1 Appraisal Committee's preliminary recommendations

1.1 Vemurafenib is not recommended for the treatment of unresectable locally advanced or metastatic BRAF V600 mutation-positive melanoma.

1.2 People currently receiving vemurafenib that is not recommended according to 1.1 should be able to continue treatment until they and their clinician consider it appropriate to stop.

2 The technology

2.1 Vemurafenib (Zelboraf, Roche Products) is an oral tyrosine kinase inhibitor of the oncogenic BRAF V600 protein kinase. It has a UK marketing authorisation for ‘the treatment of adult patients with BRAF V600 mutation-positive unresectable or metastatic melanoma’. All people should have a positive test for the BRAF V600 mutation before starting treatment with vemurafenib. Vemurafenib was developed alongside the Roche cobas 4800 BRAF V600 mutation test, which is commercially available in the European Union. The manufacturer of vemurafenib is currently making BRAF V600 mutation testing free of charge by funding three BRAF reference testing centres in the UK.

2.2 Vemurafenib is most commonly associated with the following adverse reactions: arthralgia, fatigue, rash, photosensitivity reaction, nausea, alopecia and pruritus. It can also lead to the formation of cutaneous squamous‑cell carcinomas. For full details of adverse reactions and contraindications, see the summary of product characteristics.

2.3 The recommended dose of vemurafenib is 960 mg (four 240-mg tablets) twice daily (equivalent to a total daily dose of 1920 mg). The summary of product characteristics states that the doses should be given approximately 12 hours apart, and that treatment with vemurafenib should continue until ‘disease progression or the development of unacceptable toxicity’. Vemurafenib costs £1750 for one pack of 56 x 240-mg tablets (1 week’s supply) (excluding VAT; ‘Monthly Index of Medical Specialities’ [MIMS] May 2012). Costs may vary in different settings because of negotiated procurement discounts. The manufacturer of vemurafenib has agreed a patient access scheme with the Department of Health, in which a discount on the list price of vemurafenib is offered. The size of the discount is commercial-in-confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.

3 The manufacturer's submission

The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of vemurafenib and a review of this submission by the Evidence Review Group (ERG; appendix B). The decision problem addressed by the manufacturer considered people with BRAF V600 mutation-positive melanoma who have not previously received treatment, which is in contrast to the original decision problem which allowed for vemurafenib to be considered in both first and subsequent-line treatment settings.

3.1 The key clinical evidence came from one multicentre, randomised, open-label, active-controlled trial (BRIM3) that compared vemurafenib (960 mg twice daily orally; n = 337) with dacarbazine (1000 mg per square metre of body-surface area by intravenous infusion every 3 weeks; n = 338) in adults with previously untreated stage IIIc or IV BRAF V600 mutation-positive metastatic melanoma until disease progression or unacceptable toxicity. The randomisation process produced equivalent-sized groups, however 14% of patients (n = 48 of 338) randomised to receive dacarbazine did not receive treatment, primarily because of withdrawal of consent or refusal of treatment. The median age of patients in the trial was 56 years and 52 years for people receiving vemurafenib and dacarbazine respectively. About 60% of patients were from Western Europe, and the proportion of patients with an Eastern Cooperative Oncology Group (ECOG) performance score of 0 was 68% in both the vemurafenib and dacarbazine groups. At study entry, more than 90% of patients had stage IV disease.

3.2 The primary outcome in the BRIM3 study changed from overall survival to a joint primary outcome of overall survival and progression-free survival during the study at the request of the Food and Drug Administration. Secondary outcomes included confirmed best overall response rate, duration of response and time to response.

3.3 The manufacturer presented three analyses for overall survival based on three different data cut-off points (December 2010, March 2011 and October 2011). The data safety monitoring board recommended the release of the interim results of efficacy, based on a review of the results of the planned interim analysis of overall survival, and the study was ended and cross-over allowed at this time (December 2010). Two additional analyses have been performed by the manufacturer (using March 2011 and October 2011 data cut-off time periods) to demonstrate the survival benefit conferred by vemurafenib during follow-up.

3.4 Results from the December 2010 data cut-off of the BRIM3 trial showed that treatment with vemurafenib led to a statistically significant reduction in death (hazard ratio [HR] 0.37; 95% confidence interval [CI] 0.26 to 0.55; p < 0.001). At 6 months, overall survival was 84% (95% CI 78 to 89) in the vemurafenib group and 64% (95% CI 56 to 73) in the dacarbazine group. People treated with vemurafenib also had a statistically significant reduction in tumour progression (HR 0.26; 95% CI 0.20 to 0.33; p < 0.001). The estimated median progression-free survival (evaluated in 549 patients) was 5.32 months (95% CI 4.86 to 6.57) in the vemurafenib group and 1.61 months (95% CI 1.58 to 1.74) in the dacarbazine group.

3.5 The secondary outcome of confirmed tumour response could be calculated for 439 patients for the December 2010 data cut-off. In the vemurafenib treatment group, 106 of 219 patients (48%; 95% CI 42 to 55) had a confirmed objective response (including two patients with a complete response and 104 patients with a partial response), with a median time to response of 1.45 months. Only 12 of the 220 patients (5%; 95% CI 3 to 9) treated with dacarbazine had a partial response (no patients had a complete response), with a median time to response of 2.7 months.

3.6 Results from the March 2011 data cut-off included 50 patients (15%) who crossed over from dacarbazine to vemurafenib. The censored hazard ratio for overall survival was 0.44 (95% CI 0.33 to 0.59). Results from the October 2011 data cut-off, which included 24% crossover (n = 81) showed that median overall survival was 13.2 months for the vemurafenib group and 9.6 months for people treated with dacarbazine (censored HR 0.62; 95% CI 0.49 to 0.77).

3.7 The manufacturer reported results from a range of pre-specified subgroups, including age, sex, ECOG performance status, tumour stage and geographical regions. The results showed that the survival benefit conferred by vemurafenib treatment was generally maintained across each subgroup.

