Nivolumab for treating advanced (unresectable or metastatic) melanoma

Evidence-based recommendations on nivolumab (Opdivo) for treating advanced (unresectable or metastatic) melanoma in adults.

# Recommendations
Nivolumab as monotherapy is recommended, within its marketing authorisation, as an option for treating advanced (unresectable or metastatic) melanoma in adults.# The technology
Nivolumab (Opdivo, BristolMyers Squibb) is a human monoclonal antibody (immunoglobulin G4) that blocks the programmed cell death1 receptor (PD1). 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. For full details of adverse reactions and contraindications, see the summary of product characteristics.
The acquisition cost of nivolumab is 439 per 4 ml (40 mg) vial and 1097 per 10 ml (100 mg) vial (excluding VAT; company's submission). Costs may vary in different settings because of negotiated procurement discounts.# Evidence
The Appraisal Committee (section 7) considered evidence submitted by BristolMyers Squibb and a review of this submission by the Evidence Review Group (ERG; section 8). See the Committee papers for full details of the evidence.

# Clinical effectiveness
The company presented evidence from 3 ongoing phase III randomised controlled trials (RCTs; CheckMate066, CheckMate067 and CheckMate037). These trials evaluated the clinical effectiveness of nivolumab monotherapy, administered intravenously (IV) every 2 weeks at a dose of 3 mg per kg of body weight. The company also included a phase I dose escalating study (CheckMate033) as supporting evidence.
CheckMate066 was a multicentre, international (no centres in the UK), double-blind RCT that compared nivolumab (n=210) with dacarbazine 1000mg/m2 IV every 3 weeks (n=208), in people with untreated advanced melanoma without a BRAF mutation. CheckMate067 was a multicentre, international (7 UK centres), double-blind RCT that compared nivolumab monotherapy (n=316) or nivolumab combined with ipilimumab (n=314) with ipilimumab monotherapy 3mg/kg IV every 3 weeks (n=315) in people with untreated advanced melanoma with and without the BRAF mutation. The company did not present results for the nivolumab plus ipilimumab arm because it is outside the scope of this appraisal. CheckMate037 was a multicentre, international (5 UK centres), open-label RCT that compared nivolumab (n=272) with the investigators' choice of chemotherapy (n=133), in people with BRAF mutationnegative advanced melanoma that progressed on or after ipilimumab, and BRAF mutationpositive advanced melanoma that progressed on or after ipilimumab and a BRAF inhibitor (vemurafenib or dabrafenib). The investigators' choice of chemotherapy was dacarbazine or carboplatin plus paclitaxel.
The company stated that baseline demographics and disease characteristics were generally well balanced across the trials, with the exception of a higher proportion of patients with a history of brain metastases (19.5% compared with 13.5%) and elevated LDH (51.1% compared with 34.6%) in the nivolumab arm of CheckMate037.
Overall survival data were only available from CheckMate066. In CheckMate067 and 037 the minimum followup period was not reached or an insufficient number of events (deaths) had occurred at the time of analysis. Overall survival from CheckMate066 was based on an interim analysis at a median followup of 8.9 months in the nivolumab group and 6.8 months in the dacarbazine group. In the nivolumab group 50 out of 210 (23.8%) of patients had died at the time of the analysis therefore median overall survival could not be estimated. Patients in the dacarbazine group had a median survival of 10.8 months. The corresponding hazard ratio for death in the nivolumab group compared with the dacarbazine group was 0.42 (95% confidence interval : 0.30 to 0.60).
All 3 trials reported progressionfree survival, defined as the time interval between randomisation and disease progression or death. Nivolumab was associated with statistically significant increases in progressionfree survival, compared with dacarbazine and ipilimumab in CheckMate066 and 067 respectively. However, in CheckMate037 there was no statistically significant difference in progressionfree survival between nivolumab and the comparator (investigators' choice of chemotherapy); see table 1 for results. The company stated that the results from CheckMate037 were confounded by immaturity of the data, imbalances in the prognostic factors between trial groups, high withdrawal rates in the comparator arm and falsepositive progression assessments in the nivolumab arm resulting from the use of Response Evaluation Criteria in Solid Tumours (RECIST criteria).

