Pembrolizumab for advanced melanoma not previously treated with ipilimumab

Evidence-based recommendations on pembrolizumab (Keytruda) for treating advanced melanoma in adults who have not had ipilimumab.

# Guidance
Pembrolizumab is recommended as an option for treating advanced (unresectable or metastatic) melanoma that has not been previously treated with ipilimumab, in adults, only when the company provides pembrolizumab in line with the commercial access agreement with NHS England.# The technology
Pembrolizumab (Keytruda, Merck Sharp & Dohme) is a humanised monoclonal antibody. It acts on the programmed cell death protein1 immunecheckpoint receptor pathway, blocking its interaction with ligand on the tumour cells. This allows reactivation of antitumour immunity. It has a marketing authorisation in the UK as monotherapy 'for the treatment of advanced (unresectable or metastatic) melanoma in adults'. Pembrolizumab is administered intravenously for 30 minutes at a dose of 2 mg/kg every 3 weeks until disease progression or unacceptable toxicity.
The most common (occurring in 1 in 10 people or more) adverse reactions with pembrolizumab in clinical trials were diarrhoea, nausea, itching, rash, joint pain and fatigue. The most serious adverse reactions were immunerelated adverse reactions and severe infusionrelated reactions. For full details of adverse reactions and contraindications, see the summary of product characteristics.
The acquisition cost of pembrolizumab is 1,315 per 50mg vial (excluding VAT; company's submission). The pricing arrangement considered during guidance development was that Merck Sharp & Dohme had agreed a patient access scheme with the Department of Health. This scheme provided a simple discount to the list price of pembrolizumab with the discount applied at the point of purchase or invoice. After guidance publication in November 2015, the company agreed a commercial access agreement with NHS England that replaces the patient access scheme on equivalent terms. The financial terms of the agreement are commercial in confidence.# The company's submission
The Appraisal Committee (section 7) considered evidence submitted by Merck Sharp & Dohme and a review of this submission by the Evidence Review Group (ERG; section 8).

# Clinical effectiveness
The company presented clinicaleffectiveness evidence for pembrolizumab from 2 clinical trials: KEYNOTE006 and KEYNOTE001. KEYNOTE006 was a randomised, international, multicentre, phase III trial of pembrolizumab 10 mg/kg every 2 weeks (n=279) or every 3 weeks (n=277), continued until disease progression or unacceptable toxicity, compared with ipilimumab 3 mg/kg every 3 weeks, continued for 4 doses (n=278). Results were analysed at 2 planned interim analyses, after 6 months of followup (September 2014) and after 912 months of followup (March 2015). After the second interim analysis the study was stopped, because the primary endpoint had been met. KEYNOTE001 was a combined phase I and II study. Evidence was presented from a substudy of this trial, referred to as KEYNOTE001 part D: this was a randomised, openlabel study comparing pembrolizumab 2 mg/kg every 3 weeks (n=51; the licensed dose) with 10 mg/kg every 3 weeks (n=52). Both KEYNOTE006 and KEYNOTE001 part D included people with advanced melanoma, with or without BRAF mutations, who had not had ipilimumab before (previous treatment with 1 or 2 other therapies was permitted).
In KEYNOTE006, pembrolizumab was associated with statistically significant increases in both progressionfree survival (first interim analysis) and overall survival (second interim analysis), compared with ipilimumab (table 1). Pembrolizumab was also associated with statistically significantly higher overall response rates compared with ipilimumab (table 1; p<0.001). Prespecified subgroup analyses based on demographic and clinical characteristics suggested that the treatment effect associated with pembrolizumab was generally consistent across subgroups, although some variations in effect based on the line of therapy and the expression of ligands for the 'programmed death 1' protein (termed 'PDL1 status') were seen. No significant differences in clinical effectiveness between pembrolizumab doses (that is, 10 mg/kg every 3 weeks, 10 mg/kg every 2 weeks or 2 mg/kg every 3 weeks) were seen in either KEYNOTE006 or KEYNOTE001 part D.

