Trametinib in combination with dabrafenib for treating unresectable or metastatic melanoma

Clinical effectiveness

4.1 The committee discussed the clinical need of people with unresectable or metastatic BRAF V600 mutation-positive melanoma. It heard from the patient experts that advanced melanoma can be associated with both disease-related symptoms and adverse effects from treatment, and the disease has a major impact on quality and length of life. It also heard that patients welcomed the combination of trametinib and dabrafenib, which they considered to be an effective and well tolerated new treatment. The committee concluded that the availability of a new combination treatment that slows disease progression and improves quality of life is very important to patients and their families.

4.2 The committee considered the current clinical management of unresectable and metastatic melanoma, and the potential place of trametinib plus dabrafenib in the pathway of care. It acknowledged that the management of advanced melanoma is changing rapidly with the availability of new immunotherapy and other treatments. It heard from the clinical experts that immunotherapy agents are thought to have a very long-lasting effect in some people and there is emerging evidence that some people may also obtain long-term benefit from BRAF-specific therapy, although typically resistance to these agents develops relatively early. Survival data for various combination therapies is still immature, but they show promising survival gains compared with monotherapies. The committee understood from the clinical experts that trametinib plus dabrafenib would be used in place of BRAF-inhibitor monotherapy as the standard of care in 2 groups of patients with BRAF mutation-positive disease; previously untreated melanoma in patients with features such as high-volume disease, high serum LDH, rapid disease progression, poor performance status or brain metastases, or for those in whom the disease has progressed after immunotherapy. The committee concluded that trametinib plus dabrafenib is expected to replace the use of BRAF-inhibitor monotherapies in clinical practice, but that the evolving nature of the management of advanced melanoma made it difficult to determine its precise positioning in the pathway of care.

4.3 The committee discussed the generalisability of the clinical evidence presented in the company's submission from COMBI‑d and COMBI‑v, noting that there were several issues to consider. Firstly, in both trials, patients had not had previous treatment for unresectable or metastatic BRAF V600 mutation-positive melanoma. In addition, patients had a high performance status (ECOG status of 0 or 1) and fewer than 20 patients had brain metastases. The committee recalled the clinical experts' evidence (see section 4.2) that these characteristics did not fully reflect the groups of people for whom trametinib plus dabrafenib would be recommended in clinical practice. The clinical experts highlighted that the pivotal trials of BRAF-inhibitor monotherapies had also included only patients with previously untreated melanoma, but extensive subsequent clinical experience suggested that their efficacy was unaffected by prior immunotherapy. Therefore, they could infer that this would also be the case when BRAF inhibitors were used in combination with a MEK inhibitor. The committee also heard from the clinical experts that there is no biological reason why trametinib plus dabrafenib would be relatively less effective in patients with a poorer performance status. The committee considered that in clinical practice some people would have a lower performance status than those in the trials, and that some would have previously had treatment with immunotherapy. However, it was prepared to accept that the results from the trials were broadly generalisable to the patients who would be offered the treatment in practice.

4.4 The committee examined the results from COMBI‑d and COMBI‑v. It noted that trametinib plus dabrafenib increased median progression-free survival by a statistically significant 2.2 months compared with dabrafenib and by 5.3 months compared with vemurafenib. It also acknowledged that trametinib plus dabrafenib increased median overall survival by a statistically significant 6.4 months compared with dabrafenib alone, and by 7.6 months compared with vemurafenib alone. The committee concluded that trametinib plus dabrafenib was clinically effective compared with the BRAF-inhibitor monotherapies.

4.5 The committee discussed the differences between COMBI‑d and COMBI‑v and the company's approach to pooling the efficacy data. It noted that COMBI‑d was blinded and placebo controlled whereas COMBI‑v was open label without a placebo control, which the ERG considered could introduce bias. However, the committee agreed that the primary outcome in COMBI‑v was overall survival which would not be subject to bias. The committee was aware that the ERG did not consider it appropriate to pool the data from the 2 trials. The committee recalled that vemurafenib and dabrafenib had been accepted to have similar health benefits in previous NICE appraisals. It concluded that the trials were not sufficiently different for the pooling of the efficacy data to be unreasonable.

4.6 The committee considered the adverse events associated with trametinib plus dabrafenib. It was mindful of the recent Medicines and Healthcare products Regulatory Agency (MHRA) warning advising its use with caution in people with risk factors for gastrointestinal perforation. It was also mindful of the ERG's comments that withdrawal rates from both trials due to adverse events were higher in the combination groups than in the monotherapy groups. However, it was told by the clinical experts that this could have been due to the design of the research protocol and would not be expected in clinical practice. The committee heard from the clinical experts that the main adverse effect specifically associated with trametinib plus dabrafenib was pyrexia, which would have led to immediate admission to hospital at the time of the trials, but is now understood to be unrelated to neutropenic sepsis and is usually managed satisfactorily without hospital admission. The committee was reassured by the patient and clinical experts that the adverse events associated with trametinib plus dabrafenib were generally tolerable, serious treatment-related adverse events were rare, and that it has a lower incidence of skin related toxicities compared with monotherapy. The committee concluded that trametinib plus dabrafenib has a manageable adverse event profile.

4.7 The committee examined the data presented on health-related quality of life in the company's submission. It noted with approval that the company had collected quality of life data in the trials, and that rates of completion were high. Data had been gathered using EQ‑5D and other instruments. The committee noted that quality of life data had been collected in a number of different countries because of the multicentre design of the trials. There were some UK patients enrolled in the trials, but it was uncertain whether the whole trial data would apply to the population treated in England. The committee concluded that the data had come directly from participants in the trials who had received the treatments, and there was no evidence to suggest that the health-related quality of life data from the trials was not generalisable to patients in England.

