Bortezomib for previously untreated mantle cell lymphoma

Clinical effectiveness

4.2 The Committee considered the LYM‑3002 trial, which compared bortezomib in combination with rituximab, cyclophosphamide, doxorubicin and prednisone (VR‑CAP), with rituximab in combination with cyclophosphamide, doxorubicin, prednisone and vincristine (R‑CHOP). The Committee noted that the age and other baseline characteristics of participants in the trial were broadly generalisable to people in England with this disease. It was aware that no patients from the UK were included in the trial, although 28% were recruited from the European Union. The Committee acknowledged that although standard of care might differ between England, the rest of the European Union, and the rest of the world; there was no reason to suggest that the course of the disease, or response to treatment would be different. The Committee therefore agreed that the results from the whole intention‑to‑treat (ITT) population were suitable for evaluating clinical effectiveness. The Committee considered that a strength of the LYM‑3002 trial was the direct comparison with R‑CHOP, which is current standard of care in England. However, it noted that the trial did not include maintenance therapy with rituximab, which is now part of routine practice. The Committee acknowledged that although this made the generalisability of the results more uncertain, rituximab maintenance was not included in either treatment group. The Committee heard from the clinical expert that it was assumed that rituximab maintenance therapy following VR‑CAP should provide the same benefit as is seen when rituximab maintenance is given subsequently to R‑CHOP. It accepted that there was no positive evidence that rituximab maintenance would affect the relative effectiveness of VR‑CAP compared with R‑CHOP as demonstrated in the trial. The Committee also noted that the trial included a number of people (16.4%) for whom haematopoietic stem cell transplant was suitable, which is outside the marketing authorisation, but as these were balanced between the 2 treatment groups, it agreed with the Evidence Review Group (ERG) that that this would not have affected the results. The Committee concluded that the population included in the LYM‑3002 trial was generalisable to practice in England.

4.3 The Committee considered the results of the LYM‑3002 trial. It noted that the primary trial outcome of progression‑free survival was statistically significantly better for VR‑CAP compared with R‑CHOP (hazard ratio [HR] 0.63, 95% confidence interval [CI] 0.50 to 0.79), based on independent review. It heard from the clinical expert that mantle cell lymphoma is an aggressive disease which becomes symptomatic when it recurs, and in this country clinicians may not routinely follow up patients with scans, as was done in the trial, but only scan when they develop symptoms in order to confirm progression before starting treatment. The Committee acknowledged that measuring disease progression on scans, as done in the trial, is a more objective indicator of disease progression than time to starting next treatment.

4.4 The Committee considered the secondary outcomes in the trial. It noted that overall survival data from the LYM‑3002 trial were immature, as the median was not reached in the VR‑CAP group. It heard from the clinical expert that there is 6‑year follow‑up data from a trial in people with lymphoma (not specifically mantle cell lymphoma), showing that longer progression‑free survival results in longer overall survival. The Committee agreed that it was not unreasonable to assume that an overall survival benefit would result from an improvement in progression‑free survival. The Committee concluded that VR‑CAP provides improved progression‑free survival compared with R‑CHOP, and is likely to improve overall survival.

4.5 The Committee considered the other secondary outcomes in the LYM‑3002 trial. It noted that 3 of these showed statistically significant benefits for VR‑CAP compared with R‑CHOP (time to next treatment, treatment‑free interval and duration of response; see section 3.5). The Committee heard from the patient expert that treatment‑free interval is of particular importance to people with mantle cell lymphoma because they would not have to tolerate the side effects of chemotherapy during that time. It noted that the difference in treatment‑free interval between VR‑CAP and R‑CHOP was almost 20 months (40.6 months compared with 20.5 months respectively, HR 0.50, p value <0.001). The Committee concluded that bortezomib, within its marketing authorisation, is a clinically effective treatment for untreated mantle cell lymphoma in people for whom haematopoietic stem cell transplant is unsuitable.

4.6 The Committee considered the adverse events reported in the LYM‑3002 trial. It noted that for the safety analysis data set, both VR‑CAP and R‑CHOP appeared to be generally well tolerated with low rates of discontinuation because of adverse events, and low fatality rates in both groups. The Committee was aware that some side effects occurred more frequently with VR‑CAP than R‑CHOP, (for example, diarrhoea, 30.4% compared with 9.1%; fever 29.2% compared with 15.3%; and thrombocytopenia 72.1% compared with 19.0% respectively). However, it acknowledged the comments from the clinical and patient experts that people with mantle cell lymphoma are sometimes willing to tolerate more side effects if a treatment is more effective. The Committee noted that the trial was conducted using intravenously administered VR‑CAP, but heard from the company and the clinical expert that it is likely to be given subcutaneously in clinical practice. It heard from the clinical expert that subcutaneous administration of bortezomib should result in a lower incidence of peripheral neuropathy and other adverse events because peaks in the concentration of bortezomib in the blood would be avoided. The Committee concluded that although bortezomib was associated with an increased adverse event profile, it is a generally well‑tolerated treatment.

4.7 The Committee discussed the company's indirect comparison, which aimed to compare bortezomib (VR‑CAP) with the comparators listed in the scope (R‑CHOP, rituximab with fludarabine and cyclophosphamide, and rituximab with bendamustine). It noted the concerns of both the company and the ERG about the heterogeneity of the trials included in the indirect comparison network. The Committee noted that the company did not use the network to inform its economic model. The Committee agreed that the indirect comparison was unlikely to be robust and concluded that because R‑CHOP was indeed the most relevant comparator to be considered, the direct evidence from LYM‑3002 trial was sufficient to enable the Committee to make a decision on the effectiveness of VR‑CAP in people with mantle cell lymphoma.

