Ipilimumab for previously untreated advanced (unresectable or metastatic) melanoma

4 Consideration of the evidence

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.

4.1 The Committee considered the nature of the condition and current clinical practice for treating patients with previously untreated advanced (unresectable or metastatic) melanoma. The Committee was aware that unresectable or metastatic melanoma substantially worsens quality of life and is a life-limiting incurable condition. Without effective new therapies, the prognosis for advanced disease is very poor. The Committee heard from the clinical specialists that for patients who have BRAF V600 mutation-negative melanoma, dacarbazine is the only first-line treatment option currently available and it has never been shown to have survival benefit. The Committee also noted comments received during consultation from patient organisations, healthcare professionals and carers that dacarbazine had not been shown to have a survival benefit. The clinical specialists stated that consequently, current practice included administering dacarbazine, usually with early scanning after 1 to 3 courses, before moving to second-line ipilimumab. For patients who have BRAF V600 mutation-positive melanoma, the Committee heard that vemurafenib was likely to remain the standard first-line treatment option especially in those with a high disease burden, but understood that ipilimumab would be valuable as a first-line option in approximately 20–30% of patients with small-volume indolent disease for whom vemurafenib could be reserved as rescue treatment later in the pathway. The clinical specialists stated that although it is not possible to identify patients most likely to experience a response with ipilimumab, in some patients whose condition responds to treatment it was associated with a very durable response. Patient experts at the first committee meeting emphasised that having the choice of ipilimumab as a first-line treatment would be valued by patients and their families and a treatment that prolongs survival could allow people to return to normal life. The Committee concluded that there was an unmet need for effective therapies in this patient population.

4.2 The Committee discussed the clinical evidence presented in the manufacturer's original submission for ipilimumab alone compared with dacarbazine as a first‑line treatment. The Committee noted that the pivotal trial in this submission, CA184‑024, assessed ipilimumab 10 mg/kg plus dacarbazine, whereas the licensed regimen was 4 doses of ipilimumab 3 mg/kg alone over 12 weeks. The Committee was aware that in using data from this trial to estimate clinical effectiveness, the manufacturer had assumed that ipilimumab 3 mg/kg and 10 mg/kg were equivalent and that ipilimumab plus dacarbazine was equivalent to ipilimumab alone. The Committee was aware of the European Medicines Agency (EMA) considerations when extending the marketing authorisation for ipilimumab 3 mg/kg into the first-line setting (see section 3.14). The Committee understood that in estimating the benefit–risk balance, the EMA concluded that sufficient evidence of the efficacy of ipilimumab 3 mg/kg in previously untreated patients had been provided. It also understood that this conclusion was partly based on having already established the efficacy of 3 mg/kg ipilimumab monotherapy in previously treated melanoma, taking into account the similarity of the previously treated and previously untreated sub-populations in the clinical studies. The Committee noted that during consultation, the manufacturer had accepted the Committee's reluctance to agree to equivalent efficacy of 10 mg/kg ipilimumab plus dacarbazine and 3 mg/kg ipilimumab alone. The manufacturer therefore proposed an alternative approach to assessing the clinical and cost effectiveness of 3 mg/kg ipilimumab monotherapy first-line. This method used data from the MDX010‑20 trial, which had been the pivotal trial for Ipilimumab for previously treated advanced (unresectable or metastatic) melanoma (NICE technology appraisal guidance 268; hereafter referred to as TA268). The Committee concluded that this provided additional relevant evidence and expressed disappointment that the manufacturer had not used the information from the full MDX010‑20 trial in its original submission.

4.3 The Committee further considered these data, which compared 3 mg/kg ipilimumab alone, 3 mg/kg ipilimumab plus gp100 and gp100 alone in the second‑line setting. The Committee agreed that the Kaplan–Meier overall survival curves from CA184‑024 and MDX010‑20 were similar, with both demonstrating an approximate 10% long-term overall survival benefit and no treatment crossover, and noted that combination treatment was used in both trials. The Committee also noted that the trials had different doses of ipilimumab, first-line compared with second-line trial populations, and different comparators. The Committee heard from the clinical specialists that treatments would usually be more effective rather than less effective if used earlier in therapy, and that there was no biologically plausible reason for ipilimumab monotherapy at a dose of 3 mg/kg to be less effective when used first-line rather than second-line. The Committee acknowledged that the shape of the Kaplan–Meier curves was similar in the first- and second-line settings and both indicated that approximately 10% of patients experienced a sustained overall survival benefit lasting until the end of the 5‑year trials. The Committee concluded that it is plausible that 3 mg/kg ipilimumab could give the same treatment effect in both untreated and previously treated melanoma and that the use of the MDX010‑20 trial data from the previous appraisal (TA268) provided more plausible estimates of the clinical effectiveness of 3 mg/kg ipilimumab in the first-line setting than those provided in the manufacturer's original submission.