4.8 The committee considered the likely duration of therapy with trametinib plus dabrafenib, noting that the trials and the marketing authorisation permitted its use beyond disease progression if the patient was still receiving benefit. However, the committee heard from the clinical experts that given the choice of alternative therapies now available patients would generally be offered an alternative treatment at the time of disease progression, and the committee accepted that this was likely. The committee also noted that a higher percentage of people in the monotherapy groups had post-progression treatment compared with those having trametinib plus dabrafenib. However, the committee concluded that, because clinical practice is changing, it was not known whether this difference would also be seen in clinical practice.

Cost effectiveness

4.9 The committee considered the company's modelling of cost effectiveness. It noted that it used a 3‑state partitioned model structure, which the company stated had been used in previous NICE appraisals. It also noted the ERG's concern that this type of model structure produces counterintuitive results whereby the less effective the intervention is assumed to be at delaying progression, the more cost effective it becomes. The committee understood that this reflects the lack of a direct modelled relationship between progression-free survival and overall survival. The committee agreed that the ERG's comments were worthy of note, but concluded that the model was in line with accepted NICE methods and was therefore appropriate for decision making.

4.10 The committee examined the modelling of overall survival, noting that the ERG had raised several concerns about the company's modelling method. When the ERG used an alternative method of modelling, its estimate for trametinib plus dabrafenib was very similar to the company's. For the control group, however, the ERG's estimate for overall survival was higher than that estimated by the company and it considered the company's estimate of survival at 5 years to be implausible. The committee heard from the company that it had estimated that 14% of people in the control group would be alive at 5 years, and that this was not implausible taken in the context of what is known about survival in advanced melanoma. However, the committee acknowledged that the ERG had used the totality of the observed Kaplan–Meier data available from the trials, which the company had not, and had used a less complex method of extrapolation using mortality hazard rates from the American Joint Committee on Cancer (AJCC) registry, and that this approach appeared reasonable. The committee concluded that there were uncertainties in modelling of overall survival which required long-term extrapolation of data beyond the end of the trial. Although the ERG's approach made more use of the available trial data, it was unclear which method produced the more plausible results.

4.11 The committee considered whether the costs included in the model were appropriate. It noted the ERG's view that the company's method of using progression-free survival data to estimate treatment cost underestimated the true costs because over a quarter of patients in both trials continued on treatment post-progression. It understood that the ERG considered that time to treatment discontinuation provided a better estimate. The committee recalled the comments from the clinical experts (see section 4.8) that patients tended to switch treatment at the time of progression because of the availability of other treatments. Therefore it concluded that the company's approach to estimating costs using progression free survival was acceptable.

4.12 The committee also considered the ERG's opinion that the company had inappropriately assumed different post-study anticancer treatment costs for the combination and monotherapy groups. The committee considered that there was considerable uncertainty about the treatments given post progression, and the associated costs. In the absence of evidence to the contrary, it was minded to accept the data from the trials which showed some differences in costs between the treatment groups.

4.13 The committee considered the quality of life data used in the cost effectiveness modelling. It appreciated that there were different ways of incorporating quality of life values into the model; for example, using the full EQ‑5D dataset from the trials or a subset of European patients in line with the ERG's preferred approach. The committee noted that the ERG also favoured using equivalent quality-of-life estimates for both treatment groups in the pre-progression health state rather than lower values for the monotherapies. However, given that the data had been gathered directly in the trials, showed some statistically significant differences between the treatment groups, and that regional differences were uncertain, the committee preferred to use the quality of life data directly from the trials.

4.14 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.

4.15 The committee discussed whether trametinib plus dabrafenib met all the criteria to be considered a life-extending, end-of-life treatment. It accepted that there is sufficient evidence to indicate that the treatment offers an extension to life of at least 3 months compared with current NHS treatment. It also accepted that the patient population for unresectable or metastatic BRAF V600 mutation-positive melanoma is small (approximately 1,000 patients annually). The committee recognised that median overall survival in the monotherapy groups of the trials was less than 24 months, but that the modelled mean survival was more than 24 months. The committee appreciated that the difference in median and mean survival estimates may reflect the small number of people who survive many years with this condition, and did so even before effective treatments were available as demonstrated in the AJCC registry. It considered that as treatment for advanced melanoma improves, overall survival is likely to increase to more than 24 months. However, the committee concluded that trametinib plus dabrafenib currently met all the criteria to be considered a life-extending end-of-life treatment.

4.16 The committee examined the cost-effectiveness estimates which incorporated the confidential patient access schemes for trametinib plus dabrafenib and for dabrafenib or vemurafenib alone. It recalled that there were uncertainties regarding the modelling of overall survival and considered that while the most plausible incremental cost-effectiveness ratio (ICER) was uncertain, it would be no higher than the ERG's estimate using its preferred method of modelling. Taking together all the evidence and uncertainties, and given the extra weight applied to quality-adjusted life years (QALYs) at the end of life, the committee agreed that the estimates presented by the ERG and the company were within the range normally considered a cost effective use of NHS resources. It concluded that trametinib plus dabrafenib could therefore be recommended as a treatment option for people with unresectable or metastatic BRAF V600 mutation-positive melanoma.

4.17 The committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion '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. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal.

4.18 The committee discussed the innovative aspects of trametinib in combination with dabrafenib. It accepted that the combination therapy has shown substantial efficacy gains, without any increase in adverse effects, and indeed reduces the incidence of a number of skin toxicities associated with BRAF inhibitor therapy. In those respects the committee agreed with the company that it could be considered innovative. However, it could not identify any health-related benefits that had not been already captured in the QALY calculation.

Summary of appraisal committee's key conclusions