## Table 1 Clinicaleffectiveness outcomes in KEYNOTE006
Pembrolizumab
Ipilimumab
n=278
mg/kg every 3 weeks
n=277
mg/kg every 2 weeks
n=279
Progressionfree survival (interim analysis 1)
Median: months (95% CI)
Hazard ratio versus ipilimumab (95% CI)
p<0.00001
p<0.00001
Overall survival (interim analysis 2)
Overall survival at 6 months1: % (95% CI)
Hazard ratio versus ipilimumab (95% CI)
p=0.00358
p=0.00052
Overall response (interim analysis 1)
Overall response rate: % (95% CI)
Abbreviations: CI, confidence interval; n, number of patients.1Median overall survival not reached.
The company presented adverse event data from KEYNOTE006, and stated that pembrolizumab was generally well tolerated. It was associated with a similar number of adverse events, but fewer drugrelated grade 35 adverse events, serious adverse events, drugrelated serious adverse events and adverse events leading to withdrawal from the trial, compared with ipilimumab (table 2). Pembrolizumab was also associated with fewer highgrade, immunerelated adverse events than ipilimumab, and fewer people in the pembrolizumab groups withdrew from the trial because of immunerelated adverse events (table 2). The most common treatmentrelated adverse events with both pembrolizumab and ipilimumab were fatigue, diarrhoea, rash and itching. The most common grade 35 immunerelated adverse events associated with pembrolizumab were colitis and hepatitis.

## Table 2 Summary of adverse events in KEYNOTE006
Ipilimumab
Pembrolizumab (both arms combined)
n
n
n
Patients with 1 or more AE
Drugrelated grade 35 AE
Serious AE
Drugrelated serious AE
Stopped because of an AE
Immunerelated AEs
Patients with 1 or more AE
Grade 35 AE
Stopped because of an AE
Abbreviations: AE, adverse event; n, number of patients.
The company compared the clinical effectiveness of pembrolizumab with ipilimumab, dabrafenib, vemurafenib and dacarbazine in a series of network metaanalyses. The analyses were performed in a Bayesian framework using a fixedeffects model, and were based on data from KEYNOTE006 and 5 other trials identified in the systematic review. The company presented results from a series of analyses, including 4 alternative network scenarios, 4 time points, and separate analyses of pembrolizumab as either a first or secondline treatment. It stated that, for the outcomes of progressionfree survival and overall survival, pembrolizumab appeared to have a similar efficacy to vemurafenib and dabrafenib, in people who have had no previous treatment. For example, in network scenario '3b' at the 6month time point, pembrolizumab was associated with a hazard ratio for progressionfree survival of 0.80 (95% credible interval  0.321.92) compared with dabrafenib, and 0.67 (95% CrI 0.371.14) compared with vemurafenib. The corresponding hazard ratios for overall survival were 0.96 (95% CrI 0.461.93) and 0.75 (95% CrI 0.401.34), compared with dabrafenib and vemurafenib respectively. The company highlighted that pembrolizumab was associated with greater progressionfree survival and overall survival than both ipilimumab (scenario 3b, 6month timepoint: hazard ratio for progressionfree survival 0.45, 95% CrI 0.330.62; hazard ratio for overall survival 0.59, 95% CrI 0.410.84) and dacarbazine (scenario 3b, 6month timepoint: hazard ratio for progressionfree survival 0.36, 95% CrI 0.210.59; hazard ratio for overall survival 0.54, 95% CrI 0.300.91) for previously untreated disease, and was at least as effective as ipilimumab for people who have had 1 previous line of treatment (scenario 3b, 6month timepoint: hazard ratio for progressionfree survival 0.74, 95% CrI 0.481.12; hazard ratio for overall survival 0.80, 95% CrI 0.521.22).

# Cost effectiveness
The company presented an economic model comparing pembrolizumab (2 mg/kg every 3 weeks) with ipilimumab, dabrafenib and vemurafenib. The model comprised 3 states: preprogression, postprogression and death. The model used a cycle length of 1 week and a time horizon of 30 years (lifetime), taking the perspective of the NHS and personal social services, with costs and benefits discounted at a rate of 3.5% per year. The model included costs associated with melanoma treatment, costs in each health state (based on a study of resource use for melanoma treatment in the UK), management of adverse events and complications, and care at the end of life.
