Zanubrutinib for treating Waldenstrom’s macroglobulinaemia

3.1 Waldenstrom's macroglobulinaemia is an incurable form of non-Hodgkin's lymphoma. It typically affects older people and has a long trajectory, with a median overall survival of 16 years in people with symptoms. Because the condition progresses slowly, many people die from causes other than Waldenstrom's macroglobulinaemia. The clinical experts explained that although there is variation in the clinical pathway, the first-line treatment options are commonly bendamustine plus rituximab (BR) and dexamethasone plus rituximab and cyclophosphamide (DRC) if chemoimmunotherapy is suitable. The clinical experts further explained that patient- and disease-related factors can influence the choice of first-line treatment. They stated that BR tends to produce a more rapid and deeper response, so may be preferred if disease burden needs to be quickly reduced. But BR has a less favourable toxicity profile than DRC, so DRC may be preferred in people who are frail or have comorbidities. Although purine analogues such as fludarabine were included in the NICE scope, their use is no longer recommended because of toxicity concerns and the risk of secondary malignancies. This is reflected in the latest clinical guidelines on managing Waldenstrom's macroglobulinaemia from the British Society for Haematology. An autologous stem cell transplant is also an option for people who are fit enough. But, because Waldenstrom's macroglobulinaemia mainly affects older people, this is not suitable for most. Until recently, when the condition relapsed or became refractory to first-line treatment most people were offered ibrutinib (a Bruton's tyrosine kinase inhibitor), which was available through the Cancer Drugs Fund. But, during the time course of this appraisal, a separate NICE appraisal of ibrutinib for treating Waldenstrom's macroglobulinemia was done. This found that ibrutinib could not be recommended for routine use in the NHS for this indication. Other second-line treatment options include rituximab-containing regimens (such as BR or DRC, if not used as a first-line treatment). After these treatments, practice varies, but repeated rounds of chemotherapy are often used. When chemoimmunotherapy is unsuitable, treatment options include rituximab or chlorambucil monotherapy, or best supportive care. The company noted that rituximab and chlorambucil are not widely used, particularly chlorambucil because it may be more toxic than rituximab. But the committee noted both were used in clinical practice. The clinical experts explained that, if zanubrutinib were recommended, it would be used as early as possible in the treatment pathway. But the committee noted that, when chemoimmunotherapy is suitable, zanubrutinib's licence limited it to use after at least 1 treatment. The committee was aware that there is variation in the treatment pathway for people with Waldenstrom's macroglobulinaemia, particularly when it is relapsed or refractory. It concluded that BR and DRC were the 2 most relevant comparators when chemoimmunotherapy is suitable. It also concluded that rituximab or chlorambucil alone were relevant comparators when chemoimmunotherapy is unsuitable. This is when the marketing authorisation allows zanubrutinib as a first-line treatment option.

3.2 The patient expert explained that Waldenstrom's macroglobulinaemia and its treatment can have a profound effect on quality of life. The condition itself can cause severe pain, fatigue, reduced mobility and increased susceptibility to infections. Current chemoimmunotherapy treatments can cause severe adverse reactions and the need for frequent hospital visits. Even though Waldenstrom's macroglobulinaemia may respond well to first-line treatment, the constant threat of relapse can be a huge burden on people with the condition and their families. For people who cannot have chemoimmunotherapy, treatment options are very limited. The patient expert said that people with the condition are acutely aware of this. Also, there is a desire among the patient community to have additional options as their condition progresses. The committee noted that zanubrutinib is a Bruton's tyrosine kinase inhibitor and has a different mechanism of action to existing chemoimmunotherapy treatments. Both the patient and clinical experts emphasised that zanubrutinib is highly effective and better tolerated than existing chemoimmunotherapy options. It is also an oral treatment, which is greatly valued by people with the condition because it avoids the need for hospital visits and infusions. The patient expert said that zanubrutinib had rapidly and dramatically made him "feel better" and improved his quality of life. He explained that it had allowed him to participate in general day-to-day activities and return to the normal life he had enjoyed before diagnosis. He explained that this was in stark contrast to his experience with chemoimmunotherapy treatments, with which he had had significant intolerance issues and side effects, some of which were persistent. The committee concluded that the availability of an effective and well-tolerated oral treatment would be highly valued by people with Waldenstrom's macroglobulinaemia and would address a significant unmet need.

