Mogamulizumab for previously treated mycosis fungoides and Sézary syndrome

3.1 Cutaneous T-cell lymphoma is a rare type of non-Hodgkin lymphoma that affects the skin. It includes mycosis fungoides, the most common type, and Sézary syndrome, which is closely related. The clinical experts explained that Sézary syndrome is an aggressive disease and prognosis tends to be poor. Both patient experts described how living with a scaly itching rash all the time significantly affects their health-related quality of life. Sleep is affected. Cracks and open wounds are common, particularly on the hands and feet, which limits the ability to walk and carry out daily activities. The clinical experts explained that the disease particularly affects people's appearance and people sometimes rely on carers to help with daily activities. They confirmed that the treatments recommended in the British Association of Dermatologists and UK Cutaneous Lymphoma Group guidelines on managing primary cutaneous lymphomas after at least 1 systemic treatment were used in clinical practice. These included brentuximab vedotin, methotrexate, bexarotene, peginterferon and chemotherapy. The patient experts said that treatments such as chemotherapy had little benefit but mogamulizumab had a dramatic improvement. Mogamulizumab improved their itching and skin condition, so they could carry out daily activities more easily, and considerably improved their quality of life. The committee concluded that people with mycosis fungoides or Sézary syndrome who have had at least 1 systemic treatment would welcome an additional treatment option.

3.2 Mogamulizumab is indicated for treating mycosis fungoides or Sézary syndrome after at least 1 systemic treatment (see section 2.1). For the first and second committee meetings, the company proposed mogamulizumab as an option for a subgroup of the population covered by the marketing authorisation; that is, after at least 1 systemic treatment for people with severe disease that has progressed with brentuximab vedotin or if it is not appropriate. Severe disease was defined as stage 2B and above for mycosis fungoides and all stages of Sézary syndrome. Brentuximab vedotin is recommended as an option for severe CD30‑positive disease after at least 1 treatment (see NICE's technology appraisal guidance on brentuximab vedotin for treating CD30-positive cutaneous T-cell lymphoma). The committee understood that mogamulizumab would most likely be used as an option after 1 systemic treatment for CD30-negative disease and after 2 systemic treatments for CD30-positive disease. But it noted that brentuximab could also be used later in the treatment pathway. The clinical experts explained that around 15% to 20% of people have CD30-positive disease. After the appeal, the company further refined the positioning of mogamulizumab for advanced mycosis fungoides to adults who have had 2 or more systemic treatments. It maintained the positioning in Sézary syndrome for adults who have had 1 or more systemic treatments. Few people with Sézary syndrome have CD30-positive disease. So, this positioning means that in both conditions, most people will have had brentuximab vedotin, or it will be unsuitable. The company explained that this is the population with the greatest unmet need because the only treatment options available to them are repeating previous treatments or clinical trials. The clinical experts confirmed that the company's proposed subgroup with severe disease was clinically relevant and that people in this subgroup had limited treatment options. The committee considered that there was a very high unmet need in this population. The committee concluded that the company positioned mogamulizumab for a subgroup of the population covered by the marketing authorisation and it would account for this in its recommendations.

3.3 The company originally submitted cost-effectiveness analyses, which used clinical-effectiveness data comparing mogamulizumab with vorinostat, a treatment that is not licensed or used in the UK (see section 3.4). In its revised base case after technical engagement, the company included the costs of having bexarotene alone for everyone in the standard care arm. This is because it considered it to be the most common NHS treatment for mycosis fungoides and Sézary syndrome. A clinical expert explained that triple therapy with bexarotene, extracorporeal photopheresis and peginterferon is used in clinical practice. But bexarotene alone would not generally be used, particularly for Sézary syndrome, because it was not effective. Another clinical expert suggested that chemotherapy may also be an option for people who were eligible for mogamulizumab. The committee considered that the company's approach may oversimplify a complex treatment pathway. The company also submitted clinical-effectiveness data for standard care from the hospital episode statistics (HES) database, including other relevant treatments in the standard care arm. These included methotrexate, bexarotene, peginterferon and chemotherapy. Overall, the committee concluded that standard care was the most appropriate comparator.

