Mogamulizumab is licensed for treating mycosis fungoides and Sézary syndrome in adults who have had at least 1 systemic treatment. The company has positioned it for Sézary syndrome after 1 or more systemic treatments but only for advanced mycosis fungoides after 2 or more systemic treatments. This is because there are limited treatment options for this population. 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. 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 noted that mogamulizumab improved progression-free survival in MAVORIC compared with vorinostat, the overall survival estimates were uncertain because MAVORIC was not powered to detect overall survival differences, and 72% of people in the severe disease subgroup crossed over from vorinostat to mogamulizumab, so crossover adjustment was needed. Overall, the committee was concerned about using these clinical-effectiveness data because vorinostat was not licensed for use in the UK and did not represent NHS standard care. The committee considered that evidence for the relative effectiveness of mogamulizumab was limited and concluded that evidence from clinical trials, used to estimate the relative treatment effect of mogamulizumab, was highly uncertain compared with NHS standard care. The company submitted an unanchored indirect treatment comparison comparing mogamulizumab outcomes from MAVORIC with real-world data from England's HES database data. Overall, the committee recognised that the HES analysis addressed some of the issues with the original submission and commended the company on its efforts. But the limitations of the data and the lack of information on prognostic factors meant that the indirect analysis results were uncertain. The committee considered that although there were uncertainties in the indirect comparison it was unlikely that these could have been addressed. The committee concluded that the indirect comparison suggested that mogamulizumab was more effective than standard care but that the evidence was uncertain. The company used clinical-effectiveness data from a post-hoc subgroup of 287 people with severe disease in MAVORIC to reflect its proposed positioning. 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. 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. The company's updated base-case incremental cost-effectiveness ratio (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 company's base case excluded carer health-related quality of life. The committee considered the substantial uncertainty in all the cost-effectiveness estimates when applied in an NHS setting but noted the rarity of the cancer being appraised. The committee agreed that, based on its preferred assumptions, the most plausible ICER was within the range it considered acceptable for this appraisal. The committee concluded that mogamulizumab was cost effective for advanced mycosis fungoides after at least 2 previous systemic treatments and for Sézary syndrome after at least 1 previous systemic treatment.