The proportion of people in the each health state was based on estimates of progressionfree survival and overall survival:
Progressionfree survival was estimated using KaplanMeier curves from the KEYNOTE006, BRIM3 and BREAK3 clinical trials, extrapolated to 30 years based on a Gompertz model (for pembrolizumab and ipilimumab) or a monthly risk of progression taken from NICE's technology appraisal guidance on ipilimumab for previously untreated advanced (unresectable or metastatic) melanoma (for dabrafenib and vemurafenib).
Overall survival was estimated by initially using KaplanMeier data from clinical trials (for the first 5060 weeks of the model), followed by published mortality risks based on data from a pooled analysis of longterm survival data for people with melanoma treated with ipilimumab (Schadendorf et al. ; applied to pembrolizumab and ipilimumab) and NICE's technology appraisal guidance on ipilimumab for previously untreated advanced (unresectable or metastatic) melanoma (applied to dabrafenib and vemurafenib). Longterm survival was based on mortality rates in a published registry study (Balch et al. ).
Utility values were estimated using EuroQol EQ5D data from KEYNOTE006, by assuming that quality of life decreases as people approach the last months of life. The utility scores decreased from 0.82, for people who were more than 360 days before death, to 0.33 for people in the 30 days before death.
The company's basecase results are summarised in table 3. These results were based on the discount in the patient access scheme for pembrolizumab and the list prices for all other drugs, and therefore were not used for decisionmaking; they are included here for illustration only. Results from the company's model including the patient access schemes for pembrolizumab and all 3 comparators were presented by the ERG; these results are commercial in confidence and cannot be reported here.

## Table 3 Results of the company's basecase analysis (including pembrolizumab patient access scheme, list price for all comparators; not used for decisionmaking)
BRAF mutationpositive disease
Total cost
Total LYG
Total QALYs
Incr cost
Incr LYG
Incr QALYs
ICER (/QALY)
Dabrafenib
Pembrolizumab
Vemurafenib
Dominated
Ipilimumab
Dominated
BRAF mutationnegative disease
Total cost
Total LYG
Total QALYs
Incr cost
Incr LYG
Incr QALYs
ICER (/QALY)
Pembrolizumab
Ipilimumab
Dominated
Abbreviations: ICER, incremental costeffectiveness ratio; Incr, incremental; LYG, life years gained; QALYs, qualityadjusted life years.
Dominated: provides fewer QALYs at greater cost than the comparator.
In a deterministic sensitivity analysis, the model results for all comparisons were most sensitive to the extrapolation of progressionfree survival for pembrolizumab (shape and treatment effect in the Gompertz model). In the probabilistic sensitivity analysis, the total costs associated with pembrolizumab increased by 10,996 compared with the deterministic results, and the total QALYs decreased by 0.02, whereas the results for ipilimumab, dabrafenib and vemurafenib did not change substantially. The company stated that the change in the results for pembrolizumab was caused by uncertainty in the extrapolation of progressionfree survival from the KEYNOTE006 trial, which led to a small number of iterations with high treatment costs. The company also presented 33 scenario analyses, to explore the effects of key assumptions on the model results. These analyses explored the effects of varying the progressionfree survival and overall survival estimates, time horizon, utility estimates, treatment and terminal care costs, treatment duration for pembrolizumab, and the discounting rate. The company stated that these analyses showed that the cost effectiveness of pembrolizumab was robust to most sources of uncertainty.

# ERG comments
The ERG stated that KEYNOTE006 was well designed and well conducted. It considered that the population was representative of patients seen in the UK NHS, and patient characteristics were well balanced across treatment groups. However, it noted 3 key concerns about this trial:
The dosage of pembrolizumab (10 mg/kg every 3 weeks) did not match the licensed dose (2 mg/kg every 3 weeks). The ERG noted that the European Public Assessment Report (EPAR) states that no differences between the licensed dose and the studied dose are to be expected. Although this was largely based on data from patients who had previous therapy with ipilimumab, the ERG cautiously accepted this conclusion.
The trial was stopped early, so the overall survival data were immature. The ERG was unclear whether the true impact of pembrolizumab on survival will be identified.
The trial specified a maximum treatment duration of 24 months. The ERG considered that the effect of this rule on clinical outcomes is unknown.
The ERG considered that the clinical assumptions used in the company's network metaanalysis were reasonable, but the methods of the analysis were flawed. It stated that the populations in the control arms were not comparable, the analysis did not correctly reflect changing hazard ratios over time, and the methods used to adjust for treatment switching in the key trial for vemurafenib may not have been adequate. The ERG considered that the network metaanalysis did not provide valid treatment effect estimates, particularly for pembrolizumab compared with dabrafenib and vemurafenib.