## Table 1 Clinicaleffectiveness outcomes from the CheckMate trials
Outcomes
Nivolumab
Comparator
Hazard ratio (95% CI)
p value
Overall survival
CheckMate066 (nivolumab  vs dacarbazine )
Events (death) %
(0.30 to 0.60)
Median survival (months)
Not reached
Not applicable
Not applicable
Progression free survival
CheckMate066 (nivolumab  vs dacarbazine )
Events (death or progression), %
(0.34 to 0.56)
Median PFS (months)
CheckMate067 (nivolumab  vs ipilimumab )
Events (death or progression) %
(0.43 to 0.76)
Median PFS (months)
CheckMate037 (nivolumab  vs investigators' choice of chemotherapy )
Events (death or progression) %
(99.99% CI 0.32 to 2.05)
Not significant
Median PFS (months)
Not significant
Abbreviations: CI, confidence interval; n, number; PFS, progression free survival; vs, compared with.
The objective response rate (defined as the proportion of patients with complete or partial response assessed by RECIST criteria) was the primary outcome in CheckMate037 and a secondary outcome in CheckMate066 and CheckMate067. Patients treated with nivolumab had statistically significantly better objective response rate than in the comparator arms in all trials.
The company included healthrelated quality of life results only from CheckMate066. EQ5D utility index scores and EORTC QLQC30 global health status scores were higher at baseline and for the entire period of observation for nivolumab compared with dacarbazine. However, there was no improvement in quality of life from baseline in the nivolumab arm, or a consistent difference in quality of life between nivolumab and dacarbazine.
The company presented a series of a priori subgroup analyses from the trials, showing improved effectiveness of nivolumab compared with dacarbazine and ipilimumab across most subgroups. Subgroup analyses by BRAF mutation status in CheckMate067 and Checkmate037 showed that nivolumab was more effective than the comparator treatments in both subgroups (people with or without BRAF mutation). However, the magnitude of the effect was higher in the subgroup without BRAF mutation. For example, in the nivolumab group of CheckMate067, median progression-free survival was 7.89 months in people with BRAF mutationnegative melanoma and 5.62 months in people with BRAF mutationpositive melanoma. The median progression-free survival in the ipilimumab group was 2.83 months in people with BRAF mutationnegative melanoma and 4.04 months in people with BRAF mutationpositive melanoma. Subgroup analyses based on the expression of programmed death receptor ligand 1or PDL1 (defined as PDL1 positive if 5% or more cells expressed PDL1, and PDL1 negative or indeterminate with less than 5% expression) showed nivolumab to be more effective than the comparators regardless of PDL1 expression. The results were comparatively better in patients who were PDL1 positive than in the patients who were PDL1 negative or indeterminate.
The company also included evidence from a nonrandomised, doseescalation study (CheckMate003) of nivolumab in patients with solid tumours, including melanoma (n=107), to support the assumption of the maximum treatment duration with nivolumab of 2 years. In patients with advanced melanoma treated with the licensed dose of nivolumab (n=17), median overall survival was 20.3 months and median duration of response to treatment was approximately 2 years.
The company presented adverse event data from all 3 trials. Fewer people treated with nivolumab had treatmentrelated adverse events, particularly of grade 34, than those treated with the comparators in all 3 trials. The company also highlighted that in CheckMate067 nivolumab was associated with a favourable safety profile compared to ipilimumab, particularly for common immune system related adverse events.
The company compared the clinical effectiveness of nivolumab, indirectly, with the comparators listed in the scope using 2 separate networks; for BRAF mutationnegative advanced melanoma (compared with ipilimumab and dacarbazine) and BRAF mutationpositive advanced melanoma (compared with BRAF inhibitors vemurafenib and dabrafenib). The company used patientlevel data (for nivolumab, dacarbazine and ipilimumab) or estimated 'pseudo' patient-level data (for vemurafenib and dabrafenib) from the trials. It selected the bestfitting survival function for the outcomes needed for economic modelling after adjusting for covariates for each treatment arm.