3.8 The most commonly reported adverse events (grade 2 or more) associated with vemurafenib treatment in the BRIM3 study were cutaneous events, arthralgia and fatigue (December 2010 cut-off based on 618 patients). People treated with dacarbazine experienced fatigue, nausea, vomiting and neutropenia. A total of 61 people (18%) treated with vemurafenib experienced grade 3 cutaneous squamous-cell carcinoma, keratocanthoma or both, and were treated with simple excision. Treatment-related adverse events were recorded for more patients who received vemurafenib because they stayed on treatment longer than those who received dacarbazine (3.1 months for vemurafenib compared with 0.76 months for dacarbazine based on the December 2010 data cut-off). Adverse events led to dose modification or treatment interruption in 38% of patients in the vemurafenib group (129 of 336 patients) and in 16% of patients receiving dacarbazine (44 of 282 patients). The most common reasons for dose modification were an adverse event or missed cycle. There were more adverse events that led to discontinuation in patients treated with vemurafenib than with dacarbazine (88 compared with 15 patients).

3.9 The manufacturer undertook a systematic literature search but did not identify any economic evaluations of vemurafenib for previously untreated patients with advanced BRAF V600 mutation-positive metastatic malignant melanoma. Therefore, the manufacturer submitted a de novo ‘partitioned survival’ economic model in which vemurafenib was compared with dacarbazine. The model comprised three health states: progression-free, progressed disease and death. Hypothetical patients were assumed to enter the model in the progression-free health state and either remain in that state or progress to a worse health state (that is, progressed disease or death) at the end of each cycle. The model used weekly cycles for a lifetime (30-year) horizon. The perspective adopted in the economic evaluation was that of the NHS and personal social services, and costs and benefits were discounted at 3.5% per year.

3.10 The proportion of people in each health state was calculated using progression-free survival and overall survival data (March 2011 data cut-off) from the BRIM3 study. The probability of remaining in the progression-free state was calculated using results observed in the BRIM3 study until month 9 for vemurafenib and month 7 for dacarbazine, after which survival for each intervention was extrapolated using exponential functions. Overall survival after treatment with vemurafenib was estimated directly from the BRIM3 study for the first 9.5 months (March 2011 data cut-off). A ‘stabilised’ hazard ratio representing the differences between the vemurafenib and dacarbazine arms up to month 14 was then applied, after which the manufacturer assumed that vemurafenib provided no further treatment benefit. Overall survival in the dacarbazine arm was based on three different sets of data. The probability of overall survival in the BRIM3 study was used directly for 40 weeks (9.2 months), with the longer-term outcomes up to 46 months derived from a study by Robert et al. (2011) which compared ipilimumab plus dacarbazine with dacarbazine alone in people with previously untreated advanced melanoma. For months 46 and beyond, a long-term hazard estimate taken from the Surveillance, Epidemiology and End Results (SEER) register was used.

3.11 The manufacturer collected health-related quality of life data in the BRIM3 study using the functional assessment of cancer therapy-melanoma (FACT-M) questionnaire; however results were not presented because completion rates were low. Instead, utility values from a study by Beusterien et al. (2009) were used. In this study, standard gamble methods were used to elicit utilities for advanced melanoma health states from members of the general public. These were combined with disutility values associated with adverse events (obtained from Beusterien et al. [2009] and another study by Nafees et al. [2008]). In the manufacturer’s base-case analysis, a utility for progression-free survival of 0.806 was calculated for people receiving vemurafenib and 0.767 for people receiving dacarbazine. The utility for progressed disease was estimated to be 0.59 based on the study by Beusterien et al. (2009).

3.12 Adverse event rates for vemurafenib and dacarbazine were estimated from the BRIM3 study. The resource costs included in the model were drug acquisition and administration costs, the cost for a BRAF V600 diagnostic test, and the cost of the disease, which included costs related to each health state and of treating adverse reactions. The average length of a course of treatment with vemurafenib was assumed to be 7 months.

3.13 In the manufacturer’s base-case analysis (using March 2011 data cut-off) the incremental cost-effectiveness ratio (ICER) for vemurafenib compared with dacarbazine was £56,410 per quality-adjusted life year (QALY) gained (incremental costs and benefits provided as commercial‑in‑confidence; patient access scheme included). When the October 2011 data cut-off point was used instead, the ICER increased to £75,489 per QALY gained.

3.14 The manufacturer undertook a series of one-way deterministic sensitivity analyses to test the robustness of the results by varying most of the parameters used in the economic evaluation, including transition probabilities, utilities, costs, discount rate, average age of patients, and BRAF V600 mutation incidence. Taking into account the patient access scheme, the ICERs ranged from £42,054 to £66,175 per QALY gained and indicated that vemurafenib was most sensitive to the discount rate (for example, when health benefits were discounted at 1.5% and 0%, the base-case ICER decreased to £48,249 and £42,054 per QALY gained respectively) and variations to the assumed hazard of death between months 9 and 14. In an additional analysis, when the manufacturer assumed that a in a patient diagnosed with terminal cancer an additional day of life has a utility of 1, the base-case ICER decreased to £38,831 per QALY gained.

3.15 The manufacturer also undertook a probabilistic sensitivity analysis but was unable to vary the probability of overall survival because it was not possible to determine which extrapolation approach should be given a higher likelihood of occurring. The probabilistic ICER for vemurafenib compared with dacarbazine was £56,766 per QALY gained and there was a 0% chance of vemurafenib being cost effective at £50,000 per QALY gained. At £60,000 per QALY gained, vemurafenib had an 88.4% probability of being cost effective. The manufacturer considered that the probabilistic sensitivity analyses significantly understated the uncertainty associated with the incremental QALYs gained for vemurafenib.

3.16 The manufacturer also provided additional scenario analyses that modelled the impact on the ICER of using different utility estimates from Hodi et al. 2010 (which compared ipilimumab plus gp100 with gp100 alone and ipilimumab alone). When utility values were selected from this study for progression-free survival (0.80) and progressed disease (0.76) and applied to vemurafenib and dacarbazine in the base case, the ICER fell to £50,052 per QALY gained.