The ERG's critique of the company's economic model suggested that the model was generally consistent with the NICE reference case. However, it highlighted that the structure of the model led to counterintuitive results  specifically, that pembrolizumab would become less cost effective if its effectiveness at delaying disease progression increased. The ERG stated that this was because delaying disease progression was associated with additional treatment costs but no increase in quality of life. In addition, the ERG expressed concerns about the modelling of overall survival, progressionfree survival, treatment costs and quality of life. It considered that there were limitations in the methods of extrapolation for both progressionfree survival and overall survival. In particular, for overall survival, the ERG stated that there was a risk of selection bias in the data taken from the study by Schadendorf et al. (2015), and there were limitations in the algorithm used to adjust for patient characteristics and the longterm survival data (from Balch et al. ) used to project longterm survival. The ERG highlighted that the company's estimates for mortality risk in people treated with pembrolizumab changed erratically during the course of the model and were not clinically plausible. For the analysis of progressionfree survival, the ERG noted limitations including the use of centrally assessed progression, the company's choice of censoring rule, inappropriate use of the proportional hazards assumption and incomplete adjustment for differences in patient characteristics between the dabrafenib, vemurafenib and pembrolizumab trials. The ERG described concerns about the duration of treatment, the weight distribution of the population, and the administration costs of ipilimumab, which meant that the costs of treatment were not accurately estimated. It considered that there were important limitations in the estimation of utility, because of the use of EQ5D data based on patients from all regions (rather than UK or European patients only) and the assumption that utility did not change when disease progressed. The ERG highlighted that 7590% of the cost differences between treatments in the company's model could be attributed to direct treatment costs, and that 87.5% of the health gain with pembrolizumab occurred after 12 months. It therefore considered that the key factors affecting results of the model were drug costs, duration of treatment and overall survival.
The ERG presented a series of exploratory analyses to address their principal concerns about the company's model (see section 3.12). In particular, it changed the modelling of overall survival (using methods developed for NICE's technology appraisal guidance on ipilimumab for previously treated advanced (unresectable or metastatic) melanoma), progressionfree survival and treatment duration, and amended the treatment costs and utility scores. It also presented 2 scenario analyses, in which the duration of progressionfree survival was extended by 3 or 6 years for people whose disease had not progressed after 2 years; the ERG presented results for all analyses using the patient access scheme price for pembrolizumab and the list prices for ipilimumab, dabrafenib and vemurafenib (summarised below) and also using patient access schemes for all drugs (commercial in confidence; cannot be reported here). The ERG's amendments, combined, increased the costs associated with pembrolizumab by 6593 and reduced the total QALYs by 0.18. The amendments also reduced the costs and QALYs associated with ipilimumab (by 2558 and 0.17 respectively), increased the costs and QALYs for vemurafenib (by 7027 and 0.5 respectively), and increased the costs but reduced the QALYs for dabrafenib (by 3,238 and 0.02 respectively). Both of the scenario analyses substantially increased the costs associated with pembrolizumab, but had no effect on the other treatments.
Full details of all the evidence are available.# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of pembrolizumab, having considered evidence on the nature of advanced (unresectable or metastatic) melanoma that has not been previously treated with ipilimumab and the value placed on the benefits of pembrolizumab 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 pembrolizumab in the treatment pathway. It was aware of the disparity between the wording of the marketing authorisation for pembrolizumab and the definition of the population in the scope; it understood that this appraisal specifically considered pembrolizumab for melanoma that had not been previously treated with ipilimumab, and that ipilimumabtreated melanoma was considered in a separate appraisal. The Committee understood that ipilimumab is the most common treatment option for advanced (unresectable or metastatic) melanoma that does not have a BRAF V600 mutation (BRAF mutationnegative or 'wild type' disease). For melanoma with BRAF V600 mutations (BRAF mutationpositive disease), the Committee heard from the clinical experts that the treatment strategy has changed in recent years. In the past, a clear distinction was made between rapidly progressing tumours (which would usually be treated with a BRAF inhibitor  that is, dabrafenib or vemurafenib), and more slowly progressing disease (which may be treated with an immunotherapy agent such as ipilimumab). More recently, the long survival benefit shown in a percentage of patients treated with ipilimumab (based on 5year overall survival data) has led to an increasing emphasis on immunotherapy. The Committee also heard from the clinical experts that pembrolizumab appeared to have a faster onset of action and higher response rate than ipilimumab, and may also be more suitable for treating highervolume disease. Consequently, although some people with rapidly progressing BRAF mutationpositive melanoma will continue to have BRAF inhibitors as a firstline treatment, the clinical experts expected that pembrolizumab would be considered for more people than just those who, in the past, would have had treatment with ipilimumab. The Committee was aware that dacarbazine is now used only after the other available treatments, if at all, because it has not been shown to improve survival compared with supportive care. The Committee concluded that ipilimumab, dabrafenib and vemurafenib were appropriate comparators for people with advanced melanoma that has not previously been treated with ipilimumab.