3.4 The clinical evidence for mogamulizumab came from MAVORIC, a phase 3, open-label, randomised controlled trial. MAVORIC compared mogamulizumab with vorinostat in 372 adults with stage 1B to 4B relapsed or refractory mycosis fungoides or Sézary syndrome. There was no evidence directly comparing mogamulizumab with treatments currently used as NHS standard care (see section 3.3). In NICE's technology appraisal guidance on brentuximab vedotin for treating CD30-positive cutaneous T-cell lymphoma, the ALCANZA trial was used. It compared brentuximab with the physician's choice of treatment (methotrexate or bexarotene). The committee understood that:

3.5 Real-world data from England's HES database was presented by the company at the first committee meeting and used to support its preferred approach to extrapolating survival for the comparator arm from MAVORIC (see section 3.9). After consultation, the company submitted an unanchored indirect treatment comparison comparing mogamulizumab outcomes from MAVORIC with HES data. The committee noted that, unlike the MAVORIC data (see section 3.4), the HES data did not need any crossover adjustment. The committee noted that NICE's Decision Support Unit technical support document 18 states that all effect modifiers and prognostic factors should be accounted for in an unanchored indirect treatment comparison. This is because 'failure of this assumption leads to an unknown amount of bias' in the comparison. It noted that the MAVORIC data was only matched to the HES data for the proportion of people with mycosis fungoides and Sézary syndrome. Age (a known prognostic factor) and sex (which can potentially affect survival) were not matched. This was because the company considered that these were similar between the MAVORIC and HES data and wanted to avoid reducing the sample size unnecessarily. The ERG explained that age and sex should have been matched and pointed out that differences in mean age increased by 2.5 years after matching. After the appeal, the company submitted a scenario analysis including age and sex, which had a negligible effect on the hazard ratio for overall survival. The hazard ratio for overall survival, adjusted for age and sex, was 0.38 (95% confidence interval 0.25 to 0.59), showing mogamulizumab was associated with an improvement in overall survival compared with standard care. The committee was aware that several additional prognostic factors recognised in the literature and in a study by the Cutaneous Lymphoma International Consortium included:

3.6 The company used clinical-effectiveness data from a post-hoc subgroup of 287 people with severe disease in MAVORIC to reflect its proposed positioning (see section 3.2). The committee recalled that severe disease was considered a clinically relevant subgroup. But it noted that in this subgroup, it could not easily determine the proportion of people who had disease progression after brentuximab vedotin (CD30‑positive disease) and those not eligible for brentuximab vedotin (CD30‑negative disease). It was also concerned that the clinical-effectiveness data included people at different stages in the treatment pathway and did not differentiate between mycosis fungoides and Sézary syndrome. It considered that this may not be appropriate given the differences in expected survival between the conditions. The committee would have liked to have seen separate analyses by disease type and line of treatment. It recalled that all analyses used vorinostat as a comparator, which did not represent NHS standard care (see section 3.4). After the appeal, the company reweighted the MAVORIC trial data to match the characteristics of the subgroup of the population covered by the marketing authorisation, as observed in the HES data. Based on the evidence, the committee concluded that the MAVORIC subgroup with severe disease was clinically relevant. But using a mixed population, which grouped several lines of treatment together, created uncertainty. Also, MAVORIC did not compare mogamulizumab with a relevant comparator.

3.7 In the company's partitioned survival model, 3 different treatment pathways were modelled:

3.8 The company originally modelled standard care using MAVORIC clinical-effectiveness data because it considered that vorinostat could be used as a proxy for standard care (see section 3.4). In its revised base case after technical engagement, the company preferred to use the costs of bexarotene alone for 48 weeks to represent the likely costs for people who have NHS standard care. After consultation, the company reverted to the ERG's preferred assumption of using the time on treatment for vorinostat and for relevant standard care treatments. In addition, clinical-effectiveness data for the standard care arm was updated to reflect data from the HES analysis (see section 3.5). After the appeal, the company estimated next-treatment-free survival and time on treatment for both arms from the reweighted MAVORIC trial, focusing on the refined population. The committee heard that the ERG agreed with the company's choice of distribution for next-treatment-free survival and using Kaplan–Meier curves to estimate time on treatment. Despite the limitations in the data sources, the committee concluded that the data was the most appropriate for decision making.