3.17 The ERG considered the BRIM3 study to be well designed and that the clinical-effectiveness evidence presented by the manufacturer was relevant to the decision problem. The ERG noted that the data from the BRIM3 study demonstrated a statistically significant difference for both overall survival and progression-free survival for vemurafenib over dacarbazine in patients who had not received previous treatment. It cautioned however, that the short-term nature of the results from the BRIM3 study and the heterogeneity of the patient population led to substantial uncertainty when projecting long-term benefits of treatment.

3.18 The ERG noted that dose modification was needed in 159 (47%) patients treated with vemurafenib in the BRIM3 study and, of these, 112 patients (33%) had at least one dose reduction, and 147 patients (44%) had one or more dose interruptions (of a mean duration of 8 days) because of an adverse event. Clinical advisers to the ERG agreed with the manufacturer’s interpretation that dose modifications and interruptions are manageable. The ERG also noted that the manufacturer did not apply a disutility to adverse events that led to dose reductions, and suggested that the progression-free survival benefit applied to vemurafenib in the manufacturer’s model may be optimistic given the number of patients who needed a dose reduction and/or interruption in the BRIM3 study.

3.19 The ERG acknowledged that the manufacturer had adapted an economic model previously used in NICE technology appraisals of cancer drugs. It expressed concern that the manufacturer’s modelling of overall survival was overly elaborate and that it assumed survival gains continued to accrue after vemurafenib treatment was stopped. In addition, the ERG disagreed with the following methods in the manufacturer’s model:

• The application of a hazard ratio estimated from the BRIM3 data to extend the treatment benefit of vemurafenib to 14 months.
• The use of a small sample of an arm of the Robert et al. (2011) trial to provide estimates for modelling the outcomes of patients receiving dacarbazine and of those receiving vemurafenib beyond 14 months of survival to 46 months.
• Representing the long-term survival beyond 46 months by a single mortality risk factor parameter calibrated to reconcile data from the study by Robert et al. (2011) with a single value from the SEER database at 10 years (ignoring the SEER hazard profile of over 1000 patients). 

3.20 The ERG questioned some of the manufacturer’s assumptions relating to the costs in the model, and provided some alternative cost estimates. These included a re-estimation of costs for dacarbazine therapy based on distributions of body weight and body surface found in a cohort of UK patients, and the assumption that dacarbazine would be administered as an oncology day case. The ERG also queried long-term monitoring costs (that is, computed tomography [CT] scan and outpatient visits to an oncologist) for both vemurafenib and dacarbazine with clinical advisers, and found that a programme of three to four times per year for 2 years, then twice a year for 2 years, and then finally once a year thereafter was more likely than the manufacturer’s estimate. After incorporating these revisions, the manufacturer’s base-case ICER decreased to £51,888 per QALY gained (incremental costs and benefits are commercial‑in‑confidence).

3.21 The ERG also explored an alternative approach to modelling overall survival. After examining the Kaplan-Meier overall survival curves from the BRIM3 study, the ERG proposed that vemurafenib is effective at suppressing disease progression leading to death in the early phase (that is, on average 97 days) but, after a short period, this effect ceases and patients revert to the pattern of mortality risk seen in the dacarbazine arm. The ERG suggested that the assumption of a limited window of effectiveness might be supported by the observation that resistance is common with new tyrosine kinase inhibitor drugs, reflecting the fact that cancer cells use multiple signalling pathways. The ERG also noted that there appear to be two distinct populations of patients with malignant melanoma: the majority who have a poor prognosis and have a high risk of death within 12 months; and a small group who appear to have good prognosis and can survive for 10 years or more. To address this, the ERG used a simple survival model that included each subgroup split in an unknown ratio and governed by a separate long-term mortality risk (equivalent to an exponential function). The ERG used a study by Balch et al. (2009), which provided survival curves for each of the four metastatic melanoma categories (M0: no distance metastases; M1a: distant skin, subcutaneous, or nodal metastases; M1b: metastases to lung; M1c: metastases to all other visceral sites or distant metastases to any site combined with an elevated serum lactate dehydrogenase) based on the American Joint Committee on Cancer Melanoma Staging Databaseto construct a case-mix-adjusted survival curve according to the proportions of patients in the BRIM3 study with each melanoma category (15.9% melanoma stage M0/M1a, 18.8% M1b and 65.3% M1c). The ERG then fitted a two-part exponential model to take into account its view of two distinct melanoma populations (as described above). The ERG’s compound survival model and the BRIM3 case-mix-adjusted survival curve showed strong similarities, with the compound survival model indicating that 80.6% of patients would have a mean survival of 11 months (0.91 years) and 19.4% of people with advanced melanoma would have an expected mean survival of over 12 years (145 months).

3.22 Taking into account the ERG’s approach to modelling overall survival (but not correcting for any other changes), the revised estimate for the manufacturer’s base-case ICER for vemurafenib compared with dacarbazine was £133,138 per QALY gained. When all of the ERG’s suggested adjustments (section 3.19) were also included, the base-case ICER for vemurafenib compared with dacarbazine was £129,962 per QALY gained.

3.23 The ERG highlighted that the manufacturer’s assumed utility of 0.59 for long-term survivors was likely to be an underestimate, and noted that if it was assumed that a utility of 0.767 (equivalent to the utility for the progression-free survival and stable disease health states) was applied for patients who survived longer than 5 years, the base-case ICER decreased to £49,467 per QALY gained. If the ERG’s revised cost estimates (section 3.19) and utility estimates were incorporated into the manufacturer’s model, but the ERG’s approach to modelling overall survival was not included, the manufacturer’s base-case ICER decreased to £45,618 per QALY gained.

3.24 Full details of all the evidence are in the manufacturer’s submission and the ERG report, which are available from www.nice.org.uk/guidance/TAXXX

4 Consideration of the evidence

The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of vemurafenib, having considered evidence on the nature of locally advanced or metastatic BRAF V600 mutation-positive malignant melanoma and the value placed on the benefits of vemurafenib by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.