4.4 The Committee discussed the overall survival results from the clinical trials and noted that the difference in median overall survival was 2.1 months when given first-line at 10 mg/kg in combination with dacarbazine, and 3.7 months when given alone at 3 mg/kg as a second-line treatment. The Committee noted that, because of the long duration and lack of crossover in the CA184‑024 trial, patient-level data on mean overall survival were also available, which included all patients in the trial up to 5 years. This demonstrated a mean overall survival gain of 5.7 months for patients in the ipilimumab arm. The Committee concluded that both trials had demonstrated an overall survival gain for patients treated with ipilimumab, and that this gain was at least 3 months.

4.5 The Committee discussed the evidence available for ipilimumab 3 mg/kg alone compared with vemurafenib in the BRAF V600 mutation-positive population. The Committee was aware that no data were available for a direct comparison and the manufacturer had attempted to conduct an indirect comparison using the CA184‑024 and BRIM‑3 trials in its original submission. In addition to its previous observations on the 10 mg/kg dose of ipilimumab in the CA184‑024 trial, the Committee had expressed concern that patients in the vemurafenib BRIM‑3 trial may have had a worse prognosis than those in the ipilimumab trial, which would affect the calculation of differential effectiveness. In its updated analysis in response to consultation, the manufacturer had made an adjustment to take account of the worse prognosis of patients in BRIM‑3, and also the degree of subsequent ipilimumab therapy. Following the various adjustments, the Committee concluded that the data were suitable for estimating the clinical effectiveness of ipilimumab 3 mg/kg compared with vemurafenib.

4.6 The Committee discussed comments received during consultation about patients with ocular melanoma who might be excluded from the preliminary 'only in the context of research' recommendation because they are usually excluded from clinical trials. The Committee heard from the clinical specialists that, even though ocular melanoma is biologically different from cutaneous melanoma, patients are offered the same treatment options. The Committee concluded that patients with ocular melanoma could be included in the final guidance.

4.7 The Committee discussed the incremental cost-effectiveness ratios (ICERs) presented in the manufacturer's original model, focusing in particular on the extent of the impact of the manufacturer's assumptions on the results. The Committee noted that the Evidence Review Group (ERG) had performed exploratory analyses that were intended to better reflect the clinical effectiveness of ipilimumab 3 mg/kg alone in the model, as well as adjusting a parameter in the overall survival data for concomitant dacarbazine. The Committee noted that this resulted in ICERs ranging from approximately £60,000 to £74,000 per quality‑adjusted life year (QALY) gained for ipilimumab compared with dacarbazine in the BRAF V600 mutation-negative population and in ipilimumab being less costly and less effective compared with vemurafenib in the BRAF V600 mutation‑positive population. The Committee noted that there was a difference in the cost of ipilimumab between first- and second-line use in the manufacturer's model. The manufacturer explained that the costs were based on trial data and that the number of patients who received the fourth ipilimumab 10 mg/kg dose first-line in the CA184‑024 trial was smaller than the number who received the fourth ipilimumab 3 mg/kg dose second-line in the MDX010‑020 trial. The Committee discussed whether this was because of greater adverse events associated with the higher dose of ipilimumab, but the manufacturer stated that the higher efficacy of ipilimumab would also need to be taken into account. The Committee considered that this suggestion of increased effectiveness with more doses was not in line with the manufacturer's assumption that ipilimumab 10 mg/kg was clinically equivalent to ipilimumab 3 mg/kg. It also noted that the ERG's analyses, which explored the impact of assuming that first-line costs also apply in second‑line treatment, resulted in an increase in the ICER for ipilimumab compared with dacarbazine from approximately £17,000 to £25,700 per QALY gained in the BRAF V600 mutation-negative population.