3.3 The clinical evidence for zanubrutinib came from the ASPEN study, a randomised clinical trial that compared zanubrutinib with ibrutinib. The committee noted that ibrutinib was not a comparator in this appraisal (see section 3.1). The people in the trial were divided into 2 cohorts:

3.4 The committee noted that, at a median follow up of 19.5 months in ASPEN, the very good partial response rate was 28.4% in the zanubrutinib arm and 19.2% in the ibrutinib arm. This response occurred at a median time of 4.8 months in the zanubrutinib arm. The committee also noted that there was not a complete response in anyone. But 1 clinical expert said that this was not unexpected because it is acknowledged that this class of drugs is not curative. The clinical expert also noted that it was important to consider the durability of that response, and not just its depth. Median progression-free and overall survival had not been reached at the point of data cut-off, so the survival data for zanubrutinib was immature. This is to be expected because Waldenstrom's macroglobulinaemia is a slowly progressing condition. At 12 months, 97.0% (95% confidence interval 90.9 to 99.0) of people in the zanubrutinib arm were alive, and the condition had not yet progressed in 89.7% (95% confidence interval 81.7 to 94.3). Although ibrutinib was not a comparator in this appraisal, the committee noted that overall (93.9%) and progression-free survival (87.2%) was similar to that with zanubrutinib at 12 months. The clinical experts explained that zanubrutinib would be expected to have similar clinical efficacy to ibrutinib in clinical practice because they are in the same drug class. The committee concluded that zanubrutinib was clinically effective, but that data on progression-free and overall survival was immature.

3.5 Clinical evidence for the chemoimmunotherapy comparators (BR and DRC) in people who had had previous treatment came from 2 main studies:

3.6 The overall-survival hazard ratios for BR compared with zanubrutinib were lower than the hazard ratios for DRC compared with zanubrutinib. This was regardless of whether the STC or MAIC approach was used. The committee noted that these hazard ratios suggested DRC may be more effective than BR used second line. But it could not determine whether this reflected a real difference in the benefits of these comparators or resulted from a difference in the populations being compared in each indirect comparison. The specific results of the analysis are confidential and cannot be shared here. The clinical experts explained that real-world data comparisons have consistently shown a favourable progression-free survival outcome for BR compared with DRC. But they added that the data for overall survival is less conclusive. This is because people with Waldenstrom's macroglobulinaemia often do not die because of the condition itself. Also, DRC tends to be used in people who are frail or have comorbidities, which may affect their life expectancy. The committee was not aware of any direct comparative evidence to determine whether BR and DRC would be equally effective had they been studied at the same stage in the treatment pathway. So, the committee accepted the company's estimates for its decision making.

3.7 The clinical evidence for the chemoimmunotherapy unsuitable comparators (rituximab monotherapy and chlorambucil monotherapy) came from 2 main studies:

3.8 The company developed a cohort partitioned survival model to project the long-term clinical and economic consequences. This consisted of 3 mutually exclusive health states: preprogression, postprogression, and death. The committee noted the ERG's concerns that this type of model relies on estimating progression-free and overall survival over a long period. This can be uncertain if the trial data for these outcomes is immature, as was the case in ASPEN. But, overall, the committee concluded that it was acceptable for decision making.

3.9 The company used parametric models to extrapolate the data over a 30‑year time horizon to estimate overall survival beyond the data collection periods for zanubrutinib and its comparators in the relapsed or refractory population. This population comprised people who had had at least 1 treatment. The models generated 5- and 10‑year survival estimates, which are confidential and cannot be shared here. The clinical experts explained that long-term overall survival on zanubrutinib and ibrutinib was likely to be similar (see section 3.4). So, the committee compared the modelled 5‑year overall-survival estimates in the zanubrutinib arm with long-term trial data from study 118E for ibrutinib. The 5‑year overall-survival data for ibrutinib was broadly consistent with the 5‑year overall-survival data estimated for zanubrutinib. The committee accepted that the extrapolated survival estimates for zanubrutinib were appropriate for decision making, noting that there were uncertainties in the data that underpinned them.

