Ibrutinib for treating Waldenstrom's macroglobulinaemia

There is high clinical need for alternative treatments to rituximab and chemotherapy

3.1 Waldenstrom's macroglobulinaemia is an incurable, rare type of non-Hodgkin's lymphoma with limited treatment options. There is no established standard care. Apart from ibrutinib, there are no treatments specifically licensed for treating Waldenstrom's macroglobulinaemia. Commonly used treatment options include chemoimmunotherapy, such as rituximab combined with a range of chemotherapy regimens including alkylating agents (such as cyclophosphamide) or nucleoside analogues (cladribine or fludarabine). When chemoimmunotherapy is unsuitable, treatment options include monotherapy with rituximab or chlorambucil. The marketing authorisation for ibrutinib includes people for whom chemoimmunotherapy is unsuitable but this population was not included in the managed access arrangement for use of ibrutinib in the Cancer Drugs Fund. The clinical experts explained that generally, the disease responds well to chemotherapy but there are a restricted number of lines of chemotherapy that can be used because of cumulative toxicity. Chemotherapy options can rapidly become exhausted, leaving no effective therapies available to patients. Some people may also have intolerance to rituximab. The patient expert highlighted that the constant risk of relapse has a significant effect on the mental wellbeing of patients and families. The committee noted that Waldenstrom's macroglobulinaemia is associated with major disease-related symptoms such as neutropenia which can cause infections, weakness, extreme fatigue and breathlessness. The patient expert explained that symptoms like fatigue can be intense, disabling and significantly impair day-to-day life. The committee concluded that there is no standard care for treating Waldenstrom's macroglobulinaemia and there is high unmet clinical need for new and effective therapies.

Ibrutinib is a step-change in the management of Waldenstrom's macroglobulinaemia

3.2 The clinical experts explained that ibrutinib is a novel and effective non-chemoimmunotherapy treatment option for disease that is refractory to first-line treatment or that has relapsed after successful first-line therapy. Both the patient and clinical experts emphasised that ibrutinib is highly effective compared with existing treatments, and very well tolerated. The convenience of an oral therapy is also greatly valued by patients because it allows them to take the treatment at home, with no need for hospital visits for infusions. The patient expert explained that he had been having ibrutinib for several years. He found it to be a life-transforming drug that had dramatically improved his quality of life, allowing him to take part in general day-to-day activities and very quickly return to normal life. The clinical experts noted that although the condition often responds to chemoimmunotherapy, the speed and durability of response is better with ibrutinib, meaning that people having ibrutinib "feel better" a lot more quickly than with chemoimmunotherapy. The clinical experts attributed the highly effective, immediate, and durable disease control with ibrutinib to be a step-change in the management of Waldenstrom's macroglobulinaemia. The committee agreed and concluded that the availability of an effective and well-tolerated oral treatment option as an alternative to chemoimmunotherapy is highly valued by both patients and clinicians and ibrutinib is a step-change in the management of Waldenstrom's macroglobulinaemia.

SACT data is generalisable to NHS clinical practice and more relevant than updated trial data from study 1118E and iNNOVATE arm C

3.3 In the original appraisal, clinical-effectiveness evidence for ibrutinib came from 2 sources:

The committee noted that the original appraisal concluded that further data collection on progression and overall survival was needed in the Cancer Drugs Fund because of uncertainties about long-term survival. The updated data submitted by the company included:

The committee understood that the SACT database did not collect data on disease progression. It also noted that the cost-effectiveness estimates are dependent on the progression-free survival of people having ibrutinib compared with standard care. The committee noted that the proportion of patients alive at 24 months in study 1118E and the SACT was 95% and 73% respectively. People who had ibrutinib through the Cancer Drugs Fund (and who were included in the SACT data set) were on average older than people in the trials. So, it acknowledged that real world evidence could be associated with lower overall survival rates than trial evidence because of potential differences in patient baseline characteristics. The committee also noted that people having ibrutinib in the SACT dataset may have had multiple previous treatments before ibrutinib, and that it was expected to be used primarily as a second- or third-line treatment in the future. The Cancer Drugs Fund clinical lead explained that real world evidence from 823 patients for a rare disease like Waldenstrom's macroglobulinaemia offers best available data and noted that 84% of people in the SACT cohort had only 1 or 2 lines of prior therapies in keeping with expected use. The clinical experts also agreed that the SACT cohort was reflective of current and future use of ibrutinib in the NHS. The committee concluded that SACT data is generalisable to NHS clinical practice and is more relevant than updated trial data from study 1118E and iNNOVATE arm C.