4.1 The Committee discussed the place of vemurafenib in the clinical pathway of care for people with locally advanced or metastatic BRAF V600 mutation-positive malignant melanoma. It heard from the clinical specialists that dacarbazine has been used for the last 30 years for first-line management and, although well tolerated, it needs to be administered intravenously in a hospital setting, and is not very effective. The Committee noted the very limited effective treatment options currently available for patients with metastatic melanoma but acknowledged that there are an increasing number of clinical trials investigating a range of new therapies for this disease. The Committee heard from the clinical specialists that vemurafenib has a very high disease response rate compared with dacarbazine, and that symptomatic improvement is often rapid, even for those with very advanced disease. The patient experts also expressed the view that vemurafenib improves people’s quality of life by alleviating symptoms within days or weeks, that it has more manageable side effects, and is easier and more convenient to use than dacarbazine because of its oral formulation. As a result, vemurafenib offers some people the opportunity to return to work and resume a normal life. The Committee heard from the clinical specialists and accepted that vemurafenib is a step change in the management of advanced malignant melanoma and that there is a significant need for effective therapies in this patient population.  

Clinical effectiveness

4.2 The Committee considered the three different data cut-off points from the BRIM3 study presented by the manufacturer. It acknowledged that the data safety monitoring board ended the study and permitted crossover based on the evidence of efficacy of vemurafenib after interim analysis. The Committee noted that vemurafenib, irrespective of the data cut-off, was clinically superior to dacarbazine with respect to the primary endpoints of overall survival and progression-free survival. The Committee acknowledged that the March 2011 cut-off data included 15% of participants who had crossed over to the vemurafenib arm, and that although the October 2011 data cut-off provided an additional 7 months of data, it also included a further 9% crossover (bringing the crossover rate to 24%). The Committee was cautioned by the clinical specialists that the data on overall survival from the October 2011 data cut-off was confounded both by crossover and by the fact that patients whose disease did not show an objective response with dacarbazine were able to receive a range of other therapies including ipilimumab (another treatment for metastatic melanoma) and investigational treatments. The Committee acknowledged the clinical specialists’ concerns but were minded to accept that more information on the long-term clinical effectiveness of vemurafenib at the October 2011 data cut-off outweighed concerns about the robustness of the data compared with the March 2011 data cut-off.

4.3 The Committee considered the results presented by the manufacturer on the clinical effectiveness of vemurafenib. It noted that the manufacturer derived efficacy data primarily from the BRIM3 study, which showed that treatment with vemurafenib led to a statistically significant gain in median progression-free survival of 3.7 months (HR 0.26; 95% CI 0.20 to 0.33) based on the December 2010 data cut-off, and a median overall survival gain of approximately 3.6 months (HR 0.62; 95% CI 0.49 to 0.77; October 2011 data cut-off) compared with dacarbazine for people with previously untreated advanced or metastatic disease. The Committee concluded that vemurafenib is an effective treatment option for locally advanced or metastatic BRAF V600 mutation-positive malignant melanoma.

4.4 The Committee discussed whether the BRIM3 study is generalisable to UK clinical practice. The Committee noted that patients with an ECOG performance status of 0 or 1 were included in the BRIM3 study, and discussed whether people with an ECOG performance status of 2 or 3 are likely to receive vemurafenib treatment in UK clinical practice. The Committee heard from the clinical specialists that the use of vemurafenib is unlikely to be restricted to people with a good performance status, because case studies have demonstrated that even people with the poorest prognosis can still benefit from treatment. The Committee concluded that the results of the BRIM3 study were generalisable to UK clinical practice.

4.5 The Committee considered the adverse events associated with treatment with vemurafenib. It noted that cutaneous events were commonly reported in the BRIM3 study, with 61 people (18%) needing treatment for grade 3 cutaneous squamous-cell carcinoma, keratocanthoma or both. The Committee heard from the clinical specialists and patient experts that people being treated with vemurafenib can have significant skin toxicities, but these are manageable with dose reductions, topical treatments or local excision of lesions. The Committee concluded that treatment with vemurafenib had an acceptable adverse event profile compared with dacarbazine.

Cost effectiveness

4.6 The Committee discussed the cost-effectiveness estimates from the manufacturer’s model and the assumptions on which they were based. The Committee noted that the manufacturer assumed a mean time on treatment of 7 months, which the clinical specialists considered was a reasonable estimate, and used data from the March 2011 cut-off to inform the economic model. It also noted that the length of follow-up in the BRIM3 study was too short to provide robust evidence of the overall survival gain beyond the length of the trial. Therefore, hazard ratio estimates from the BRIM3 study for up to 9.5 months were used, and then patients initially treated with vemurafenib were assumed to continue to have a lower risk of mortality (hazard ratio < 1) from 9.5 months up to 14 months compared with those who had initially received dacarbazine, even after treatment with vemurafenib had been stopped. Thereafter, overall survival was modelled so that patients initially treated with vemurafenib maintained, but did not further improve, their overall survival benefit compared with those who had received dacarbazine. This extended benefit was still apparent beyond 10 years in the manufacturer’s model. The Committee acknowledged that modelling overall survival in the absence of long-term effectiveness data is difficult but questioned whether there was any supportive trial evidence to justify the manufacturer’s assumption of additional benefit from treatment after disease progression, and the maintenance of benefit in the long term. The Committee concluded that there was considerable uncertainty about whether people who received vemurafenib would maintain a significant long-term survival benefit over those who received dacarbazine, and about the magnitude of that benefit.

4.7 The Committee discussed the ERG’s exploration of an alternative approach to modelling overall survival. It noted that the ERG used the October 2011 data cut-off and assumed that after 14 months the benefit of vemurafenib decreased so that by 10 years the subsequent risk of death in the vemurafenib and dacarbazine arms would be equal. This model resulted in a calculated mean overall survival benefit of 97 days for patients treated with vemurafenib compared with those who received dacarbazine, which the Committee noted was slightly less than the overall survival benefit of 3.6 months demonstrated in the October 2011 data cut-off in the trial. The Committee reiterated its conclusion that there was significant uncertainty about the magnitude and duration of the long-term survival benefit attributable to vemurafenib.

