Pembrolizumab for advanced melanoma not previously treated with ipilimumab

Clinical effectiveness

4.1 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 ipilimumab‑treated 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 mutation‑negative or 'wild type' disease). For melanoma with BRAF V600 mutations (BRAF mutation‑positive 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 5‑year 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 higher‑volume disease. Consequently, although some people with rapidly progressing BRAF mutation‑positive melanoma will continue to have BRAF inhibitors as a first‑line 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.

4.2 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 KEYNOTE‑006 trial protocol specified a maximum treatment duration of 2 years, and heard from the company that although the 2‑year point had not yet been reached, the maximum treatment duration will be adhered to as follow‑up 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 KEYNOTE‑006, 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.

4.3 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, fixed‑duration or continuous treatment, or different side‑effect 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.

4.4 The Committee considered the generalisability of the KEYNOTE‑006 trial. It understood that the percentage of people with BRAF mutation‑positive 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 KEYNOTE‑006 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 2‑mg/kg dose to be as effective as 10 mg/kg, and there is no evidence for a dose–response effect over this range. The Committee reviewed evidence from the KEYNOTE‑001 trial comparing the 10‑mg/kg and 2‑mg/kg doses, and considered that it had not seen any evidence to suggest a difference in effectiveness. The Committee concluded that the clinical‑effectiveness evidence presented was broadly generalisable to clinical practice in the NHS.

4.5 The Committee considered the results of the KEYNOTE‑006 trial. It noted that pembrolizumab provided significant improvements in progression‑free 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 follow‑up 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 long‑term 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 long‑term 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 long‑term 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.

4.6 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 less‑severe adverse effects and leads to fewer hospitalisations. The Committee considered that although evidence from KEYNOTE‑006 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 2‑mg/kg dose. The Committee concluded that pembrolizumab is likely to offer a better tolerability profile than ipilimumab.

4.7 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 meta‑analysis, 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 meta‑analysis 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

4.8 The Committee considered the company's model, which compared pembrolizumab with ipilimumab in BRAF mutation‑negative disease, and with ipilimumab, vemurafenib and dabrafenib in BRAF mutation‑positive 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:

4.9 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 'stress‑test' the model, and considered that the second scenario (in which progression‑free survival was extended by 6 years for some people; see section 3.13) was at the upper end of the plausible range for the cost‑effectiveness 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.

4.10 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 cost‑effectiveness ratios (ICERs) for pembrolizumab (compared with ipilimumab in BRAF mutation‑negative disease, and with ipilimumab, dabrafenib and vemurafenib in BRAF mutation‑positive disease) were less than £50,000 per quality‑adjusted 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 back‑calculated.

4.11 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 long‑term survival benefit, similar to ipilimumab, had not yet been confirmed. The Committee concluded that pembrolizumab is innovative, but it could not identify any specific health‑related benefits that had not been captured in the QALY calculation.

4.12 The Committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with a short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met.

4.13 The Committee 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 KEYNOTE‑006 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 life‑extending, end‑of‑life treatment.

4.14 Taking into account the most plausible ICERs, the uncertainties in the clinical and cost‑effectiveness evidence and the supplementary advice for appraising life‑extending, end‑of‑life treatments, the Committee concluded that, on balance, pembrolizumab could be considered a cost‑effective use of NHS resources for people with advanced (unresectable or metastatic) melanoma that has not been previously treated with ipilimumab.

4.15 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