The Committee considered how pembrolizumab might be used in clinical practice, and in particular whether treatment may be limited to a fixed duration. It noted that the KEYNOTE006 trial protocol specified a maximum treatment duration of 2 years, and heard from the company that although the 2year point had not yet been reached, the maximum treatment duration will be adhered to as followup continues. The Committee understood that the trial had been unblinded early, after which people in the ipilimumab group could start treatment with pembrolizumab. The Committee heard from the clinical experts that there is no evidence to indicate the optimum duration of treatment with pembrolizumab. The clinical experts considered the likely treatment duration in clinical practice and stated that if a maximum duration were specified, consideration should be given to whether pembrolizumab could be restarted if the disease progressed. The Committee was aware that in KEYNOTE006, people could stop treatment if they had a complete response and could restart treatment if their disease progressed, but that there was limited evidence on the clinical effectiveness of this approach. The Committee highlighted that the marketing authorisation for pembrolizumab specifies that treatment should continue until disease progression or unacceptable toxicity. The Committee concluded that, consistent with the limited evidence available, it was appropriate to appraise pembrolizumab in line with its marketing authorisation. However, it appreciated that there is uncertainty about the optimum duration of treatment with pembrolizumab.
The Committee discussed the clinical needs of people with advanced melanoma. It heard from the patient experts 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. For example, when considering different treatment options, some people might take into account their preferences for oral or intravenous administration, fixedduration or continuous treatment, or different sideeffect profiles. The Committee heard from the patient experts that treatment with ipilimumab can be associated with severe side effects, and this may be a major consideration. The Committee concluded that the availability of an effective new treatment option with an acceptable tolerability profile would be valuable for people with advanced melanoma.
The Committee considered the generalisability of the KEYNOTE006 trial. It understood that the percentage of people with BRAF mutationpositive melanoma in this trial (35%) was likely to reflect the use of pembrolizumab if it becomes established in clinical practice. The Committee noted that the dosage of pembrolizumab in KEYNOTE006 was 10 mg/kg every 2 or 3 weeks, but that the dosage specified in the marketing authorisation is 2 mg/kg every 3 weeks. It heard from the clinical experts that they expect the 2mg/kg dose to be as effective as 10 mg/kg, and there is no evidence for a doseresponse effect over this range. The Committee reviewed evidence from the KEYNOTE001 trial comparing the 10mg/kg and 2mg/kg doses, and considered that it had not seen any evidence to suggest a difference in effectiveness. The Committee concluded that the clinicaleffectiveness evidence presented was broadly generalisable to clinical practice in the NHS.
The Committee considered the results of the KEYNOTE006 trial. It noted that pembrolizumab provided significant improvements in progressionfree survival, overall survival and overall response rates compared with ipilimumab. However, it noted that the trial was stopped early (because the primary endpoints had been met). Consequently, the evidence available was based on a limited duration of followup and the overall survival data were immature (that is, fewer than half of the people in the trial had died). It therefore considered that the longterm benefits of pembrolizumab were very uncertain. The Committee acknowledged that further survival data were expected to be available soon, but that there were no data beyond 2 years at the time of the appraisal. The Committee heard from the clinical experts that pembrolizumab was expected to provide a longterm survival benefit consistent with that shown in the ipilimumab trials. It recognised that this expectation is biologically plausible and that there is currently no evidence to suggest pembrolizumab will differ from ipilimumab in this respect. However, it emphasised that there was not enough clinical evidence to directly support this conclusion. The Committee concluded that pembrolizumab is likely to provide improved clinical effectiveness compared with ipilimumab in the short term, but that the longterm benefits of pembrolizumab are highly uncertain. The Committee considered that the choice of treatment should be made on an individual basis, taking into account the potential risks and benefits of each treatment.