4.8 The Committee discussed the uncertainty surrounding the costs associated with supporting BRAF V600 mutation testing. It heard from clinical specialists that the test is currently being used in selected reference centres around the UK, with the cost of implementation being supported by the manufacturer. The clinical specialists expressed the view that while it can take weeks to provide a test result, the main time-limiting factor is accessing and preparing the tumour blocks, and transporting them, rather than performing the test. The Committee recognised the additional burden on pathology laboratories associated with vemurafenib treatment but it was satisfied that BRAF V600 mutation testing is likely to become part of routine management for people with advanced melanoma and that it would not impose a significant resource impact on the NHS in the future.

4.9 The Committee considered the results of the cost-effectiveness analysis, taking into account the patient access scheme. It noted that the manufacturer’s base-case deterministic ICER for vemurafenib compared with dacarbazine was £56,400 per QALY gained when the March 2011 data cut-off point was used, and that the ICER increased to £75,500 per QALY gained when the October 2011 data cut-off was used. The Committee acknowledged that these figures were calculated using the manufacturer’s preferred method of modelling overall survival many years beyond the relatively short duration of the clinical trial, and that when the ERG’s alternative, equally plausible approach to modelling overall survival was adopted (section 3.20), the ICER increased to £133,100 per QALY gained. The Committee was not persuaded that there is any evidence available to provide a plausible rationale for expecting vemurafenib therapy to be associated with any better post‑progression survival than dacarbazine, and noted that the methodological assumptions used to estimate overall survival substantially affected the ICER and were a major factor contributing to the uncertainty in the model. On this basis, the Committee concluded that the most plausible ICER was highly uncertain and was likely to be considerably higher than £50,000 per QALY gained.

4.10 The Committee noted that utility values in the manufacturer’s model were sourced from the literature in the absence of robust data from the BRIM3 study. The Committee agreed that the manufacturer’s assumption that a higher utility value for progression-free survival should be applied to vemurafenib, given its improved clinical profile over dacarbazine, was reasonable. The Committee noted that a utility of 0.59 was applied to the progressed disease state, which is lower than utilities for the same state accepted previously by the Committee for ipilimumab. It heard from the ERG that people who survive in the long term are likely to have a higher quality of life than those with rapidly progressive disease and therefore a higher utility for long-term survival (that is, survival greater than 5 years) is justified. The Committee acknowledged the logic of this approach and noted the sensitivity analysis from the ERG, which assumed a utility value of 0.767 for progressed disease, which decreased the manufacturer’s base-case ICER to £49,400 per QALY gained. The Committee noted that there was insufficient information in the manufacturer’s submission about how the utility data used in the model had been aggregated from the literature, and that there was considerable uncertainty about the magnitude of the difference in utility for progressed disease pre- and post-5 years of survival in light of the lack of clinical evidence on the long-term effectiveness of vemurafenib. The Committee was therefore persuaded that an improved utility value for the progressed disease state post-5 year survival was justified, but the utility which should be assigned was uncertain.

4.11 The Committee considered whether it would be appropriate to consider sensitivity analyses on the discount rates used in the model and their effects on the revised ICER. It noted that a sensitivity analysis on the base-case ICER, which included 3.5% discounting of costs and 1.5% discounting of benefits, gave an ICER of £48,200 per QALY gained. The ‘Guide to the methods of technology appraisal’ clarification issued by the Board of NICE states that ‘where the Appraisal Committee has considered it appropriate to undertake sensitivity analysis on the effects of discounting because treatment effects are both substantial in restoring health and sustained over a very long period (normally at least 30 years), the Committee should apply a rate of 1.5% for health effects and 3.5% for costs’. Having referred to this clarification, the Committee considered that substantial restoration of health for a very long period equated to restoration of health to the extent that the person could be considered as having been effectively cured of their condition. The Committee noted that only two patients in the vemurafenib arm of the BRIM3 study showed a complete disease response, and felt that there was considerable uncertainty about how prolonged the benefit from the treatment would be. The Committee heard from clinical specialists that there is no evidence at present to suggest that vemurafenib is a curative treatment, and that it was unlikely to have substantial benefits beyond 30 years. The Committee therefore concluded that there was no case for differential discounting to be applied.

4.12 The Committee considered supplementary advice from NICE that should be taken into account when appraising treatments which may extend the life of people 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.

4.13 The Committee heard from the clinical specialists that the average life expectancy for people with locally advanced or metastatic BRAF V600 mutation-positive malignant melanoma, particularly for those with distant metastases, as reflected in the trial population, was 3 to 9 months, and was unlikely to be greater than 24 months. The Committee also agreed that there was sufficient evidence from the BRIM3 study to indicate that treatment offers an extension to life of at least an additional 3 months, compared with current NHS treatment. The Committee heard from the manufacturer and clinical specialists that the total number of people who would be eligible for treatment with vemurafenib was less than 1000 each year in England and Wales, which the Committee accepted represents a small patient population. Therefore the Committee was satisfied that vemurafenib met all criteria for being a life-extending, end-of-life treatment and that the trial evidence presented for this consideration was robust.

4.14 The Committee was aware that the NICE ‘Guide to the methods of technology appraisal’ (2008) states that a strong case should be identified for accepting an ICER that is higher than £30,000 per QALY gained. The Committee noted that in these circumstances the NICE methods guide states that judgements about the acceptability of the technology as an effective use of NHS resources will specifically take account of:

• the degree of certainty around the ICER
• any strong reasons to indicate that the assessment of the change in health-related quality of life has been inadequately captured
• whether the innovative nature of the technology adds demonstrable and distinctive benefits of a substantial nature which may not have been adequately captured in the QALY measure.

Furthermore the Committee was aware of NICE’s response to Sir Ian Kennedy’s report ‘Appraising the value of innovation and other benefits’, which states that when considering a technology identified as having innovative characteristics, the Appraisal Committee should satisfy itself that:

• it can be regarded as a ‘step-change’ in the management of the condition, and
• either that the identified innovative characteristics have been taken into account in the QALY calculation (in other words, that their impact on health-related quality of life has been fully captured) or, if not, that they have been separately evaluated including their impact (if any) on the Committee’s judgement of the most plausible ICER.