3.10 In the first committee meeting, the committee concluded that ibrutinib should not be included as a subsequent treatment option because it is not available through routine commissioning. The committee noted that, in its original submission, the company had included the costs of follow-on treatment with ibrutinib. But it had removed these costs in its updated base case after consultation. The company stated that the populations in the BR and DRC trials did not have follow-on ibrutinib. But it added that the extrapolated modelled overall survival beyond the end of the study period may have included some benefit from follow-on ibrutinib. The company explained it had sought clinical opinion on the expected long-term survival outcomes for BR and DRC. This was to select a modelled distribution that gave clinically plausible extrapolated long-term survival outcomes. The company further stated that this opinion was based on current practice at that time, when 72% of people had ibrutinib after BR or DRC through the Cancer Drugs Fund. The company suggested that its modelled estimates of overall survival with BR and DRC may have been overestimated. This was because ibrutinib is no longer available in the NHS, and people on BR or DRC are expected to have poorer outcomes without this effective follow-on treatment. The company stated that its original modelled estimate of the difference in survival at 6 years between zanubrutinib and BR or DRC was smaller than that presented by an ERG during the NICE technology appraisal of ibrutinib for treating Waldenstrom's macroglobulinaemia. This difference was based on clinical expert opinion. The company suggested that the curves for overall survival in the BR and DRC arms should be adjusted downwards, while keeping the zanubrutinib curves the same. This was so that the probability of survival was 50% lower than the survival in the zanubrutinib arm at 6 years. The company also included this adjustment in its base case for the population for whom chemoimmunotherapy is unsuitable. This used the BR or DRC curves for overall survival as surrogate estimates for rituximab monotherapy. The clinical experts considered that some adjustment may be warranted. They noted that zanubrutinib delivers benefit both as an improvement on chemoimmunotherapy and as an additional treatment line for people with relapsed or refractory disease. They also noted that people in the BR and DRC trials may have had other effective treatments that are not available in the NHS, such as bortezomib. The clinical experts stated that it was challenging to confirm the level of adjustment needed. This was because of the difficulty in considering hypothetical situations that do not reflect current or previous clinical practice in the NHS. The ERG noted that the company had already used the parametric distribution giving the second most pessimistic modelled overall survival in the BR arm. So, even if the most pessimistic modelled distribution had been selected to reflect the absence of ibrutinib as a subsequent treatment, the effect on the cost-effectiveness results was minor. The ERG further considered that the extent of adjustment was based on clinical opinion rather than data. It preferred not to include adjustment of overall survival in the comparator overall-survival arms. The committee noted that the level of adjustment had a large effect on the incremental cost-effectiveness ratios (ICERs). It added that any adjustment would mean, in effect, that the overall-survival hazard ratio from the company's MAIC was not directly used in the analysis. It concluded that the modelled overall survival of BR and DRC was highly uncertain. It agreed that some adjustment to postprogression survival in the BR- or DRC-modelled arms might have been justified to account for the potential effect of follow-on treatments not available in the NHS. But it concluded that the ERG's base case was more reflective of the relative difference in overall survival of zanubrutinib compared with BR and DRC. This was because it was based on estimates from the MAIC, while the company's downward adjustment of the effectiveness of BR and DRC was based on clinical opinion. The committee concluded that this meant the company's approach was highly uncertain.

3.11 For the population for which chemoimmunotherapy is unsuitable, the company modelled the cost effectiveness of zanubrutinib compared with rituximab. To represent progression-free survival and overall survival in the rituximab population, it used the modelled progression-free survival and overall survival for BR or DRC from its model for the relapsed or refractory population. The hazard ratios derived from the company's MAIC analysis comparing zanubrutinib with rituximab were then applied to the BR and DRC curves to generate curves for progression-free and overall survival for zanubrutinib. To reflect the cost of rituximab monotherapy, the company removed the treatment acquisition and administration costs of bendamustine from the BR-modelled costs, and of dexamethasone and cyclophosphamide from the DRC-modelled costs. This left only the costs of rituximab monotherapy in the analysis. The company explained that it used BR- and DRC-modelled estimates as a surrogate for rituximab. This was because of a lack of data for rituximab monotherapy to include in its economic model. The clinical experts stated that rituximab is less clinically effective than BR or DRC. The company agreed, stating that it considered its modelling approach to be conservative. The committee recalled that the data for BR had been from people whose condition was relapsed or refractory and for DRC had been from people who had not had previous chemoimmunotherapy (see section 3.7). This meant that the analysis in which DRC data was used as a baseline control arm was potentially more applicable to how rituximab monotherapy would be used in clinical practice (that is in people who had not had previous chemoimmunotherapy). The committee concluded that it preferred using DRC rather than BR as a surrogate for rituximab. It also noted that the company had already reduced the estimated survival for DRC in its model (on the basis of no follow-on ibrutinib being available, see section 3.10). It did not consider any further reduction was justified on the basis that the modelling approach was considered conservative. The committee also concluded that, although highly uncertain, the company's approach was broadly appropriate for decision making for the population for which chemoimmunotherapy is unsuitable.

3.12 The utility value for preprogression was obtained from EQ‑5D data collected during the ASPEN study. The committee noted that the value was higher than that for the general UK population, which it thought was unrealistic. But it noted that this is commonly seen when comparing trial populations with the general population. There was not enough data in ASPEN to estimate the postprogression utility value for progressed Waldenstrom's macroglobulinaemia. So, the company and ERG agreed a reduction of 0.18 on the preprogression value. This was based on previous NICE technology appraisal guidance on ibrutinib for treating relapsed or refractory mantle cell lymphoma and on ibrutinib for treating Waldenstrom's macroglobulinaemia. The committee acknowledged that this value was uncertain but was suitable for decision making. It also noted that adjusting this value did not have a big effect on the cost-effectiveness results.