The Committee discussed the adverse effects associated with pembrolizumab. The Committee heard about the experiences of people with melanoma and clinicians treating them, which suggested that pembrolizumab is often better tolerated than ipilimumab. It heard that pembrolizumab causes lesssevere adverse effects and leads to fewer hospitalisations. The Committee considered that although evidence from KEYNOTE006 suggested that pembrolizumab was better tolerated than ipilimumab, the difference was not as dramatic as the individual experiences reported by the experts. It did, however, note that a higher dose (10 mg/kg) was used in the trial, and that this dose might be associated with greater toxicity than the licensed 2mg/kg dose. The Committee concluded that pembrolizumab is likely to offer a better tolerability profile than ipilimumab.
The Committee considered the clinical effectiveness of pembrolizumab compared with dabrafenib and vemurafenib. The Committee noted that there was no direct clinical trial evidence comparing pembrolizumab with dabrafenib or vemurafenib. The company had carried out a network metaanalysis, but the Committee considered that this had a number of methodological flaws. The clinical experts indicated that in clinical practice dabrafenib and vemurafenib are not considered to have different effectiveness and are broadly interchangeable. The Committee understood that the choice between pembrolizumab and dabrafenib or vemurafenib may be made partly on clinical grounds, taking into account disease progression and the preferences of the person having treatment. The Committee considered that the company's metaanalysis did not provide robust evidence to compare pembrolizumab with dabrafenib and vemurafenib; it therefore concluded that the effectiveness of pembrolizumab compared with dabrafenib and vemurafenib is highly uncertain, and there is not enough evidence to reliably assess their comparative effectiveness. The Committee reiterated that people with melanoma and clinicians should discuss the potential risks and benefits of each treatment when considering therapy options.

# Cost effectiveness
The Committee considered the company's model, which compared pembrolizumab with ipilimumab in BRAF mutationnegative disease, and with ipilimumab, vemurafenib and dabrafenib in BRAF mutationpositive disease, for people with advanced (unresectable or metastatic) melanoma that had not been previously treated with ipilimumab. The Committee considered that the Evidence Review Group (ERG) had identified a number of important uncertainties in the economic modelling, and it expressed concerns about some of the company's assumptions. In particular, it highlighted that:
The model results were strongly influenced by extrapolated survival benefits after 12 months. However, there were potential issues with the methods of extrapolation, as highlighted by the ERG (see section 3.12); in particular, the Committee noted the ERG's view that the proportional hazards assumption was not appropriate, there were limitations in the use of data from Schadendorf et al. (2015) and Balch et al. (2001), and the modelled overall survival was consequently not plausible.
The results for dabrafenib and vemurafenib were highly uncertain because of the substantial uncertainty in the comparative clinical effectiveness of these treatments (see section 4.7).
The predicted total costs associated with adverse effects seemed low given the number of events in clinical trials; these costs were not plausible and were unlikely to reflect the costs in clinical practice.
The Committee reviewed the exploratory analyses that the ERG presented to address some of its concerns about the company's modelling (see section 3.13). The Committee noted that the ERG's exploratory analyses, combined, decreased the cost effectiveness of pembrolizumab. It understood that the ERG's scenario analyses primarily aimed to 'stresstest' the model, and considered that the second scenario (in which progressionfree survival was extended by 6 years for some people; see section 3.13) was at the upper end of the plausible range for the costeffectiveness estimate. The Committee concluded that there were a number of uncertainties in the economic modelling, but considered that the company's and ERG's analyses provided sufficient information on which to base a decision.
Having reviewed the company's base case, the scenario and sensitivity analyses, and the exploratory analyses from the ERG, and taking into account all 4 patient access schemes, the Committee concluded that the most plausible incremental costeffectiveness ratios (ICERs) for pembrolizumab (compared with ipilimumab in BRAF mutationnegative disease, and with ipilimumab, dabrafenib and vemurafenib in BRAF mutationpositive disease) were less than 50,000 per qualityadjusted life year (QALY) gained. The exact ICERs are confidential and cannot be reported here, because this could allow the discounts in the patient access schemes for ipilimumab, dabrafenib and vemurafenib to be backcalculated.