Cost effectiveness

4.8 The Committee considered the company's economic model. It noted that the model used a 20‑year time horizon, and agreed with the company and the ERG that this was reasonable given that the average age of people in the trial was 69 years and that median survival was less than 5 years. The model included 5 states, including 2 lines of therapy and a treatment free interval; the Committee noted that the company's economic model was primarily focused on the comparison between VR‑CAP and R‑CHOP because it was considered that R‑CHOP is the most appropriate comparator. The Committee concluded that the company's model followed a logical approach, and agreed that the principal comparator is R‑CHOP.

4.9 The Committee considered the company's approach to estimating progression‑free survival in the economic model. It noted that the company used the same parametric curves (log‑logistic) for both treatment groups, in line with guidance from Decision Support Unit. The Committee also noted the opinion expressed by the ERG that an exponential distribution was a better fit for the VR‑CAP group; and that the ERG had explored this approach in its exploratory analyses (see sections 3.42–3.46 and section 4.14). The ERG's preferred method, using different parametric curves for the 2 treatments, had a substantial effect on the cost‑effectiveness estimate, increasing the company's base‑case incremental cost‑effectiveness ratio (ICER) of £20,300 to £33,100 per quality‑adjusted life year (QALY) gained. The Committee discussed the guidance published by the Decision Support Unit, and concluded that the same distribution should be used for both treatment groups unless there is a clinically plausible reason to do otherwise. The Committee concluded that the company's approach, using log-logistic distributions for both treatment groups was appropriate in this case.

4.10 The Committee considered the clinical effectiveness estimates used in the company's model. It noted that for the comparison of VR‑CAP with R‑CHOP, the company had used direct evidence from the ITT population in the LYM‑3002 trial. The Committee was aware of the ERG's concerns that no patients from the UK were included in the LYM‑3002 trial, and that the results might not be generalisable to clinical practice in the UK. The ERG's preference was to use data from the European Union subgroup rather than the whole trial population. However, the Committee also noted the ERG's concerns that all outcomes for this subgroup were likely to be underpowered. In the absence of a test for interaction showing a different effect of VR‑CAP in different regions, the Committee concluded that it was appropriate to use data from the ITT population of the LYM‑3002 trial in the economic model.

4.11 The Committee considered the way in which overall survival had been extrapolated in the company's model. It was aware that because overall survival data were immature, a number of different approaches could potentially be used to estimate survival beyond the end of the trial (see sections 3.22–3.24). The Committee noted that the survival estimates for everyone in the model appeared implausibly long, but that the company had tried to remedy this by applying an adjustment for all cause-mortality. The Company also estimated overall survival differently depending on whether or not people's disease had progressed. The Committee noted the ERG's comment that because the data is immature it may not be possible to identify any differences in overall survival between the treatment groups, and the suggestion that a more conservative approach would be to assume no effect on overall survival, only on progression‑free survival. The Committee appreciated the difficulty of predicting survival in absolute terms, but was aware that it was the difference in overall survival between VR‑CAP and R‑CHOP, which was the most relevant to its assessment of cost effectiveness. It concluded that the overall survival benefit as predicted in the company's model was not unreasonable, given the progression free survival benefit demonstrated in the trial.

4.12 The Committee considered the utility values used in the model. It was aware that the ERG did not agree with the company's value of 0.45 for 'progressed disease from second‑line treatment'. This was because it was based on a study in aggressive non‑Hodgkin's lymphoma, and was conducted in a small patient population. The Committee noted that both the company and the ERG had explored the effect of using alternative values (0.693 and 0.624 respectively). It heard from the clinical expert that after second‑line treatment, further treatment tends not to work very well, and may result in more toxicity than benefit, with a negative effect on quality of life. The expert highlighted that after 2 lines of therapy, people would be unlikely to regain the same or similar utility as those having first‑line treatment. The Committee concluded that the company's choice of a lower utility of 0.45 for its base case was reasonable.

4.13 The Committee considered the costs used in the company's economic model. It was aware that the clinical trials were all conducted using intravenously administered bortezomib, and it noted that this was also assumed in the company's economic model. The Committee was aware that bortezomib is available as a subcutaneous formulation and is likely to be the preferred method of administration in clinical practice. The Committee heard from the clinical expert that the subcutaneous formulation could reduce the risk of peripheral neuropathy and also the need for thromboprophylaxis, as well as being associated with lower costs of administration. The Committee concluded that subcutaneous administration would be used in clinical practice, and the costs would, therefore, likely be lower than those used in the company's model.

4.14 The Committee considered the company's base‑case cost‑effectiveness results, and the ERG's exploratory analyses. It noted that the company's base‑case deterministic and probabilistic ICERs for VR‑CAP compared with R‑CHOP were £20,400 and £20,300 per QALY gained. The Committee considered the ERG's exploratory analyses, which amended 16 assumptions compared with the company's model (see section 3.42). It noted that the ERG's combined analyses resulted in an ICER of £34,000 per QALY gained. The Committee agreed with the majority of the ERG's amendments but noted 5 amendments in particular, which it questioned:

4.15 The Committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS Payment Mechanism, when appraising bortezomib. 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 on the relevance of the PPRS to this appraisal of bortezomib. It therefore concluded that the PPRS Payment Mechanism was irrelevant for the consideration of the cost effectiveness of bortezomib.

Summary of Appraisal Committee's key conclusions