3.13 The company's base case assumed lifelong treatment effectiveness. But the ERG thought that this was not realistic and implemented a 5‑year treatment effect cut-off. This was based on NICE's technology appraisal guidance on lenalidomide with rituximab for previously treated follicular lymphoma. Once people had been on zanubrutinib for 5 years, the hazard ratio for progression-free and overall survival was assumed to become equal to that in the comparator arms. The people in the model continued to take zanubrutinib until their condition progressed rather than a stopping rule being applied. The NHS England Cancer Drugs Fund clinical lead stated that the risk of people's condition progressing while they were on treatment was already accounted for in the model. So, it was overly pessimistic to apply a sudden treatment effect cut-off. The clinical experts agreed with this view. They explained they have experience in other indications in which people have been taking the same type of drug, ibrutinib, for many years and are still deriving benefit. The committee concluded that there was insufficient evidence to justify this treatment effect cut-off. It noted that 'treatment waning effects' (meaning a reduced treatment effect over time) are typically applied after treatment has stopped, not while people are still on treatment. The committee concluded that a treatment effect cut-off was implausible and should not have been applied in the absence of any evidence to support this assumption.

3.14 The company provided cost-effectiveness results for the comparison of zanubrutinib with BR and with DRC separately, and for a blended comparator. The blended comparator was produced using a weighted average of the results of the BR and DRC comparisons. The weighted average was calculated using the estimated proportions of who would have each treatment in clinical practice. The company used data from the Rory Morrison Registry to estimate that, in the absence of ibrutinib, 49% of people would have BR and 51% would have DRC. The clinical experts agreed that it was reasonable to estimate that about 50% of people would have each treatment. This was because, typically, people would initially have treatment with either BR or DRC, and their second-line treatment would be whichever they had not had first line (BR followed by DRC, or DRC followed by BR). The company also presented scenarios to account for variation in clinical practice across the UK, with use of BR and DRC varying between 40% and 60%. The committee recalled that the data for BR had been from people whose condition was relapsed or refractory and who had had previous treatment. It also recalled that the data for DRC had been from people who had not had previous chemoimmunotherapy. This meant that the comparison with BR was more applicable to how zanubrutinib would be used within its marketing authorisation (that is after 1 or more treatments). It also meant that it was more robust than the comparison with DRC. The committee noted that there was methodological difficulty with the blended comparator. This was because it relied on an assumption of the proportions of people who would have BR or DRC in clinical practice. It also included the comparison with DRC, which was the more uncertain. The committee concluded that it would take into account the cost-effectiveness results for both the blended and the pairwise comparisons. But it also took into account the greater uncertainty around the estimates compared with DRC, and from the blended comparator.

3.15 The committee noted that the company had agreed a patient access scheme for zanubrutinib. There are confidential prices for BR and DRC, so the exact ICERs cannot be reported here. The committee's preferred modelling assumptions after the first meeting were:

3.16 NICE's guide to the methods of technology appraisal notes that, above a most plausible 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 considered that an acceptable ICER for zanubrutinib would need to be comfortably below £30,000 per QALY gained to be considered a cost-effective use of NHS resources. This decision took into account:

3.17 The committee accepted that zanubrutinib has several benefits over chemoimmunotherapy including oral administration, manageable adverse reactions, low toxicity and fewer hospital visits. The committee concluded that zanubrutinib could be considered a step-change in managing Waldenstrom's macroglobulinaemia compared with the treatment options available in UK clinical practice.

3.18 The committee concluded that it was not possible to recommend zanubrutinib for all people who had had previous treatment. This was because the ICER for zanubrutinib compared with the blended comparator was not below £30,000 per QALY gained. Also, the pairwise ICERs of zanubrutinib compared with DRC were consistently above £30,000 per QALY gained. The committee also concluded that it was only possible to recommend zanubrutinib in people who had had previous treatment and when BR is also suitable. This was because the ICER for this group was below £30,000 per QALY gained, so was an acceptable use of NHS resources. The committee also concluded that it was not possible to recommend zanubrutinib for the population for which chemoimmunotherapy is unsuitable. This was because the ICER for zanubrutinib compared with rituximab was not below £30,000 per QALY gained.

3.19 The committee recognised that its recommendation could affect the treatment pathway for Waldenstrom's macroglobulinaemia. This was because whether BR would be considered a second-line or later treatment would be related to the treatments people had already had. The committee considered opinions from the clinical and patient experts that: