NICE UK recommended nivolumab as monotherapy, within its marketing authorisation, as an option for treating advanced (unresectable or metastatic) melanoma in adults. The guidance was published on 18 February 2016. NHS England has committed to funding this treatment, in line with the evidence-based recommendations, within 30 days of publication. Next review date is foreseen in February 2018.
Nivolumab is a human monoclonal antibody (immunoglobulin G4) that blocks the programmed cell death 1 receptor (PD 1). This receptor is part of the immune checkpoint pathway, and blocking its activity may promote an anti-tumour immune response. Nivolumab has a marketing authorisation as monotherapy for treating advanced (unresectable or metastatic) melanoma in adults. It is administered intravenously over 60 minutes at a dose of 3 mg/kg every 2 weeks. The summary of product characteristics recommends that treatment should be continued as long as clinical benefit is observed or until treatment is no longer tolerated.
The most common (occurring in 15% or more of people) adverse reactions with nivolumab in clinical trials of advanced melanoma were fatigue, rash, itching, diarrhoea, and nausea.
The acquisition cost of nivolumab is 439 GBP per 4 ml (40 mg) vial and 1097 GBP per 10 ml (100 mg) vial (excluding VAT; company's submission). Costs may vary in different settings because of negotiated procurement discounts.
The NICE Appraisal Committee concluded that:
- nivolumab is more effective in advanced melanoma in the short term than ipilimumab, but the long term benefit of nivolumab remains highly uncertain
- there is considerable uncertainty about the optimum duration of treatment with nivolumab
- nivolumab meets all the criteria to be considered a life extending, end of life treatment
- the incremental cost-effectiveness ratio (ICER) for nivolumab is likely to be less than 30,000 GBP per quality adjusted life year (QALY) gained in both BRAF mutation positive and BRAF mutation negative advanced melanoma, making it a cost effective use of NHS resources
- review of this guidance after 2 years should be recommended, when matured overall survival data and the results of studies investigating optimum treatment duration will be available.
Clinical need of patients, including the availability of alternative treatments
The NICE Appraisal Committee heard that ipilimumab is the most common treatment option for BRAF mutation negative advanced melanoma, and for BRAF mutation positive disease there is a choice between the BRAF inhibitor agents (vemurafenib and dabrafenib) and ipilimumab.
The NICE Appraisal Committee concluded that the availability of an effective new treatment option with acceptable tolerability would be valuable for people with advanced melanoma.
The technology
How innovative is the technology in its potential to make a significant and substantial impact on health related benefits?
The NICE Appraisal Committee noted that 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.
The NICE Appraisal Committee agreed that the low toxicity and the favourable adverse effects 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.
What is the position of the treatment in the pathway of care for the condition?
The NICE Appraisal Committee heard from the clinical experts that nivolumab and pembrolizumab would be considered for the same group of patients. Because pembrolizumab is not yet in routine clinical use, it concluded that ipilimumab, vemurafenib and dabrafenib were appropriate comparators for this appraisal.
Adverse reactions
The NICE Appraisal Committee concluded that the adverse events related to nivolumab were manageable, and also favourable when compared with chemotherapy and ipilimumab.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The NICE Appraisal Committee noted that overall survival data are only available from the CheckMate 066 trial that compared nivolumab with dacarbazine. It also considered the updated 2 year overall survival data from CheckMate 066. 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 considered the Kaplan–Meier curves for progression free survival from CheckMate 067.
Relevance to general clinical practice in the NHS
The NICE Appraisal 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 NICE Appraisal 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 NICE Appraisal Committee concluded that the availability of an effective new treatment option with acceptable tolerability would be valuable for people with advanced melanoma.
Uncertainties generated by the evidence
The NICE Appraisal 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.
The NICE Appraisal Committee concluded that the long term benefit of nivolumab remains highly uncertain until further follow up data are available.
The NICE Appraisal Committee appreciated that there is considerable uncertainty about the optimum duration of treatment with nivolumab.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
The NICE Appraisal Committee noted that 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. However, it heard that these differences were not substantial.
The NICE Appraisal Committee noted that subgroup analyses also showed that nivolumab appeared effective regardless of PD L1 expression, but that comparatively better outcomes were seen in people with positive PD L1 expression.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The NICE Appraisal Committee heard that updated 2 year overall survival data 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]).
Evidence for cost effectiveness
Availability, nature and quality of evidence
The NICE Appraisal Committee noted that overall survival data are only available from the CheckMate 066 trial that compared nivolumab with dacarbazine. It also considered the updated 2 year overall survival data from CheckMate 066. The NICE Appraisal 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 NICE Appraisal Committee noted that overall survival data from CheckMate 067 (which compared nivolumab with ipilimumab) are not yet available and considered the Kaplan–Meier curves for progression free survival from CheckMate 067.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The NICE Appraisal Committee considered the company's assumption, that patients having nivolumab would have a comparable long term survival benefit to that seen in the ipilimumab trials, to be highly uncertain. However, the NICE Appraisal Committee agreed that it would not be unreasonable to expect that the short term progression free survival benefit for nivolumab compared with ipilimumab would translate into a survival benefit.
The NICE Appraisal Committee concluded that lack of evidence on the optimal duration of treatment made the cost effectiveness results uncertain.
Incorporation of health-related quality-of-life benefits and utility values
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
The company used EQ 5D values from CheckMate 066, using regression analysis to estimate utility values for health states in the model.
The modelled utility decrements for adverse events were based on Beusterien et al., 2009.
The NICE Appraisal Committee could not identify any specific health related benefit that had not already been captured in the QALY calculation.
Are there specific groups of people for whom the technology is particularly cost effective?
No subgroups were considered.
What are the key drivers of cost effectiveness?
The NICE Appraisal Committee noted that in the company's deterministic sensitivity analyses, the results were most sensitive to the choice of the fitted parametric curves.
The NICE Appraisal Committee noted that time spent on treatment was a key factor influencing the cost effectiveness results.
Most likely cost effectiveness estimate (given as an ICER)
The NICE Appraisal Committee concluded that the ICER for nivolumab is likely to be less than 30,000 GBP per QALY gained in both BRAF mutation positive and BRAF mutation negative advanced melanoma.
The exact ICERs are confidential and cannot be reported on NICE website.
Patient access schemes
The NICE Appraisal 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.
End-of-life considerations
The NICE Appraisal Committee agreed that the life expectancy of people with advanced (unresectable or metastatic) melanoma is short. It also agreed that nivolumab is indicated for a small patient population and survival gain with nivolumab compared with current NHS treatment is likely to be more than 3 months. The NICE Appraisal Committee therefore concluded that nivolumab meets all the criteria to be considered a life extending, end of life treatment.
Equalities considerations and social value judgements
No equality issues were identified.
Read the full NICE guidance here.