4.15 Having accepted that the supplementary advice for appraising a life-extending end-of-life treatment applies, the Committee reiterated its concern that the structural uncertainty resulting from extrapolation of overall survival was large. Given this, combined with the fact that the ICER is likely to be significantly higher than £50,000 per QALY gained, and higher than the highest ICER previously accepted by Appraisal Committees in the context of the supplementary advice, it concluded that the magnitude of additional weight that would need to be assigned to the QALY gains for people with BRAF V600 mutation-positive metastatic malignant melanoma would be too great for vemurafenib to be considered a cost-effective use of NHS resources.

4.16 The Committee discussed whether the assessment of the change in health-related quality of life had been adequately captured in the economic analysis. It heard from a patient expert that successfully treated people could lead an active and fulfilling life and were able to contribute to society. The Committee accepted that vemurafenib represents a valuable new therapy and that its mechanism of action is novel. It acknowledged that few advances had been made in the treatment of advanced melanoma in recent years and vemurafenib could be considered a significant innovation for a disease with a high unmet clinical need. It also heard from the clinical specialists that vemurafenib had advanced the understanding of this disease and opened the way to new treatments. The Committee considered that the oral formulation and symptomatic improvement attributable to vemurafenib had been captured in the higher utility value assigned to the progression-free survival health state for those receiving vemurafenib compared with dacarbazine. The Committee did not therefore consider that vemurafenib added demonstrable and distinctive benefits of a substantial nature other than those captured in the QALY calculation. The Committee concluded that vemurafenib had not been demonstrated to be a cost-effective use of NHS resources, and could not recommend vemurafenib for the treatment of unresectable locally advanced or metastatic BRAF V600 mutation-positive melanoma.

Summary of Appraisal Committee's key conclusions

TAXXX	Appraisal title: ‘Vemurafenib for the treatment of locally advanced or metastatic BRAF V600 mutation-positive malignant melanoma’		Section
Key conclusion
Vemurafenib is not recommended for the treatment of unresectable locally advanced or metastatic BRAF V600 mutation-positive melanoma. The Committee felt that there was considerable uncertainty about how prolonged the benefit from treatment would be, but concluded that vemurafenib, although not curative, is an effective treatment option for locally advanced or metastatic BRAF V600 mutation-positive malignant melanoma. The methodological assumptions used to estimate overall survival substantially affected the incremental cost effectiveness ratio (ICER) and were major factors contributing to the uncertainty in the model. The Committee concluded that the most plausible ICER was highly uncertain and was likely to be considerably higher than £50,000 per quality-adjusted life year (QALY) gained. The Committee was satisfied that vemurafenib met all criteria for being a life-extending, end-of-life treatment and that the trial evidence presented for this consideration was robust. The Committee accepted that vemurafenib represents a valuable new therapy and that its mechanism of action is novel. However, the Committee felt that the oral formulation and symptomatic improvement attributable to vemurafenib had been captured in the higher utility value assigned to the progression-free survival health state for those receiving vemurafenib compared with dacarbazine. Therefore it did not consider that vemurafenib added demonstrable and distinctive benefits of a substantial nature other than those captured in the QALY calculation.			1.1 4.11, 4.3 4.9 4.13 4.16
Current practice
Clinical need of patients, including the availability of alternative treatments		Current first-line management of metastatic melanoma is with dacarbazine, an intravenously administered medication that is not very effective. The Committee heard from the clinical specialists and accepted that vemurafenib is a step change in the management of advanced malignant melanoma and that there is a significant need for effective therapies in this patient population.	4.1
The technology
Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?		The Committee heard from clinical specialists that vemurafenib has a very high disease response rate compared with dacarbazine, and patient experts noted that vemurafenib improves people’s quality of life by alleviating symptoms within days or weeks, has manageable side effects, and is easier and more convenient to use than dacarbazine because of its oral formulation. The Committee acknowledged the lack of available therapeutic options for this disease, and concluded that vemurafenib was a step-change in the management of advanced metastatic melanoma.	4.1
What is the position of the treatment in the pathway of care for the condition?		Vemurafenib has a UK marketing authorisation for the treatment of adult patients with BRAF V600 mutation-positive unresectable or metastatic melanoma.	2.1
Adverse reactions		The Committee noted that treatment with vemurafenib is associated with significant skin toxicities such as cutaneous events, which are manageable with local excision of lesions, topical treatments and dose modifications. The Committee accepted that vemurafenib had an acceptable adverse event profile compared with dacarbazine.	4.5
Evidence for clinical effectiveness
Availability, nature and quality of evidence		The clinical effectiveness of vemurafenib compared with dacarbazine was derived primarily from the BRIM3 study, for people with previously-untreated advanced or metastatic disease. The Committee concluded that the results of the BRIM3 study were generalisable to UK clinical practice.	4.3. 4.4
Relevance to general clinical practice in the NHS		Few advances had been made in the treatment of advanced melanoma in recent years and vemurafenib is considered to be a significant innovation for a disease with a high unmet clinical need. The Committee heard from the clinical specialists that vemurafenib had advanced the understanding of this disease and opened the way to new treatments.	4.16
Uncertainties generated by the evidence		The Committee was cautioned by the clinical specialists that the data on overall survival from the October 2011 data cut-off was confounded both by crossover and by the fact that patients whose disease did not show an objective response with dacarbazine were able to receive a range of other therapies including ipilimumab and investigational treatments. The short-term nature of the results from the BRIM3 study contributed to the uncertainty of the long-term benefits of vemurafenib treatment.	4.2
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?		Not applicable.
Estimate of the size of the clinical effectiveness including strength of supporting evidence		The estimated median progression-free survival (evaluated in 549 patients) was 5.32 months in the vemurafenib arm and 1.61 months in the dacarbazine arm (December 2010 data cut-off). The Committee noted that treatment with vemurafenib led to a statistically significant median progression-free survival gain of 3.7 months (HR 0.26; 95% CI 0.20 to 0.33) based on the December 2010 data cut-off, and a median overall survival of approximately 3.6 months (HR 0.62; 95% CI 0.49 to 0.77) from the October 2011 data cut-off. . The Committee concluded that vemurafenib, although not curative, is an effective treatment option for locally advanced or metastatic BRAF V600 mutation-positive malignant melanoma.	3.44.3 4.11, 4.3
Evidence for cost effectiveness
Availability and nature of evidence		The manufacturer presented a de novo economic model comparing vemurafenib with dacarbazine, and used effectiveness data from the March 2011 data cut-off of the BRIM3 trial (that is, for up to 9.5 months of treatment), the Robert et al. (2011) trial to estimate treatment effects for dacarbazine and the SEER registry to estimate the long-term survival of people with advanced malignant melanoma.	3.9, 3.10, 4.6
Uncertainties around and plausibility of assumptions and inputs in the economic model		The Committee acknowledged that there is significant difficulty in estimating overall survival beyond the trial period, and noted that a number of assumptions need to be made in estimating the relative treatment effects for vemurafenib and dacarbazine. The Committee was not persuaded that there is any evidence available to provide a plausible rationale for expecting vemurafenib therapy to be associated with any better post‑progression survival than dacarbazine, and noted that the methodological assumptions used to estimate overall survival substantially affected the ICER and were a major factor contributing to the uncertainty in the model.	4.6. 4.9
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 manufacturer’s economic model used utility values sourced from the literature. The manufacturer provided a scenario analysis which showed that when people diagnosed with terminal cancer value each additional day of life at a utility of 1, the base-case ICER decreased to £38,831 per QALY gained. The Committed noted that a utility value of 0.59 applied to progressed disease is low, and considered a scenario analysis in which the ERG applied a higher utility value of 0.767 for progressed disease to take into account people with longer survival. The base-case ICER for this scenario was £49,400 per QALY gained. While the Committee acknowledged a higher utility value for long-term survival (that is, survival greater than 5 years) is logical, it concluded that there is a lack of clinical evidence on the long-term effectiveness of vemurafenib and therefore the utility value which should be assigned for progressed disease was uncertain.	3.11 3.14, 4.10
Are there specific groups of people for whom the technology is particularly cost effective?		Not applicable.
What are the key drivers of cost effectiveness?		The Committee noted that there was a lack of evidence available to provide a plausible rationale for expecting vemurafenib therapy to be associated with any better post-progression survival than dacarbazine. It therefore concluded that the methods used to estimate overall survival were a major factor of the uncertainty in the model.	4.9
Most likely cost-effectiveness estimate (given as an ICER)		The Committee noted that the manufacturer’s base-case ICER for vemurafenib compared with dacarbazine was £56,400 per QALY gained. Alternative estimates for overall survival proposed by the ERG increased the manufacturer’s base-case to £133,100 per QALY gained. The Committee agreed that the most plausible ICER for vemurafenib was highly uncertain and likely to be considerably higher than £50,000 per QALY gained.	4.9
Additional factors taken into account
Patient access schemes (PPRS)		The manufacturer of vemurafenib agreed to a patient access scheme with the Department of Health which involves a confidential discount of the list price of vemurafenib.	2.3
End-of-life considerations		The average life expectancy for people with locally advanced or metastatic BRAF V600 mutation-positive malignant melanoma, particularly for those with distant metastases, as reflected in the trial population, was 3 to 9 months, and is unlikely to be greater than 24 months. The Committee agreed that there was sufficient evidence from the BRIM3 study to indicate that treatment offers an extension to life of at least an additional 3 months, compared with current NHS treatment. The Committee heard from the manufacturer and clinical specialists that the total number of people who would be eligible for treatment with vemurafenib was less than 1000 each year in England and Wales, which the Committee accepted represents a small patient population. The Committee was satisfied that vemurafenib met all of the criteria for being a life-extending, end-of-life treatment and that the trial evidence presented for this consideration was robust.	4.12, 4.13
Equalities considerations and social value judgements		No equality issues were raised during the scoping exercise or the course of the appraisal.	-

