Nivolumab for treating advanced (unresectable or metastatic) melanoma

Clinical effectiveness

4.1 The Committee discussed the current management of advanced melanoma in the NHS, and the potential place of nivolumab in the treatment pathway. The Committee understood that for advanced (unresectable or metastatic) melanoma that does not have a BRAF‑V600 mutation (BRAF mutation‑negative or 'wild type' disease) ipilimumab is the most common treatment option. For melanoma with BRAF‑V600 mutations (BRAF mutation‑positive disease), the Committee heard that there is a choice between the BRAF inhibitor agents (vemurafenib and dabrafenib), or the immunotherapy agent ipilimumab. The choice would usually be based on whether the disease is progressing rapidly (when a BRAF inhibitor would be used) or more slowly, when ipilimumab would be used. The long survival benefit shown in a proportion of patients treated with ipilimumab (based on 5‑year overall survival data) has led to an increasing interest in immunotherapy agents. The Committee noted that programmed cell death‑1 (PD‑1) receptor inhibitors such as nivolumab and pembrolizumab appear to have a faster onset of action and higher response rate than ipilimumab, and may also be more suitable for treating high‑volume disease. Nivolumab and pembrolizumab have similar mechanisms of action (consisting of an antibody, which blocks the PD‑1 receptor), and both are recommended for use in the same place in the treatment pathway. The clinical experts considered that although some people with rapidly progressing BRAF mutation‑positive melanoma will continue to have BRAF inhibitors as first‑line treatment, it was expected that nivolumab and pembrolizumab would be suitable for more people than ipilimumab. The Committee noted that pembrolizumab was not included in the scope of this appraisal. However, following the recent positive NICE recommendations for pembrolizumab (pembrolizumab for advanced melanoma after disease progression with ipilimumab or not previously treated with ipilimumab) the Committee heard from the clinical experts that nivolumab and pembrolizumab would be considered for the same group of patients. However, pembrolizumab is not yet in routine clinical use and therefore could not be considered as a comparator for the purpose of this appraisal. The Committee was aware that dacarbazine is now used only after the other available treatments, because it has not been shown to improve overall survival. The Committee concluded that the most relevant comparators for this appraisal were ipilimumab, vemurafenib and dabrafenib.

4.2 The Committee discussed the clinical needs of people with advanced melanoma. It heard from the patient expert that melanoma has a major effect on people's health and quality of life. Having a choice of treatments would be particularly valuable to people with this condition, allowing them and their doctors to choose treatments that take into account their individual needs and preferences and giving them a feeling of more control over their condition. The Committee noted that a course of nivolumab treatment requires more frequent intravenous administration for a longer duration (every 2 weeks for as long as continued clinical benefit is observed, potentially up to 2 years or more) than ipilimumab (every 3 weeks, up to a total of 4 doses) and discussed whether this would affect patients' treatment choices. They heard from the patient expert that, above all, patients want effective therapies and would wish to have access to those which were most effective, even if the treatment schedule was more challenging to accommodate. The Committee was also aware that treatment with ipilimumab can be associated with severe side effects, and heard that patients would be willing to take an alternative with an improved toxicity profile even if it requires more frequent administration. The Committee concluded that the availability of an effective new treatment option with acceptable tolerability would be valuable for people with advanced melanoma.

4.3 The Committee discussed the clinical effectiveness of nivolumab. It noted that overall survival data are currently only available from the CheckMate‑066 trial that compared nivolumab with dacarbazine. These data were based on short‑term follow‑up (median duration 8.9 months in the nivolumab group). Early analysis of the data showed a significant overall survival benefit for nivolumab, resulting in the trial being stopped early and being unblinded. The Committee heard from the company that updated 2‑year overall survival data, published in abstract form, showed that the overall survival benefit was maintained at 2 years (57.7% of patients in the nivolumab arm were alive compared with 26.7% of patients in the dacarbazine arm [hazard ratio of 0.43, 95% confidence interval: 0.33 to 0.57]). The Committee recognised that dacarbazine is now infrequently used except in the context of palliative care, and that the effectiveness of nivolumab compared with ipilimumab is more relevant to clinical practice. The Committee noted that overall survival data from CheckMate‑067 (which compared nivolumab with ipilimumab) are not yet available, and it was therefore difficult to draw any firm conclusion on relative overall survival benefit.

4.4 The Committee considered the Kaplan–Meier curves for progression‑free survival from CheckMate‑067, noting that they showed better progression‑free survival with nivolumab than ipilimumab for the entire duration of observation (approximately 20 months). The Committee discussed whether, in some patients, the benefit of nivolumab was likely to be maintained long term, as had been shown in the ipilimumab trials. It recognised that this depended on the biological plausibility of nivolumab and ipilimumab, both immunotherapy agents, having a similar effect on disease suppression. The Committee recognised that there is currently no evidence to suggest that nivolumab will differ from ipilimumab in this respect. However, it emphasised that there was no trial evidence to directly support this conclusion. The Committee concluded that nivolumab is more effective in the short term than ipilimumab, but the long‑term benefit of nivolumab remains highly uncertain until further follow-up data are available.