3.9 In MAVORIC, 72% of people in the severe subgroup crossed over from vorinostat to mogamulizumab after disease progression. Therefore, overall survival in the vorinostat arm was heavily confounded. The ERG and company agreed that an adjustment was needed to estimate what would have happened in the comparator arm if there was no crossover. In the first 2 committee meetings, the company preferred to use the inverse probability of censoring weights (IPCW) method and the ERG preferred a 2‑stage estimation method to adjust for crossover. Alongside the company's preferred IPCW crossover adjustment, it chose a log-normal curve to extrapolate overall survival in the mogamulizumab arm and applied an exponential curve to the standard care arm. The ERG preferred the exponential curve for both treatment arms. The committee preferred the ERG's approach and agreed that the company would need to make a strong case to justify using different parametric curves in each treatment arm. After the appeal, the company estimated overall survival for the mogamulizumab arm from the reweighted MAVORIC trial. The company and ERG agreed that the exponential extrapolation in the mogamulizumab arm was the best fitting curve and was clinically plausible. The company also updated the data source for overall survival in the standard care arm to the HES data after the appeal. The company chose the exponential extrapolation to estimate overall survival in the standard care arm. The company explained that although the generalised gamma was the best fitting curve, it did not consider the extrapolation to be clinically plausible because it predicted a plateau in survival. The ERG noted that the exponential extrapolation was the best fitting curve for the mogamulizumab arm but the worst fitting curve for the standard care arm. So, the ERG preferred the log-normal extrapolation because it was the second-best fitting extrapolation. The log-normal curve showed that 10% of people who had standard care would be alive at 10 years. The clinical experts explained that only people who had allogeneic stem cell transplants would be alive at 10 years. The clinical experts added that people whose disease progresses and need second- and third-line treatments do not have a good prognosis and would not be long-term survivors. The committee agreed with the company and clinical experts that because the modelling did not include people who have had allogeneic stem cell transplant, the log-normal curve was not clinically plausible. The committee concluded that the company and ERG's preferred exponential curve for the mogamulizumab arm and the company's preferred exponential curve for the standard care arm were acceptable for decision making.

3.10 The company included a 2‑year stopping rule for mogamulizumab in its revised base case. There was no evidence to support a stopping rule because it was not included in either the summary of product characteristics or the MAVORIC trial. The committee understood that the estimated treatment effect could have differed if a stopping rule had been used. The company suggested that the treatment effect was unlikely to differ substantially because in MAVORIC, only a small proportion of people had mogamulizumab after 2 years (the data is confidential and cannot be reported here). The committee recalled that it was not convinced that there would be a prolonged treatment benefit after stopping treatment. Before technical engagement, 1 clinical expert suggested that a 2‑year stopping rule would not be appropriate if people were still benefitting from treatment. At the committee meeting, the clinical experts explained that treatment would not normally be stopped if it was tolerated and there was an ongoing clinical benefit. The patient experts said they would feel distressed if mogamulizumab was stopped at 2 years, leaving them without any effective treatment options. The committee concluded that a 2‑year stopping rule was not appropriate.