4.8 The Committee considered the exploratory cost-effectiveness analysis presented by the ERG, based on the manufacturer's original model, which included modelling of only first-line use, and assumed a reduction in efficacy for a 3 mg/kg rather than a 10 mg/kg dose and a reduction in effectiveness in the absence of concomitant dacarbazine. The Committee noted in the first committee meeting that this approach resulted in high ICERs compared with dacarbazine. It also resulted in ipilimumab being dominated by (that is, being more expensive and less effective than) vemurafenib. It also noted that these estimates included an estimate of QALYs gained approximately 10 to 20 times lower than the original base case for the comparison of ipilimumab with dacarbazine. The Committee considered that these estimated QALY gains were not plausible when taking into account the long-term survival shown in approximately 10% of patients in CA184‑024 and the second-line trial MDX010‑020 and did not consider this exploratory analysis further.

4.9 The Committee considered the manufacturer's response to consultation and the updated analyses using the adjusted overall survival curve from the second-line trial MDX010‑20 to estimate the clinical effectiveness of 3 mg/kg ipilimumab first‑line. The Committee was aware that in the updated base-case analysis, the manufacturer used overall survival and progression-free survival rates for ipilimumab from the previous appraisal (TA268), and overall survival and progression-free survival for dacarbazine were taken from the CA184‑024 trial. Overall survival was then adjusted to take into account differences in the patient baseline characteristics. The Committee noted the ERG's concerns that the approach used by the manufacturer was inconsistent with the previous appraisal. The Committee heard from the manufacturer who clarified how the adjustments were applied. The Committee was satisfied that the adjustment and use of prognostic factors by the manufacturer in its updated analyses was appropriate.

4.10 The Committee considered the manufacturer's updated base-case results submitted in response to consultation (see section 3.39 onwards). It noted that the ICER for ipilimumab compared with dacarbazine was substantially higher than that in the original submission (£47,900 compared with £17,000 per QALY gained). It also noted that the ICER for ipilimumab compared with vemurafenib was £28,600 per QALY gained, whereas in the original submission ipilimumab dominated vemurafenib. The Committee discussed the reasons for these differences and noted that the main reason was the use of a 3‑state model, which had been preferred by the ERG, instead of the sequential modelling used in the manufacturer's original submission. The Committee also noted that the updated model incorporated a lower estimate of effectiveness for ipilimumab than that used in the original model, informed by the data from the MDX010‑20 trial. The Committee agreed with the use of the 3‑state model and accepted that there are some uncertainties about the assumption of equivalent effect of ipilimumab in previously untreated and treated melanoma. The Committee accepted that the updated ICER of £28,600 per QALY gained for ipilimumab compared with vemurafenib was plausible. It also accepted that the updated ICER of £47,900 per QALY gained for ipilimumab compared with dacarbazine was plausible, although it accepted that the ICER could be higher if other approaches were used to model overall survival.

4.11 The Committee discussed whether ipilimumab was innovative in its potential to make a significant and substantial impact on health-related benefits. The Committee heard from the clinical specialists and a patient representative (at the first meeting) that, after successful treatment, patients could lead an active and fulfilled life. The Committee acknowledged that few advances had been made in the treatment of advanced melanoma in recent years and that ipilimumab could be considered a significant innovation for a disease with a high unmet clinical need.

4.12 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:

4.13 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 was less than 24 months. The Committee then discussed whether ipilimumab offered a 3‑month survival gain. It 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 (see section 4.4). The Committee heard from the clinical specialists that there are fewer than 1000 people in England with advanced melanoma who need first-line treatment, and this represents a small patient population. 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.

4.14 Having accepted that the supplementary advice for appraising a life-extending, end-of-life treatment applies, the Committee then considered the ICERs for ipilimumab compared with dacarbazine and compared with vemurafenib. It accepted the manufacturer's ICER for ipilimumab compared with vemurafenib, which was £28,600 per QALY gained. It accepted that the ICER of £47,900 per QALY gained for ipilimumab compared with dacarbazine was plausible, while recognising that it could be higher if other approaches to modelling overall survival were used. The Committee concluded that, on balance, ipilimumab could be considered a cost-effective use of NHS resources for adults with previously untreated advanced (unresectable or metastatic) melanoma.