4.5 The Committee considered whether there were likely to be differences in the clinical effectiveness of nivolumab for people with and without BRAF mutation. The Committee noted that CheckMate‑066 only included people with BRAF mutation‑negative melanoma, but subgroup analyses from CheckMate‑067 and CheckMate‑037 suggest that nivolumab is somewhat less effective in BRAF mutation‑positive disease compared with BRAF mutation‑negative disease. The Committee heard from the company that these differences were not substantial. The Committee also heard from the clinical experts that there is no biologically plausible reason why treatment effect would be dependent on BRAF mutation status, and that in clinical practice the effectiveness of immunotherapy agents is considered to be independent of BRAF status. The Committee concluded that nivolumab is effective for both BRAF mutation‑negative and BRAF mutation‑positive melanoma.

4.6 The Committee discussed whether there were likely to be differences in the clinical effectiveness of nivolumab depending on the expression of programmed death receptor ligand 1 (PD‑L1). The Committee heard from the clinical experts that PD‑L1 expression is not routinely assessed in clinical practice. It also heard that although in the clinical trials an arbitrary threshold of 5% was used to define subgroups (PD‑L1 positive ≥5%, or indeterminate <5%), there is no universally agreed threshold. The Committee noted that subgroup analyses showed that nivolumab appeared effective regardless of PD‑L1 expression. The Committee agreed that because of its mechanism of action, nivolumab was expected to be effective in patients with PD‑L1 expression. However, it concluded that the clinical effectiveness of nivolumab had also been demonstrated in the PD‑L1 indeterminate group.

4.7 The Committee discussed the adverse events associated with nivolumab. It noted that, in the trials, nivolumab was associated with a lower incidence of high‑grade or serious adverse events than ipilimumab or chemotherapy. The Committee concluded that the adverse events related to nivolumab were manageable, and also favourable when compared with chemotherapy and ipilimumab.

4.8 The Committee considered the likely duration of nivolumab treatment in clinical practice. It noted that the summary of product characteristics recommends treatment 'as long as clinical benefit is observed or until treatment is no longer tolerated by the patient'. Clinical advisers to the company had assumed that nivolumab will be given up to a maximum of 2 years. The Committee heard from the clinical experts that there is no evidence to indicate an optimum duration of treatment with nivolumab. It heard from the company that nivolumab reactivates the immune system and that it was plausible that a course of treatment shorter than 2 years might be equally effective. The Committee also heard that regimens shorter than 2 years are currently being investigated in clinical trials. Nevertheless, the clinical experts acknowledged that it may be difficult to stop nivolumab treatment at 2 years if patients are still experiencing benefit. The Committee appreciated that there is considerable uncertainty about the optimum duration of treatment with nivolumab, which will not be clarified until further trials are published. The Committee also expressed the view that a review of this guidance after 2 years (to coincide with the review of pembrolizumab guidance) should be recommended, at which time overall survival data will be more mature, and the optimum duration of treatment may have been clarified.

Cost effectiveness

4.9 The Committee considered the company's model, which compared nivolumab with ipilimumab and dacarbazine in BRAF mutation‑negative disease, and with ipilimumab, vemurafenib and dabrafenib in BRAF mutation‑positive disease, for people with previously untreated advanced (unresectable or metastatic) melanoma. The Committee noted that the ERG considered the structure of the model to be reasonable and consistent with the disease pathway. The Committee noted that the company used covariate‑adjusted parametric curves fitted to patient‑level data from different trials to capture the clinical effectiveness of nivolumab and the comparators, rather than relative effectiveness from the clinical trials or an indirect treatment comparison. The Committee noted that in the company's deterministic sensitivity analyses, the results were most sensitive to the choice of the fitted parametric curves. The Committee noted the particular concerns expressed by the ERG about the company's approach to modelling overall survival. The Committee accepted the structure of the company's model, but gave further consideration to the assumptions used in the modelling of survival.

4.10 The Committee noted that in the company's base‑case analysis, nivolumab was more effective than ipilimumab, with an incremental quality‑adjusted life year (QALY) gained of 1.67 and 1.82 for BRAF mutation negative‑melanoma and BRAF mutation‑positive melanoma, respectively. However, in the ERG's preferred scenario, nivolumab appeared less effective than ipilimumab. The Committee expressed concerns about the substantial difference between these results and discussed possible reasons for the difference. It understood that the main reason for this discrepancy was the different approaches taken by the company and the ERG for modelling time to progression and long‑term survival for patients having nivolumab.