The Committee discussed the innovative aspects of pembrolizumab. It noted that the company stated that pembrolizumab is innovative because it has a novel mechanism of action and is expected to provide a durable response for a significant number of people with a high unmet need. The Committee understood that an improved tolerability profile of pembrolizumab compared with ipilimumab may be valuable for some people with melanoma, although it recalled that the benefit in the trial was not as dramatic as the individual experiences reported by the experts (see section 4.6). It also noted that a longterm survival benefit, similar to ipilimumab, had not yet been confirmed. The Committee concluded that pembrolizumab is innovative, but it could not identify any specific healthrelated benefits that had not 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 considered that the life expectancy of people with advanced melanoma that has not previously been treated with ipilimumab is short. It understood that the median survival for people with previously untreated melanoma that is treated with ipilimumab, dabrafenib or vemurafenib ranges from about 14 to 20 months. The Committee considered that the extension to life offered by pembrolizumab was somewhat uncertain. It highlighted that the median overall survival was not reached in the KEYNOTE006 trial, so the estimates of survival gain were dependent on extrapolation. However, the Committee noted that the estimates for overall survival gain presented by the company and the ERG were consistently greater than 3 months. It therefore concluded that pembrolizumab was likely to provide a survival gain of at least 3 months. Although this is subject to some uncertainty, the Committee considered that it was plausible, objective and robust enough for this criterion to be met. The Committee noted that the company estimated the population for which pembrolizumab is indicated to be about 1300 people, and concluded that this represented a small patient population. The Committee therefore concluded that pembrolizumab meets all the criteria to be considered a lifeextending, endoflife treatment.
Taking into account the most plausible ICERs, the uncertainties in the clinical and costeffectiveness evidence and the supplementary advice for appraising lifeextending, endoflife treatments, the Committee concluded that, on balance, pembrolizumab could be considered a costeffective use of NHS resources for people with advanced (unresectable or metastatic) melanoma that has not been previously treated with ipilimumab.
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 pembrolizumab. It therefore concluded that the PPRS Payment Mechanism was irrelevant for the consideration of the cost effectiveness of pembrolizumab for treating advanced melanoma that has not been previously treated with ipilimumab.

# Summary of Appraisal Committee's key conclusions
TA366
Appraisal title: Pembrolizumab for advanced melanoma not previously treated with ipilimumab
Section
Key conclusion
Pembrolizumab is recommended as an option for treating advanced (unresectable or metastatic) melanoma that has not been previously treated with ipilimumab, in adults, when the company provides pembrolizumab with the discount agreed in the patient access scheme.
Pembrolizumab is likely to provide improved shortterm clinical effectiveness and a better tolerability profile compared with ipilimumab. The longterm benefits compared with ipilimumab and the effectiveness compared with dabrafenib and vemurafenib are highly uncertain.
The most plausible incremental costeffectiveness ratios (ICERs) were less than 50,000 per qualityadjusted life year (QALY) gained.
The Committee concluded that pembrolizumab meets all the criteria to be considered a lifeextending, endoflife treatment.
Current practice
Clinical need of patients, including the availability of alternative treatments
The Committee heard from the patient experts that melanoma has a major effect on people's health and quality of life, and that having a choice of treatments would be particularly valuable to people with this condition.
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 pembrolizumab provided significant improvements in progressionfree survival, overall survival and overall response rates, and a better tolerability profile, compared with ipilimumab.
The company stated that pembrolizumab is innovative because it has a novel mechanism of action and is expected to provide a durable response for a significant number of people with a high unmet need. The Committee concluded that pembrolizumab is innovative.
What is the position of the treatment in the pathway of care for the condition?
This appraisal considered pembrolizumab for melanoma that had not been previously treated with ipilimumab.
The Committee heard that pembrolizumab would be considered for more people than just those who, in the past, would have had treatment with ipilimumab, and concluded that ipilimumab, dabrafenib and vemurafenib were appropriate comparators.
Adverse reactions
The most common adverse reactions with pembrolizumab in clinical trials were diarrhoea, nausea, itching, rash, joint pain and fatigue.