The agreed approach for estimating ibrutinib progression-free survival indirectly from SACT data is reasonable but uncertain

3.4 Because progression-free survival data was not collected in SACT, the company indirectly estimated progression-free survival for ibrutinib using time to treatment discontinuation data from SACT. In the original appraisal for ibrutinib, time to treatment discontinuation had been assumed to be equal to progression-free survival. For the current appraisal, the company did not consider time to treatment discontinuation a good proxy for progression-free survival because 67% of people stopped treatment before disease progression in SACT. At technical engagement, the company accepted the ERG preferred approach of estimating progression-free survival for the ibrutinib group by assuming a proportional relationship between time to treatment discontinuation and progression-free survival in the Rory Morrison registry, based on a comparison of exponential survival models fitted to this data. The hazard ratio between time to treatment discontinuation and progression-free survival was then applied to the time to treatment discontinuation SACT data. The ERG noted that this approach assumes that the hazards for time to treatment discontinuation compared with progression-free survival in the Rory Morrison registry are proportional and that the same relationship is found in other populations such as people in the whole SACT cohort. The clinical experts stated that people generally stay on treatment until disease progression and may even stay on treatment after disease progression because ibrutinib may slow subsequent disease progression. However, some people will stop treatment before progression and progression happens soon after treatment discontinuation. The committee noted that time to treatment discontinuation in SACT was lower than in the Rory Morrison registry. A clinical expert considered this may have been because of variation in clinical practice. They explained that some people would stay on treatment with ibrutinib because of clinical benefit despite clinical assessment of disease progression. The committee concluded that in the absence of progression-free survival data from SACT, the agreed approach to indirectly estimate it was reasonable but subject to uncertainty.

Based on an indirect comparison the extent to which ibrutinib improves progression-free survival compared with standard therapies is uncertain

3.5 The company did not update its estimate of the hazard ratio for progression-free survival on ibrutinib compared with standard therapies from the original appraisal of ibrutinib. But it updated its estimate of progression-free survival on ibrutinib to be applicable to the SACT cohort. In the original appraisal for ibrutinib, the company presented an indirect comparison of progression-free survival with ibrutinib compared with existing treatments for Waldenstrom's macroglobulinaemia. This was referred to as 'physician's choice of standard therapies' (a blend of alternative second-line or more rituximab plus chemotherapy options) and will be referred to as standard therapies going forward in this document. The data for standard therapies came from a European Chart Review; a retrospective observational study that generated data on epidemiology, treatment and efficacy outcomes for untreated and relapsed Waldenstrom's macroglobulinaemia over 10 years. The committee recalled that in the original appraisal, the company created a matched cohort to the study 1118E population by selecting a subset of the European Chart Review cohort who had had similar lines of therapy to the patients in study 1118E. The indirect comparison estimated a hazard ratio for progression-free survival for ibrutinib compared with standard therapies of 0.25 (95% CI: 0.11 to 0.57, p=0.001). This suggested a substantial reduction in the risk of disease progression with ibrutinib compared with standard therapies. The committee noted that the indirect comparison was of trial data for ibrutinib compared with data from a non-trial setting (real world evidence) for standard therapies which made the hazard ratio highly uncertain. The ERG explained it had concerns about methods used to select patients in the matched cohort. In the submission for the current appraisal, the company stated that it considered its original estimate, based on 24 months data from study 1118E to be relevant and best available estimate of the hazard ratio for progression-free survival with ibrutinib compared with standard therapies. On the ERG's request, the company updated the indirect treatment comparison with additional study 1118E long-term data using an unanchored matching-adjusted indirect comparison (MAIC) with the full dataset from the European Chart Review after technical engagement. The hazard ratio from this analysis is 0.28 (95% CI:0.10 to 0.49). The ERG explained that the MAIC is useful in providing supporting evidence of the relative treatment effect on progression-free survival for ibrutinib compared with standard therapies but is an unanchored comparison meaning that data from single-arm studies, rather than studies with a common comparator, had been included. This approach assumes that prognostic variables and effect modifiers have been accounted for. Given limited data on prognostic variables available with most trial data needing to be imputed, the results from the MAIC based on this assumption are highly uncertain. The committee discussed the size of the estimated treatment effect of ibrutinib compared with standard care which showed a large benefit of ibrutinib in delaying disease progression. The clinical experts and Cancer Drugs Fund clinical lead stated that a large benefit was plausible, and the committee noted the statements from the clinical and patient experts that ibrutinib was a step-change in managing Waldenstrom's macroglobulinaemia (see section 3.2). The committee recalled its conclusion in the original appraisal that the hazard ratio was highly uncertain. The committee accepted, based on the results of the indirect comparison and the testimonies from patients and clinical experts, that ibrutinib appears to be more clinically effective than existing treatments but concluded that there remains significant uncertainty around the extent to which ibrutinib improves progression-free survival.

