp100. The Committee agreed with the clinical specialists that gp100 is likely to be an acceptable proxy for best supportive care in the model.

4.8 The Committee heard from the manufacturer that EORTC-QLQ and SF-36 data were collected in the MDX010-20 trial. It noted the ERG's concerns that the number of respondents to the questionnaires dropped off considerably after week 12 in the MDX010-20 trial and that there was little difference between the utilities assigned to the progression-free and the progressive disease health states. The Committee noted that additional sensitivity analyses conducted by the manufacturer in response to the appraisal consultation document showed that the utility assumed for the progressive disease state was not a major driver of cost effectiveness. The Committee concluded that the utility estimates derived by the manufacturer were acceptable.

4.9 The Committee noted that the length of follow-up in the MDX010-20 trial was too short to provide robust evidence of the overall survival gain beyond the length of the trial. The Committee expressed confidence in the data from the MDX010-20 trial, supported by data from 3 smaller trials, but noted that beyond this time period the calculation of overall survival gain was dependent on the modelling approach used for extrapolation. It was aware that the manufacturer and the ERG had each presented 2 different approaches. The manufacturer considered that the ERG's initial approach overestimated survival in the short term and underestimated it in the long term, such that the survival curve for the 3 mg/kg ipilimumab dose was below that seen in the observational data, which the Committee considered was implausible. The ERG considered that its updated approach using a mixed exponential approach better fitted the data than the manufacturer's model. The Committee accepted that the MDX010-20 trial showed that ipilimumab provides a 3.7 month median increase in overall survival when compared with best supportive care. However, when taking into account the small number of long-term survivors, there is a substantial degree of uncertainty about the modelling of long-term survival benefits.

4.10 The Committee considered the revised base-case ICERs presented by the manufacturer, taking into account the patient access scheme. The Committee noted that the manufacturer's base-case ICER based on the pooled 3 mg data and its preferred modelling approach was £46,700 per QALY gained and that there was an 81% probability of ipilimumab being cost effective if the maximum acceptable ICER was £50,000 per QALY gained. The ICER showed relatively little change when re-evaluated using a single curve fit, or sensitivity analyses changing the cut-off points in the 3-part model. The ICER, however, rose to £55,800 per QALY gained when the manufacturer used the ERG's prior overall survival modelling approach. The Committee also noted that, when data from only the pivotal MDX010-20 trial were included, the manufacturer's ICER was £42,200 per QALY gained. The corresponding ICER calculated by the ERG using their preferred mixed exponential approach was £58,600 per QALY gained. The Committee previously considered (see section 4.4) that pooling of the 3 mg/kg data from the CA 184-022 trial with data from the MDX010-20 trial was inappropriate, and therefore only the ICERs calculated using the MDX010-20 data alone were appropriate for further consideration. It therefore gave further consideration to the manufacturer's ICER of £42,200 per QALY gained and the ERG's updated preferred estimate of £58,600 per QALY gained. The Committee appreciated that the correct modelling approach was uncertain, but found no evidence to indicate that the ERG's approach was based on more plausible assumptions than the manufacturer's approach. The Committee concluded that the manufacturer's ICER of £42,200 per QALY gained was a plausible estimate.

4.11 The Committee considered the manufacturer's additional scenario analysis on vial sharing and noted that, if it was assumed that 50% of ipilimumab wastage could be avoided, the manufacturer's revised base-case deterministic ICER reduced by approximately £2000 per QALY gained (patient access scheme included). The Committee heard from the clinical specialists that it may be possible to avoid some wastage through vial sharing, particularly in the largest specialist centres, but that the manufacturer's estimate of 50% was overly optimistic. The Committee acknowledged that, although vial sharing may lead to cost savings in some specialist centres, this could be associated with additional administrative costs and logistic difficulties, and therefore it concluded that overall the impact of vial sharing on the cost effectiveness of ipilimumab was likely to be minimal.

4.12 The Committee considered whether it would be appropriate to consider sensitivity analyses on the discount rates used in the model and their effects on the revised ICER. The Guide to the methods of technology appraisal clarification issued by the Board of NICE states that 'where the Appraisal Committee has considered it appropriate to undertake sensitivity analysis on the effects of discounting because treatment effects are both substantial in restoring health and sustained over a very long period (normally at least 30 years), the Committee should apply a rate of 1.5% for health effects and 3.5% for costs'. Having referred to this clarification, the Committee considered that substantial restoration of health for a very long period equated to restoration of health to the extent that the person could be considered as having been effectively cured of their condition. It then considered whether ipilimumab is a treatment given with curative intent. It heard from the clinical specialists that unresectable malignant melanoma that has progressed on previous therapy is not considered to be curable. The Committee noted that a curative treatment would be expected to result in the disappearance of all visible disease (complete response), but that less than 1% of patients in the ipilimumab arms of the MDX010-20 trial showed a complete disease response. In addition, although there was trial evidence of some people whose disease remained stable after being treated with ipilimumab, it was not clear how prolonged that response might be. The clinical specialists agreed that it is too early to regard this as a curative treatment. The Committee concluded that evidence that ipilimumab was a curative treatment was lacking, and that it was unlikely to have substantial benefits for at least 30 years. The Committee therefore concluded that there was no case for differential discounting to be applied.

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 incurable illnesses. For this advice to be applied, all the following criteria must be met:

4.14 The Committee discussed whether ipilimumab met the criteria set out for consideration as an end-of-life treatment. The Committee agreed that the life expectancy for people with advanced melanoma, particularly for those with distant metastases, as reflected in the trial population, was less than 24 months. The Committee also agreed that there was sufficient evidence to indicate that the treatment offers an extension to life of at least an additional 3 months, compared with current NHS treatment. The Committee heard from the clinical specialists that there are approximately 400–500 people with advanced melanoma that has progressed after chemotherapy each year in the UK, which represents a small patient population. Therefore the Committee was satisfied that ipilimumab met the criteria for being a life-extending end-of-life treatment and that the trial evidence presented for this was robust.

4.15 The Committee was mindful that the NICE Guide to the methods of technology appraisal (2008) states that a strong case should be identified for accepting an ICER that is higher than £30,000 per QALY gained. The Committee noted that in these circumstances the NICE methods guide states that judgements about the acceptability of the technology as an effective use of NHS resources will specifically take account of:

4.16 Having accepted that the supplementary advice for appraising a life-extending end-of-life treatment applies, and that the manufacturer's ICER of £42,200 per QALY gained was plausible, but also recognising that it could be higher using other approaches to modelling overall survival, the Committee considered whether ipilimumab could be considered a cost-effective use of NHS resources. On balance, the Committee considered that, given the robust clinical data available for a period of 50 to 70 months, the likelihood of long-term effectiveness in a small proportion of patients and the innovative nature of ipilimumab, it could be concluded that ipilimumab is a cost-effective use of NHS resources.

4.17 The Committee discussed whether the assessment of the change in health-related quality of life had been adequately captured in the economic analysis. It heard from a patient expert that people who are successfully treated, although in the minority, could lead an active and fulfilling life and were able to contribute to society. The Committee accepted that ipilimumab represents a valuable new therapy and that the mechanism of action is novel. It acknowledged that few advances had been made in the treatment of advanced melanoma in recent years and ipilimumab could be considered a significant innovation for a disease with a high unmet clinical need. Nevertheless, the Committee considered that the clinical benefit of ipilimumab had been fully captured in the QALY calculation and concluded that, with the patient access scheme applied to the cost of ipilimumab, it had been demonstrated to be a cost-effective use of NHS resources for the treatment of advanced (unresectable or metastatic) malignant melanoma for people who have received prior therapy.