# Cost effectiveness
The company submitted a semiMarkov survival model to estimate the cost effectiveness of nivolumab in people with previously untreated advanced (unresectable, metastatic) melanoma. The economic analyses were presented separately for BRAF mutationnegative disease (compared with dacarbazine and ipilimumab) and BRAF mutationpositive disease (compared with dabrafenib, ipilimumab and vemurafenib). The model had 3 health states: preprogression, progression and death. Utility in the progression-free and progressed states was subdivided into 2 further states: 30 days or more before death; and less than 30 days before death. For modelling resource use, the entire time horizon was divided in to 4 periods: first year after treatment initiation; second year after treatment initiation; third and subsequent years after treatment initiation; and 12 weeks before death. The model adopted a lifetime time horizon of 40 years and a cycle length of 1 week. The model perspective was NHS and personal social services and costs and benefits were discounted at a rate of 3.5% per year.
The company based the patient characteristics in the model on CheckMate066 for BRAF mutationnegative disease and from the vemurafenib arm of BRIM3 for BRAF mutationpositive disease. The model allowed subsequent treatment with ipilimumab for people having nivolumab and other comparator treatments except ipilimumab. In the base case, 29.7% and 22.0% people with BRAF mutationnegative and BRAF mutationpositive melanoma respectively, had subsequent ipilimumab treatments.
In the model, the clinical-effectiveness estimates for nivolumab and dacarbazine were based on patient-level data from CheckMate066. For ipilimumab, patient-level data from the MDX01020 trial were used. MDX01020 was a phase III trial that evaluated the efficacy of ipilimumab in people with previously treated advanced melanoma. For BRAF inhibitors, the company identified 2 trials; BRIM3 and BREAK3. Both were phase III trials that evaluated vemurafenib and dabrafenib respectively, in people with BRAF mutationpositive advanced melanoma. The company generated pseudo patientlevel data from published KaplanMeier curves for BRAF inhibitors based on the vemurafenib BRIM3 (base case) or dabrafenib BREAK3 (scenario analysis) and assumed that both are equally effective. The company considered the lognormal and generalised gamma distributions to be the best fit for overall survival and progressionfree survival respectively, for BRAF inhibitors. The company used the same methods for deriving transition probabilities in BRAF mutationpositive disease as it did in BRAF mutationnegative disease, except that the baseline patient characteristics for the BRAF mutationpositive disease were taken from the BRIM3 trial.
Time to progression was modelled using KaplanMeier data from CheckMate066 (for nivolumab and dacarbazine) and from MDX01020 (for ipilimumab) for the first 100 days, followed by fitted parametric curves using the Gompertz distribution in the base case. For preprogression survival, the company used KaplanMeier data adjusted by covariates for the length of follow-up because none of the fitted curves provided an acceptable visual fit to the observed data.
The company applied survival data from the trials in the model for the first 3 years for nivolumab and ipilimumab, and for the first 2 years for dacarbazine and BRAF inhibitors. Longterm overall survival was modelled using the registry data from the American Joint Committee on Cancer for BRAF inhibitors and dacarbazine. For modelling longterm survival in patients treated with nivolumab and ipilimumab, the company used pooled data on survival from 12 ipilimumab studies as reported by Schadendorf et al (2015) and applied these from year 3 onwards for nivolumab and ipilimumab. The company also applied mortality data for England as background mortality in the model.
For 'time on treatment' with nivolumab, a loglogistic parametric curve was fitted to the CheckMate066 trial data to calculate the proportion of patients continuing to have nivolumab in each cycle. The base case assumed maximum duration of treatment with nivolumab of 2 years. The model estimated that at 2 years, 23% of patients with BRAF mutationnegative melanoma and 20% of patients with BRAF mutationpositive melanoma would still be having nivolumab. The treatment effect of nivolumab was assumed to be maintained on discontinuation of therapy in the base case, based on observational data from CheckMate003 and UK clinical expert opinion. This assumption was tested in scenario analyses. For dabrafenib, vemurafenib and dacarbazine the model assumed that treatment would continue until disease progression, in accordance with the marketing authorisations. The company stated that although ipilimumab is usually given for a maximum of 4 doses, patients could have ipilimumab for up to 16 doses (4 doses for the induction and up to 12 further doses if needed, based on the design of MDX01020).