5 Implementation

5.1 The Secretary of State and the Welsh Assembly Minister for Health and Social Services have issued directions to the NHS in England and Wales on implementing NICE technology appraisal guidance. When a NICE technology appraisal recommends use of a drug or treatment, or other technology, the NHS must usually provide funding and resources for it within 3 months of the guidance being published. If the Department of Health issues a variation to the 3-month funding direction, details will be available on the NICE website. When there is no NICE technology appraisal guidance on a drug, treatment or other technology, decisions on funding should be made locally.

5.2 The technology in this appraisal may not be the only treatment for unresectable locally advanced or metastatic BRAF V600 mutation-positive malignant melanoma recommended in NICE guidance, or otherwise available in the NHS. Therefore, if a NICE technology appraisal recommends use of a technology, it is an option for the treatment of a disease or condition. This means that the technology should be available for a patient who meets the clinical criteria set out in the guidance, subject to the clinical judgement of the treating clinician. The NHS must provide funding and resources (in line with section 5.1) when the clinician concludes that the patient agrees that the recommended technology is the most appropriate to use, based on a discussion of all available treatments.

5.3 NICE has developed tools to help organisations put this guidance into practice (listed below). These are available on our website (www.nice.org.uk/guidance/TAXXX). [NICE to amend list as needed at time of publication]

• Slides highlighting key messages for local discussion.
• Costing template and report to estimate the national and local savings and costs associated with implementation.
• Implementation advice on how to put the guidance into practice and national initiatives that support this locally.
• A costing statement explaining the resource impact of this guidance.
• Audit support for monitoring local practice.

6 Related NICE guidance

Published

• Referral guidelines for suspected cancer. NICE clinical guideline 27 (2005).
• Skin cancer prevention: information, resources and environmental changes. NICE public health guidance 32 (2011).
• Improving supportive and palliative care for adults with cancer. NICE cancer service guidance (2004).
• Improving outcomes for people with skin tumours including melanoma. NICE cancer service guidance (2006).

Under development

NICE is developing the following guidance (details available from www.nice.org.uk):

• Ipilimumab for previously treated advanced (unresectable or metastatic) malignant melanoma (publication date to be confirmed).
• Ipilimumab in combination with dacarbazine for previously untreated unresectable stage III or IV malignant melanoma (publication date to be confirmed).

