The evidence for monotherapy use for Waldenström’s macroglobulinaemia comes from one open-label, single-arm, phase II study (1118E). At the time of the final analysis, median progression-free survival and overall survival were not estimable. The Kaplan-Meier estimated rates for PFS were 83% at 18 months, 69% at 24 months and 54% at 60 months; corresponding overall survival rates were 93%, 95% and 87% respectively. The company submitted a cost-minimisation analysis and a cost-utility analysis of ibrutinib monotherapy for the treatment of adult patients with Waldenström's macroglobulinaemia who have received at least one prior therapy. The economic analysis was performed against a comparator of ibrutinib plus rituximab, which is the only licensed treatment accepted for use by SMC for this indication. There were a number of limitations with the analysis which include the following: • Direct comparative evidence between ibrutinib monotherapy and ibrutinib plus rituximab is lacking. The company considered that a robust indirect treatment comparison was not feasible and the naïve comparison performed, which generated a HR suggesting that there was no statistically significant difference between the two treatments is uncertain. SMC considered that the evidence base to support the use of the cost-minimisation analysis (ie no differences between treatments) was particularly uncertain and was not a suitable basis for decision-making. • In the cost-effectiveness analysis, PFS for ibrutinib monotherapy was based on a constant HR against ibrutinib plus rituximab. This HR was derived from the point estimates based on a naïve comparison. However, the confidence intervals for the HR estimate were very wide and included 1, which reflects weakness of the underlying data. There is, therefore, uncertainty regarding the predicted PFS in the model. • The analysis assumed equivalence in OS between ibrutinib monotherapy and ibrutinib plus rituximab in the cost- utility and cost-minimisation analyses. A HR of 1.0 was applied in the model because the point estimate derived from the naïve comparison indicated superior OS for ibrutinib monotherapy and was counterintuitive to the PFS HR. This further highlights the weakness in the data underlying the naïve comparison and the uncertainty with respect to estimating relative effectiveness. Varying the OS HR in the scenario analysis predictably had a major impact on the results and in the absence of better comparative data it is difficult to know which HR is the most appropriate. • There is some uncertainty associated with estimating pre-progression mortality in the ibrutinib arm because of limitations in the data available. The rate of death during PFS for ibrutinib plus rituximab was also applied to ibrutinib monotherapy but this may not be appropriate. The Committee also considered the benefits of ibrutinib in the context of the SMC decision modifiers that can be applied when encountering high cost-effectiveness ratios and agreed that as ibrutinib is an orphan medicine, SMC can accept greater uncertainty in the economic case. After considering all the available evidence and the output from the PACE process, and after application of the appropriate SMC modifiers, the Committee accepted ibrutinib for restricted use in NHSScotland.