The model included adverse events for endocrine disorder (any grade), diarrhoea (grade 2+) and other adverse events (grade 3+), based on data from CheckMate066 for nivolumab and dacarbazine, and CheckMate067, BREAK3 and BRIM3 trials for ipilimumab, dabrafenib and vemurafenib respectively.
The company used EQ5D values from CheckMate066, using regression analysis to estimate utility values for health states in the model. The values used for each stage (preprogression and post progression) depended upon time to death (30 days or more and less than 30 days):
preprogression stage and 30 days or more from death, 0.8018
preprogression stage and less than 30 days from death, 0.7795
postprogression stage and 30 days or more from death, 0.7277
postprogression stage and less than 30 days from death, 0.7054.
The modelled utility decrements for adverse events were based on Beusterien et al., 2009. These were applied at the start of the model and then periodically to patients who were still on treatment after every 35 weeks.
The resource use categories in the model were treatment costs, healthstate resourceuse costs and cost for treating adverse events. The same sources were used for estimating these costs in a recent NICE appraisal of ipilimumab for previously untreated advanced melanoma. Resource use for health states was estimated based on the MELODY observational study that collected data on resource use in patients with advanced melanoma. Other costs were sourced from MIMS, NHS reference costs 2013/4, and Personal Social Services Research Unit (PSSRU) 2014.
The company presented basecase results using the list prices for all drugs (see tables 2 and 3). In the company's base-case analyses, nivolumab provided a total of 4.31 and 4.27 quality-adjusted life years (QALYs) in the BRAF mutationnegative melanoma and BRAF mutationpositive melanoma groups respectively. When compared with ipilimumab the absolute increment in QALY gained with nivolumab was 1.67 and 1.82 for BRAF mutationnegative melanoma and BRAF mutationpositive melanoma respectively. The fully incremental comparisons with all comparators demonstrated that for BRAF mutationnegative melanoma, ipilimumab was extendedly dominated (that is, it had an incremental cost effective ratio  relative to dacarbazine, higher than that of the next most effective strategy, nivolumab). Nivolumab had an ICER of 23,583 per QALY gained compared with dacarbazine (see table 2). Similarly, in BRAF mutationpositive melanoma nivolumab dominated (that is, provided more QALYs at lower cost than) both dabrafenib and vemurafenib. Nivolumab was more costly and more effective than ipilimumab, with an ICER of 7346 per QALY gained (see table 3). Because ipilimumab, vemurafenib and dabrafenib are recommended by NICE only with patient access schemes, these results were not used for decisionmaking and are included here for illustration only. The ERG reran these analyses incorporating the confidential discounted prices agreed in the patient access schemes for all 3 comparators; these results are commercial in confidence and cannot be reported here.
The company's deterministic sensitivity analyses showed that results were most sensitive to changes in the parameters defining the fitted parametric curves, time on treatment, utility parameters and administration cost.

# ERG comments
The ERG considered that the CheckMate trials were well designed and well conducted and provide appropriate evidence for the clinical effectiveness of nivolumab. The ERG noted that the results (notably for overall survival) presented by the company were interim and therefore uncertain.
The ERG agreed with the company that differences between the trials would not allow a meaningful meta-analysis, particularly because there was not a common comparison group. The ERG expressed concern about 2 of the clinical assumptions underlying the indirect treatment comparison; that previous melanoma treatment experience does not have an independent impact on treatment effect in advanced melanoma, and that there is no difference between treatment effects by BRAF mutation status.
The ERG commented that the structure of the model was consistent with the disease pathway and that the methods applied in the economic analyses were appropriate and followed the methodological guidance stipulated in the NICE reference case. The ERG noted that the company presented economic analyses only for previously untreated melanoma although the marketing authorisation includes people who have had previous treatment.
The ERG did not agree with all of the company's modelling assumptions and noted that there is considerable uncertainty in the costeffectiveness results because of the assumptions made, particularly for longterm overall survival and time on treatment for nivolumab.