The Committee concluded that pembrolizumab is likely to offer a better tolerability profile than ipilimumab.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The company presented clinicaleffectiveness evidence for pembrolizumab from 2 clinical trials: KEYNOTE006 and KEYNOTE001.
The Evidence Review Group (ERG) stated that KEYNOTE006 was well designed and well conducted, but noted 3 key concerns about the trial  the dosage of pembrolizumab, the immature survival data and the maximum treatment duration.
Relevance to general clinical practice in the NHS
The Committee noted that the dosage of pembrolizumab in KEYNOTE006 was not the same as the marketing authorisation. It understood that the percentage of people with BRAF mutationpositive melanoma in this trial was likely to reflect clinical practice. The Committee concluded that the clinicaleffectiveness evidence presented was broadly generalisable to clinical practice in the NHS.
Uncertainties generated by the evidence
The Committee identified 4 key uncertainties:
the optimum duration of treatment with pembrolizumab
the longterm benefits of pembrolizumab compared with ipilimumab
the effectiveness of pembrolizumab compared with dabrafenib and vemurafenib
the extension to life offered by pembrolizumab.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
No subgroups were specified in the scope.
Subgroup analyses in KEYNOTE006, based on demographic and clinical characteristics, suggested that the treatment effect was generally consistent across subgroups.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
In KEYNOTE006, pembrolizumab was associated with statistically significant increases in progressionfree survival, overall survivaland overall response rate, compared with ipilimumab.
The Committee noted that the estimated overall survival gain was consistently greater than 3 months.
The evidence was based on a limited duration of followup and the survival data were immature. The Committee considered that the longterm benefits of pembrolizumab were highly uncertain.
, table 1, 4.13, 4.5
Evidence for cost effectiveness
Availability and nature of evidence
The Committee considered the company's model, which compared pembrolizumab with ipilimumab, vemurafenib and dabrafenib, in people with advanced (unresectable or metastatic) melanoma that had not been previously treated with ipilimumab.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The Committee considered that the ERG had identified a number of important uncertainties in the economic modelling, and it expressed concerns about some of the company's assumptions:
extrapolated survival benefit
clinical effectiveness of pembrolizumab compared with dabrafenib and vemurafenib
costs associated with adverse events.
Incorporation of healthrelated qualityoflife benefits and utility values
Have any potential significant and substantial healthrelated benefits been identified that were not included in the economic model, and how have they been considered?
Utility values were estimated using EuroQol EQ5D data from KEYNOTE 006, by assuming that quality of life decreases as people approach the last months of life. The utility scores decreased from 0.82, for people who were more than 360 days before death, to 0.33 for people in the 30 days before death.
The ERG considered that there were important limitations in the estimation of utility, because of the use of EQ5D data based on patients from all regions and the assumption that utility did not change when disease progressed.
The Committee could not identify any specific healthrelated benefits that had not been captured in the calculation of qualityadjusted life years (QALYs).
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?
In a deterministic sensitivity analysis, the model results were most sensitive to the extrapolation of progressionfree survival for pembrolizumab. The company also presented 33 scenario analyses, and stated that the cost effectiveness was robust to most sources of uncertainty.
The ERG considered that the key factors affecting results of the model were drug costs, duration of treatment and overall survival.
Most likely costeffectiveness estimate (given as an ICER)
The Committee concluded that the most plausible ICERs for pembrolizumab (compared with ipilimumab, dabrafenib and vemurafenib) were less than 50,000 per QALY gained. The exact ICERs are confidential and cannot be reported here.
Additional factors taken into account
Patient access schemes (PPRS)
The company has agreed a patient access scheme, in which pembrolizumab is provided with a simple discount to its list price.
The ERG presented analyses incorporating the confidential patient access schemes for pembrolizumab, ipilimumab, dabrafenib and vemurafenib. The Committee took into account all 4 patient access schemes.
Endoflife considerations
The Committee understood that the median survival for people with previously untreated melanoma is 1420 months.
It considered that the extension to life offered by pembrolizumab was somewhat uncertain, but the estimates presented were consistently greater than 3 months.
It noted that the population for which pembrolizumab is indicated is small.
The Committee concluded that pembrolizumab 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 3 years after publication. 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 ExecutiveNovember 2015