7 Proposed date for review of guidance

7.1 NICE proposes that the guidance on this technology is considered for review by the Guidance Executive in 2015. NICE welcomes comment on this proposed date. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.

Jane Adams,
Chair, Appraisal Committee A
May 2012
Appendix A: Appraisal Committee members, and NICE project team

A Appraisal Committee members

The Appraisal Committees are standing advisory committees of NICE. Members are appointed for a 3-year term. A list of the Committee members who took part in the discussions for this appraisal appears below. There are four Appraisal Committees, each with a chair and vice chair. Each Appraisal Committee meets once a month, except in December when there are no meetings. Each Committee considers its own list of technologies, and ongoing topics are not moved between Committees.

Committee members are asked to declare any interests in the technology to be appraised. If it is considered there is a conflict of interest, the member is excluded from participating further in that appraisal.

The minutes of each Appraisal Committee meeting, which include the names of the members who attended and their declarations of interests, are posted on the NICE website.

Dr Jane Adam (Chair)
Department of Diagnostic Radiology, St George’s Hospital

Professor Iain Squire (Vice-Chair)
Consultant Physician, University Hospitals of Leicester

Dr Jeremy Braybrooke
Consultant Medical Oncologist, University Hospitals Bristol NHS Foundation Trust

Dr Gerardine Bryant
General Practitioner, Heartwood Medical Centre, Derbyshire

Dr Fiona Duncan
Clinical Nurse Specialist, Anaesthetic Department, Blackpool Victoria Hospital, Blackpool

Mr Adrian Griffin
Vice President, HTA & International Policy, Johnson & Johnson

Professor Jonathan Grigg
Professor of Paediatric Respiratory and Environmental Medicine, Barts and the London School of Medicine and Dentistry, Queen Mary University London

Dr Peter Heywood
Consultant Neurologist, Frenchay Hospital

Dr Sharon Saint Lamont
Head of Quality and Innovation, North East Strategic Health Authority

Dr Ian Lewin
Consultant Endocrinologist, North Devon District Hospital

Dr Louise Longworth
Reader in Health Economics, HERG, Brunel University

Professor John McMurray
Professor of Medical Cardiology, University of Glasgow

Dr Alec Miners
Lecturer in Health Economics, London School of Hygiene and Tropical Medicine

Ms Pamela Rees
Lay Member

Dr Ann Richardson
Lay Member

Dr Paul Robinson
Medical Director, Merck Sharp & Dohme

Ms Ellen Rule
Programme Director, NHS Bristol

Mr Stephen Sharp
Senior Statistician, MRC Epidemiology Unit

Dr Peter Sims
General Practitioner, Devon

Mrs Amelia Stecher
Associate Director of Individual Funding Requests and Clinical Effectiveness, NHS Kent and Medway

Mr David Thomson
Lay Member

Dr John Watkins
Clinical Senior Lecturer/Consultant in Public Health Medicine, Cardiff University and National Public Health Service Wales  

Dr Anthony S Wierzbicki
Consultant in Metabolic Medicine/Chemical Pathology, Guy’s and St Thomas’ Hospitals NHS Trust

Dr Olivia Wu
Reader in Health Economics, University of Glasgow

B NICE project team

Each technology appraisal is assigned to a team consisting of one or more health technology analysts (who act as technical leads for the appraisal), a technical adviser and a project manager.

Kumar Perampaladas
Technical Lead

Fiona Rinaldi
Technical Adviser

Bijal Joshi
Project Manager

Appendix B: Sources of evidence considered by the Committee

A The Evidence Review Group (ERG) report for this appraisal was prepared by Liverpool Reviews and Implementation Group:

• Dickson R, Bagust A, Beale S et al. Vemurafenib for the treatment of locally advanced or metastatic BRAF V600 mutation positive malignant melanoma: A Single Technology Appraisal. Liverpool Reviews and Implementation Group, 2012.

B The following organisations accepted the invitation to participate in this appraisal as consultees and commentators. They were invited to comment on the draft scope, the ERG report and the appraisal consultation document (ACD). Organisations listed in I were also invited to make written submissions. Organisations listed in II and III had the opportunity to give their expert views. Organisations listed in I, II and III also have the opportunity to appeal against the final appraisal determination.

I Manufacturer/sponsor:

• Roche Products (vemurafenib)

II Professional/specialist and patient/carer groups:

• British Association of Dermatologists
• British Association of Skin Cancer Nurse Specialists
• Factor 50
• Royal College of Nursing
• Royal College of Pathologists
• Royal College of Physicians (NCRI/RCP/RCR/ACP/JCCO)
• United Kingdom Clinical Pharmacy Association

III Other consultees:

• Department of Health
• Welsh Assembly Government

IV Commentator organisations (did not provide written evidence and without the right of appeal):

• Bayer (dacarbazine)
• Bristol-Myers Squibb (ipilimumab)
• Commissioning Support Appraisals Service
• Department of Health, Social Services and Public Safety for Northern Ireland
• Health Improvement Scotland
• Liverpool Reviews & Implementation Group, University of Liverpool
• National Collaborating Centre for Cancer
• National Institute for Health Research Health Technology Assessment Programme

C The following individuals were selected from clinical specialist and patient expert nominations from the non-manufacturer/sponsor consultees and commentators. They gave their expert personal view on vemurafenib by attending the initial Committee discussion and providing written evidence to the Committee. They are invited to comment on the ACD.

• Dr Louise Fearfield, Consultant Dermatologist, nominated by an organisation representing the British Association of Dermatologists – clinical specialist
• Dr Paul Lorigan, Senior Lecturer in Medical Oncology, nominated by and organisation representing Roche and Royal College of Physicians – clinical specialist
• Professor Martin Gore, Consultant Medical Oncologist nominated by an organisation representing the Royal College of Physicians – clinical specialist
• Mrs Gillian Nuttall, CEO & Founder, nominated by an organisation representing Factor 50 – patient expert
• Mr Steve Chalk, nominated by an organisation representing Factor 50 – patient expert

D Representatives from the following manufacturer/sponsor attended Committee meetings. They contributed only when asked by the Committee chair to clarify specific issues and comment on factual accuracy.

• Roche Products