The company's updated model is suitable for decision making

3.6 The company used the same modelling approach as in its original appraisal for ibrutinib, that is a Markov state transition model comparing ibrutinib with standard therapies. The health states included progression-free survival and being on up to 4 follow-on treatments after progression. It also modelled the chance of dying in each health state. The modelled cohort was updated to reflect the population for whom data was collected in SACT rather than study 1118E, that is a population with an average age of 70. Updated data and assumptions used in the model included:

To model progression-free survival on standard therapies, the updated model applied the hazard ratio from the original appraisal for progression-free survival with ibrutinib compared with standard therapies. However, because the modelled progression-free survival was updated for ibrutinib in the current appraisal, this resulted in a different modelled progression-free survival for standard therapies than the original appraisal. The modelled time on treatment for standard therapies was assumed to be the same as progression-free survival. This meant that the modelled time on treatment for standard therapies was also different to that in the original appraisal. The committee noted that the company had aligned its modelling with the ERG's preferred assumptions for estimating progression-free survival for the SACT dataset (see section 3.4) and the ERG's approach for modelling pre-progression mortality with ibrutinib and calibrating modelled overall survival for ibrutinib to reflect the observed data from the SACT dataset. The committee considered the company's approach to use the SACT data is reasonable but noted that the evidence available to estimate progression-free survival for ibrutinib and any outcome in the standard therapies group, which is dependent on the progression-free survival hazard ratio for ibrutinib compared with standard therapies is subject to considerable uncertainty. The committee concluded that the company's updated model is suitable for decision making, but the modelling uncertainties should be taken into account.

The model predicted survival outcomes from the company's revised base-case model are clinically implausible and highly uncertain

3.7 The committee discussed the modelled clinical outcomes from the company's revised base case. There were 3 modelled outcomes which did not reflect outcomes seen in clinical practice:

The committee considered that although a 3 year overall survival gain for ibrutinib compared with standard therapies as predicted by the model for the original appraisal and the revised model Cancer Drugs Fund may be plausible, the modelled overall survival in the standard therapies arm was implausible. Furthermore, the modelled time between stopping ibrutinib and disease progression, and time between disease progression on a person's first treatment for relapsed or refractory Waldenstrom's macroglobulinaemia did not reflect what is seen in clinical practice. The committee agreed that these 3 modelled outcomes were dependent on the hazard ratio for progression-free survival for ibrutinib compared with standard therapies (see section 3.5) and updated estimates of progression-free survival for ibrutinib (see section 3.4). However, it agreed that although these were the most reasonable given the available data, these were uncertain because of the limitation of not having progression-free survival data from SACT and data directly comparing progression-free survival for ibrutinib compared with standard therapies. The committee concluded that although the model gave implausible outputs, given the limitations in the available data, there was no alternative analysis that could be done to address these concerns. Therefore, it should take into account the uncertainty when considering the estimates of cost effectiveness.

The cost-effectiveness estimates are outside the range considered a cost-effective use of NHS resources

3.8 The committee noted that there is a confidential patient access scheme (PAS) for ibrutinib and that some of the standard care therapies included in the standard therapies arm are available to the NHS at a confidential discount. Results from these analyses are confidential and cannot be reported here. Considering the PAS price for ibrutinib and publicly available prices for standard therapies, incremental life years gained with ibrutinib were 2.88 in the revised company base case using a hazard ratio for progression-free survival of 0.25. When higher hazard ratios (ranging from 0.28 to 0.75) were explored, life years gained with ibrutinib decreased (ranging from 2.80 to 1.78 respectively). The exact incremental costs, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs) associated with these analyses are confidential cannot be reported here. However, cost-effectiveness estimates from all analyses were outside the range considered a cost-effective use of NHS resources (£20,000 to £30,000 per QALY gained)

Because of the uncertainty, an acceptable ICER is at the lower end of the acceptable range at around £20,000 per QALY gained

3.9 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 noted the high level of uncertainty, specifically:

Therefore, it agreed that an acceptable ICER would be around £20,000 per QALY gained.

Ibrutinib cannot be recommended in the Cancer Drugs Fund

3.10 The aim of a Cancer Drugs Fund guidance review is to decide if the drug can be recommended for routine use. Ibrutinib for treating Waldenstrom's macroglobulinaemia may not remain in the Cancer Drugs Fund once the guidance review has been completed (see section 6.19 of the NICE guide to the processes of technology appraisal).

Additional health-related benefits not captured in QALY were not identified

3.11 The committee recalled its discussions of the innovative aspects of ibrutinib in the original appraisal. It accepted that the treatment has several benefits for people including oral administration, manageable adverse reactions and low toxicity. The committee concluded that ibrutinib could be considered a step-change in managing Waldenstrom's macroglobulinaemia. However, it considered it highly likely that that the clinical benefits had already been overestimated in the modelling, and did not consider that any additional health-related benefits, that had not been captured fully in the QALY calculation, would be enough to lower the ICER to within the range normally considered cost effective.