The ERG did not agree with the company's assumption that patients having nivolumab would have similar longterm survival as those having ipilimumab. It commented that extrapolation of survival data from CheckMate66 would have been the most appropriate method for estimating longterm survival. In exploratory analyses the ERG extrapolated longterm survival for nivolumab using a Gompertz distribution in its preferred scenario (see tables 2 and 3).
The ERG did not agree with the company's choice of survival curve used in the model for time to progression for nivolumab. The ERG suggested that other survival curves (instead of Gompertz) may be plausible for nivolumab, and it used a Weibull distribution (best visual fit) in its preferred scenario (see tables 2 and 3).
For BRAF mutationpositive melanoma, the ERG noted that the total cost for the BRAF inhibitors in the model depended on the type of survival curve chosen to model their effect on progression-free survival. The company used a generalised gamma curve; the ERG explored other survival curves for the BRAF inhibitors and considered a lognormal distribution to be the best fit for its preferred scenario (see table 3).
The ERG conducted exploratory analyses that included using alternative survival functions for time to progression for nivolumab, and for progression-free survival for BRAF inhibitors (vemurafenib and dabrafenib). The ERG also explored using extrapolated survival data from CheckMate066 to model longterm survival for nivolumab.
The ERG's preferred scenario included a combination of some of the scenarios mentioned in sections 3.28, 3.29 and 3.30:
a Weibull distribution for time to progression for the nivolumab arm
a lognormal distribution for progressionfree survival for BRAF inhibitors (vemurafenib and dabrafenib)
a Gompertz distribution for extrapolated trial data, for longterm overall survival for the nivolumab arm.
The ERG explored the effect of 2 alternative assumptions for maximum treatment duration with nivolumab on its preferred scenario: 3 years, or no maximum treatment duration.
The results of the ERG exploratory analyses are summarised in tables 2 and 3. Please note that all analyses presented here used the list price for comparators and were not used in the decision making process.

## Table 2 Results of the company's basecase analysis and the ERG's exploratory analyses for BRAF mutationnegative melanoma (using the list price for all comparators)
Technology
Incremental costs- ()
Incremental QALYs
ICER (/QALY)
Company's base-case analysis
Dacarbazine
Ipilimumab
Extendedly dominated by dacarbazine and nivolumab
Nivolumab
ERG exploratory analyses
Nivolumab (Weibull for TTP)
Nivolumab (extrapolated longterm OS from trial)
ERG preferred scenario (see section 3.32)
Dominated by ipilimumab
ERG preferred scenario + nivolumab for 3 years
Dominated by ipilimumab
ERG preferred scenario +
no maximum treatment duration for nivolumab
Dominated by ipilimumab
Abbreviations: ERG, Evidence Review Group; ICER, incremental costeffectiveness ratio; OS, overall survival; QALYs, qualityadjusted life years; TTP, time to progression.
Dominated: provides fewer QALYs at greater cost than the comparator. Extendedly dominated: a combination of 2 of its comparators provides equal health at a reduced cost.
- These incremental costs do not take account of the confidential discounts agreed in the patient access schemes for dabrafenib, ipilimumab and vemurafenib.

## Table 3 Results of the company's basecase analysis and the ERG's exploratory analyses for BRAF mutationpositive melanoma (using the list price for all comparators)
Technology
Incremental costs- ()
Incremental QALYs
ICER (/QALY)
Company's base-case analysis
Ipilimumab
Nivolumab
Dabrafenib
Dominated by nivolumab
Vemurafenib
Dominated by nivolumab
ERG exploratory analyses
Nivolumab (Weibull for TTP)
Dabrafenib (lognormal for PFS)
Dominated by nivolumab
Vemurafenib (lognormal for PFS)
Dominated by nivolumab
Nivolumab (extrapolated longterm OS from trial)
ERG preferred scenario (see section 3.32)
Dominated by ipilimumab
ERG preferred scenario + nivolumab for 3 years
Dominated by ipilimumab
ERG preferred scenario + no maximum treatment duration for nivolumab
Dominated by ipilimumab
Abbreviations: ERG, Evidence Review Group; ICER, incremental costeffectiveness ratio; OS, overall survival; PFS, progression free survival; QALYs, qualityadjusted life years; TTP, time to progression.
Dominated: provides fewer QALYs at greater cost than the comparator. Extendedly dominated: a combination of 2 of its comparators provides equal health at a reduced cost.
- These incremental costs do not take account of the confidential discounts agreed in the patient access schemes for dabrafenib, ipilimumab and vemurafenib.
Full details of all the evidence are in the Committee papers.# Committee discussion
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of nivolumab having considered evidence on the nature of advanced (unresectable or metastatic) melanoma and the value placed on the benefits of nivolumab by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.

# Clinical effectiveness
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 BRAFV600 mutation (BRAF mutationnegative or 'wild type' disease) ipilimumab is the most common treatment option. For melanoma with BRAFV600 mutations (BRAF mutationpositive 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 5year overall survival data) has led to an increasing interest in immunotherapy agents. The Committee noted that programmed cell death1 (PD1) 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 highvolume disease. Nivolumab and pembrolizumab have similar mechanisms of action (consisting of an antibody, which blocks the PD1 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 mutationpositive melanoma will continue to have BRAF inhibitors as firstline 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.
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.
The Committee discussed the clinical effectiveness of nivolumab. It noted that overall survival data are currently only available from the CheckMate066 trial that compared nivolumab with dacarbazine. These data were based on shortterm followup (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 2year 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 ). 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 CheckMate067 (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 Committee considered the KaplanMeier curves for progressionfree survival from CheckMate067, noting that they showed better progressionfree 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 longterm benefit of nivolumab remains highly uncertain until further follow-up data are available.
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 CheckMate066 only included people with BRAF mutationnegative melanoma, but subgroup analyses from CheckMate067 and CheckMate037 suggest that nivolumab is somewhat less effective in BRAF mutationpositive disease compared with BRAF mutationnegative 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 mutationnegative and BRAF mutationpositive melanoma.
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 (PDL1). The Committee heard from the clinical experts that PDL1 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 (PDL1 positive 5%, or indeterminate <5%), there is no universally agreed threshold. The Committee noted that subgroup analyses showed that nivolumab appeared effective regardless of PDL1 expression. The Committee agreed that because of its mechanism of action, nivolumab was expected to be effective in patients with PDL1 expression. However, it concluded that the clinical effectiveness of nivolumab had also been demonstrated in the PDL1 indeterminate group.
The Committee discussed the adverse events associated with nivolumab. It noted that, in the trials, nivolumab was associated with a lower incidence of highgrade 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.
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
The Committee considered the company's model, which compared nivolumab with ipilimumab and dacarbazine in BRAF mutationnegative disease, and with ipilimumab, vemurafenib and dabrafenib in BRAF mutationpositive 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 covariateadjusted parametric curves fitted to patientlevel 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.
The Committee noted that in the company's basecase analysis, nivolumab was more effective than ipilimumab, with an incremental qualityadjusted life year (QALY) gained of 1.67 and 1.82 for BRAF mutation negativemelanoma and BRAF mutationpositive 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 longterm survival for patients having nivolumab.
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 costeffectiveness. More significant was the company's assumption that patients having nivolumab would have a comparable longterm survival benefit to that seen in the ipilimumab trials. The Committee recalled its conclusion that the evidence on longterm 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 CheckMate066 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 shortterm progressionfree survival benefit for nivolumab compared with ipilimumab shown in CheckMate067, 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 CheckMate066 in which 57% of patients were alive at 2year 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.
The Committee noted that time spent on treatment was a key factor influencing the costeffectiveness 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 costeffectiveness results uncertain. The Committee agreed that there would be more clarity when the results from studies comparing different durations of treatment become available.
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 lifethreatening 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 healthrelated benefit that had not already been captured in the QALY calculation.
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.
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 of the economic modelling are plausible, objective and robust.
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 CheckMate066 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 CheckMate066 demonstrated that survival benefit in nivolumabtreated 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 nonsmallcell 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 lifeextending, endoflife treatment.
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 costeffectiveness evidence, and the supplementary advice for appraising lifeextending, endoflife treatments. It concluded that, on balance, the ICER for nivolumab is likely to be less than 30,000 per QALY gained in both BRAF mutationpositive and BRAF mutationnegative advanced melanoma. It therefore considered nivolumab to be a cost effective use of NHS resources.
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
TA385
Appraisal title: Nivolumab for treating advanced (unresectable or metastatic) melanoma
Section
Key conclusion
Nivolumab as monotherapy is recommended, within its marketing authorisation, as an option for treating advanced (unresectable or metastatic) melanoma in adults.
The Committee concluded that:
nivolumab is more effective in the short term than ipilimumab, but the longterm 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 lifeextending, endoflife treatment
the incremental cost-effectiveness ratio (ICER) for nivolumab is likely to be less than 30,000 per qualityadjusted life year (QALY) gained in both BRAF mutationpositive and BRAF mutationnegative advanced melanoma, making it a costeffective 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.
Current practice
Clinical need of patients, including the availability of alternative treatments
The Committee heard that ipilimumab is the most common treatment option for BRAF mutationnegative advanced melanoma, and for BRAF mutationpositive disease there is a choice between the BRAF inhibitor agents (vemurafenib and dabrafenib) and ipilimumab.
The Committee concluded that the availability of an effective new treatment option with acceptable tolerability would be valuable for people with advanced melanoma.
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on healthrelated benefits?
The Committee noted that programmed cell death1 (PD1) 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 highvolume disease.
The 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 healthrelated 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 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 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 Committee noted that overall survival data are only available from the CheckMate066 trial that compared nivolumab with dacarbazine. It also considered the updated 2 year overall survival data from CheckMate066. 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 CheckMate067 (which compared nivolumab with ipilimumab) are not yet available and considered the KaplanMeier curves for progression free survival from CheckMate067.
Relevance to general clinical practice in the NHS
The Committee noted that a course of nivolumab treatment requires more frequent intravenous administration for a longer duration than ipilimumab.
Uncertainties generated by the evidence
The Committee noted that overall survival data from CheckMate067 (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 Committee concluded that the longterm benefit of nivolumab remains highly uncertain until further followup data are available.
The 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 Committee noted that subgroup analyses from CheckMate067 and CheckMate037 suggest that nivolumab is somewhat less effective in BRAF mutationpositive disease compared with BRAF mutationnegative disease. However, it heard that these differences were not substantial.
The Committee noted that subgroup analyses also showed that nivolumab appeared effective regardless of PDL1 expression, but that comparatively better outcomes were seen in people with positive PDL1 expression.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The Committee heard that updated 2year 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 ).
Evidence for cost effectiveness
Availability and nature of evidence
The Committee considered the company's model, which compared nivolumab with ipilimumab and dacarbazine in BRAF mutationnegative disease, and with ipilimumab, vemurafenib and dabrafenib in BRAF mutationpositive disease, for people with previously untreated advanced (unresectable or metastatic) melanoma.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The Committee considered the company's assumption, that patients having nivolumab would have a comparable longterm survival benefit to that seen in the ipilimumab trials, to be highly uncertain. However, the Committee agreed that it would not be unreasonable to expect that the shortterm progressionfree survival benefit for nivolumab compared with ipilimumab would translate into a survival benefit.
The Committee concluded that lack of evidence on the optimal duration of treatment made the costeffectiveness 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 EQ5D values from CheckMate066, 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 Committee could not identify any specific healthrelated 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 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 that time spent on treatment was a key factor influencing the costeffectiveness results.
Most likely costeffectiveness estimate (given as an ICER)
The Committee concluded that the ICER for nivolumab is likely to be less than 30,000 per qualityadjusted life year (QALY) gained in both BRAF mutationpositive and BRAF mutationnegative advanced melanoma.
The exact ICERs are confidential and cannot be reported here.
Additional factors taken into account
Patient access schemes (PPRS)
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.
End-of-life considerations
The 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 Committee therefore concluded that nivolumab meets all the criteria to be considered a lifeextending, endoflife treatment.
Equalities considerations and social value judgements
No equality issues were identified.
-# Review of guidance
The guidance on this technology will be considered for review 2 years after publication along with guidance on other immunotherapies for advanced melanoma (such as technology appraisal guidance 268, 319, 357 and 366). The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.Andrew DillonChief ExecutiveFebruary 2016