4.11 The Committee then discussed the differences in the approaches taken by the company and the ERG. It noted that the ERG preferred a Weibull curve to the Gompertz curve, which had been used by the company to model time to progression for nivolumab. The Committee appreciated that this would slightly decrease the total QALY gain with nivolumab, but agreed that on its own switching to a Weibull curve would have a minimal effect on the overall cost‑effectiveness. More significant was the company's assumption that patients having nivolumab would have a comparable long‑term survival benefit to that seen in the ipilimumab trials. The Committee recalled its conclusion that the evidence on long‑term survival with nivolumab is highly uncertain, and noted that the ERG considered that overall survival for nivolumab would be better modelled by extrapolation of the CheckMate‑066 data. This approach, when combined with implementing the ERG's preferred curve for time to progression, substantially reduced the QALYs gained with nivolumab (to approximately half of those gained in the company base case), and resulted in it generating fewer QALYs (that is, being less effective) than ipilimumab. The Committee noted that this was at odds with the substantial short‑term progression‑free survival benefit for nivolumab compared with ipilimumab shown in CheckMate‑067, which it thought would not be unreasonable to expect to translate into a survival benefit. The Committee also heard from the company representative that their model predicted that 50% of patients would be alive at 2 years; this was in line with the updated survival analysis of CheckMate‑066 in which 57% of patients were alive at 2‑year follow up. The Committee, while accepting the uncertainty, considered that nivolumab was likely, on the basis of current evidence, to produce a greater QALY gain than ipilimumab. It therefore accepted that the company's analysis represented a reasonable approach to estimate the cost effectiveness of nivolumab.

4.12 The Committee noted that time spent on treatment was a key factor influencing the cost‑effectiveness results. The Committee was aware that currently the maximum duration of treatment is unclear. It noted that the ERG had explored the impact of increasing treatment duration from 2 years to 3 years, and also a scenario with no maximum treatment duration. The Committee noted that increasing treatment duration increased the total cost associated with nivolumab, but did not increase the QALY gained; this decreased slightly. It understood that this was because more time spent on nivolumab treatment resulted in more adverse events. The Committee concluded that lack of evidence on the optimal duration of treatment made the cost‑effectiveness results uncertain. The Committee agreed that there would be more clarity when the results from studies comparing different durations of treatment become available.

4.13 The Committee noted that the company stated that nivolumab was innovative and a step change in the management of advanced melanoma because it treats a life‑threatening and seriously debilitating condition, meets a high unmet need and provides a significant advantage over other treatments used in the UK. Although the Committee did not consider the mechanism of action of nivolumab to be unique, it agreed that the low toxicity and the favourable adverse effect profile of nivolumab compared with other treatments represent a promising new advance in immunotherapy for the treatment of metastatic melanoma. However, it could not identify any specific health‑related benefit that had not already been captured in the QALY calculation.

4.14 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.

4.15 The Committee agreed that the life expectancy of people with advanced (unresectable or metastatic) melanoma is short, generally less than 24 months. The Committee noted the company's comment that the difference in restricted mean survival in CheckMate‑066 between nivolumab and dacarbazine was 3.6 months. The Committee noted that the median overall survival was not reached in the nivolumab arm of any of the trials, so the magnitude of the survival gain was uncertain, but was reassured that the updated survival data from CheckMate‑066 demonstrated that survival benefit in nivolumab‑treated patients was maintained, and that the median survival in the nivolumab group had still not been reached in the updated analysis. The Committee was aware that in addition to advanced melanoma, nivolumab is also licensed for treating advanced or metastatic squamous non‑small‑cell lung cancer after prior chemotherapy; the company estimated the total population for whom nivolumab is indicated to be about 2200 people. The Committee concluded that this represented a small patient population, and that nivolumab meets all the criteria to be considered a life‑extending, end‑of‑life treatment.

4.16 The Committee considered the ICERs from the company's base cases, recalculated to include the discounted prices in the patient access schemes for 3 comparators (ipilimumab, vemurafenib and dabrafenib), which are commercial in confidence. The Committee took into account uncertainties in the clinical and cost‑effectiveness evidence, and the supplementary advice for appraising life‑extending, end‑of‑life treatments. It concluded that, on balance, the ICER for nivolumab is likely to be less than £30,000 per QALY gained in both BRAF mutation‑positive and BRAF mutation‑negative advanced melanoma. It therefore considered nivolumab to be a cost effective use of NHS resources.

4.17 The Committee was aware of NICE's position statement about the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS Payment Mechanism. It acknowledged 'that the 2014 PPRS Payment Mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The Committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal of nivolumab. It therefore concluded that the PPRS Payment Mechanism was irrelevant for the consideration of the cost effectiveness of nivolumab for treating advanced (unresectable or metastatic) melanoma.

Summary of Appraisal Committee's key conclusions