3.11 The committee recalled that people with this condition sometimes rely on help from informal carers (see section 3.1). The committee noted that some people would have help from district nurses (for example, with wound dressing). Also, costs for community-based care including home visits, skin and wound care and dressings were included in the model. In the first and second committee meetings, the company's base case modelled the effect of caring on the health-related quality of life of carers by applying an additional utility gain of 0.19 when a person is in the disease control health state. This was the difference between the direct estimates of carer's health-related quality of life when caring for someone in the disease control (0.56) and subsequent treatment states (0.37) from the company's vignette study. Therefore, only the additional time a person spent in the disease control state after having mogamulizumab compared with standard care contributed to improving carer's health-related quality of life. After consultation, the company submitted 2 scenarios for carer utilities, in which:

3.12 The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. At the first meeting, using MAVORIC data with the company's preferences, the model predicted a median survival of 21 months and a mean survival of 37 months in the standard care arm. The committee's preferred assumptions predicted a mean survival of between 33 months and 59 months in the standard care arm depending on if an IPCW or 2‑stage estimation crossover adjustment was used. The company also submitted HES data, which showed a median overall survival of around 1.3 years for people who have had 1 treatment. After consultation, the company submitted an updated HES analysis (see section 3.5) and considered that the end of life criteria had been met. The committee recognised that median life expectancy based on the new HES analysis (17.83 months) was less than 24 months. However, it noted that the mean extrapolated discounted and undiscounted life years in the standard care arm of the cost-effectiveness model based on the HES data, were 2.87 and 3.31 years respectively. The committee also considered a study by the Cutaneous Lymphoma International Consortium and the professional organisations' responses to technical engagement. After the appeal, the committee reconsidered this data and noted that the median data from the Cutaneous Lymphoma International Consortium study and the professional organisations' responses to technical engagement referred to time from diagnosis, rather than time from eligibility for second-line treatment. The committee acknowledged that time from eligibility for second-line treatment was the relevant period that should have been considered. After the appeal, the company updated the data source for overall survival in the standard care arm to the HES data. In the refined population, the HES data showed that median overall survival from time from eligibility for second-line treatment was 13 months but when the HES data was used in the model, it showed that mean overall survival was 28 months, when the exponential curve was chosen for both treatment arms. The committee noted that all other extrapolations of the HES data in the model led to a mean life expectancy greater than 28 months. The committee remained concerned about the differences between the median overall survival results from the HES analysis and the mean results produced when it was used in the model. The company considered that the mean was skewed by the long survival of around 10% of people having allogeneic stem cell transplant after current and subsequent treatments in the HES dataset. The ERG noted that people who had allogeneic stem cell transplant were part of the same cohort for which life expectancy was estimated, so their long survival does not bias life expectancy. The clinical experts explained that the life expectancy of people with the condition is variable and both the mean and median figures could be plausible. The committee recalled that cost-effectiveness results and decisions are based on mean quality-adjusted life years (QALYs) and costs. So, the committee still considered that the best estimate of expected survival came from modelling mean life expectancy. The committee noted that NICE's guide to the methods of technology appraisal states that the appraisal committee must be satisfied that:

3.13 NICE's guide to the methods of technology appraisal notes that above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per QALY gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee noted the high level of uncertainty associated with the MAVORIC analysis, specifically:

3.14 After the appeal, the company's updated base-case ICER for mogamulizumab compared with standard care was £28,233 per QALY gained, including the commercial arrangement for mogamulizumab. Adjusting the baseline characteristics of the MAVORIC trial to match the refined population had a minimal impact on the ICER. The committee understood that there was a small effect on the ICERs when including the commercial arrangement for bexarotene but the exact data is confidential so cannot be reported here. The committee considered the company's base case suitable for decision making. The company's base case included:

3.15 The company considered mogamulizumab to be innovative because there are limited effective treatment options for people with advanced mycosis fungoides after at least 2 previous systemic treatments and for people with Sézary syndrome after at least 1 previous systemic treatment. The company emphasised the importance of improved health-related quality of life for these conditions, which cause lesions that affect people's appearance. The committee recalled this, the reported benefits in improving symptoms and the burden on carers. The committee also noted that the benefits of allogeneic stem cell transplant in the standard care arm were included in the modelling, but the associated costs were not. So, the committee was willing to qualitatively consider these factors. It also noted that mogamulizumab has an innovative mechanism of action. The committee concluded that mogamulizumab is innovative and the relevant benefits associated with mogamulizumab that were not captured in the modelling were considered qualitatively in determining an acceptable ICER (see section 3.13).