Ibrutinib for previously treated chronic lymphocytic leukaemia and untreated chronic lymphocytic leukaemia with 17p deletion or TP53 mutation

Symptoms and management of chronic lymphocytic leukaemia

4.1 The committee considered the impact of CLL on patients and their families and carers. The committee heard from patient experts that the uncertainty associated with living with CLL greatly affected their quality of life. The committee understood that people with CLL risk infection, and that recurrent infections are common. The patient experts described how people become isolated from family and friends to protect themselves from infection, which stops people from living a normal life, reduces their contribution to society and can shorten life expectancy. The committee heard from clinical and patient experts that current treatment options are associated with significant adverse effects that are often life threatening, which means that not all people can have these treatments. The clinical experts also stated that, once treatment is stopped because of disease progression, if no other treatment is available, survival is poor and so additional treatment options are very valuable. A patient expert described the fatigue and illness she had experienced with chemotherapy, and said that repeat chemotherapy had resulted in only a short period of remission. The committee understood the importance of having different treatment options available for treating CLL.

Generalisability of clinical trial results

4.2 The committee discussed the generalisability of the clinical trial results to the 2 populations in the appraisal:

4.3 The committee considered the population who have had at least 1 therapy. It was aware that the key trial (RESONATE, n=391, open label) only included patients who were not eligible for treatment with a purine analogue-based therapy, but that the marketing authorisation does not include this restriction. The committee heard from clinical experts that they would wish to offer ibrutinib to patients who had had at least 1 round of fludarabine-containing chemo-immunotherapy or who otherwise reflected the population in RESONATE. The committee concluded that RESONATE was generalisable to patients who had previously had treatment in clinical practice.

4.4 The committee considered the untreated population with a 17p deletion or TP53 mutation. It noted that RESONATE had not included patients who had not had previous treatment. The company stated that the treatment effect in patients with a 17p deletion in the RESONATE trial who had previously had treatment (33% of patients) could be generalised to patients who had not had treatment. The committee agreed that, without any evidence, it was unclear how generalisable this was. It noted comments from clinical experts that treating CLL in patients with a 17p deletion with fludarabine plus cyclophosphamide and rituximab may worsen their disease and prognosis. The committee also noted that the single-arm Farooqui et al. (2014) study of ibrutinib presented by the company included a few patients with untreated CLL with a 17p deletion, but that the company did not use this to estimate clinical efficacy. The committee agreed that, in the absence of any evidence, the data from the previously treated population could be taken into account, but recognised this was associated with uncertainty.

4.5 The committee noted that there were no data available specifically for people with a TP53 mutation. It discussed whether the results from the previously treated 17p deletion population from RESONATE could be generalised to people with a TP53 mutation. The clinical experts stated that, while 17p deletion was routinely tested for in the NHS, TP53 mutation was not, but that both were on the same gene locus and tended to occur together in the same people. The committee heard that the clinical experts expected the untreated natural history would be similar in both populations, as would the response from ibrutinib. The committee concluded that it was reasonable to extrapolate data from people with a 17p deletion to people with a TP53 mutation.

Cancer Drugs Fund proposal to address the uncertainty in the untreated 17p deletion or TP53 mutation population

4.6 To improve evidence related to people with the 17p deletion or TP53 mutation, the committee had invited the company to submit a proposal for its use in the Cancer Drugs Fund (CDF). The committee understood that the company chose not to apply to the CDF. The company stated that there were already observational data available for this group, and collecting further data through the CDF would not address the uncertainty in this population. In support of this, the company submitted data that showed both median progression-free survival and overall survival were not met at 30‑month follow-up, from a study of 243 patients with 17p deletion (both those who had not had previous treatment and those whose disease had relapsed or was refractory). The committee agreed with the company that data collection through the CDF would not resolve this uncertainty.

Comparators for the previously treated population

4.7 The committee discussed the relevant comparators, in the context of current clinical practice in the UK. It noted that NICE's technology appraisal on idelalisib for treating chronic lymphocytic leukaemia recommends idelalisib plus rituximab for CLL in adults with treated disease that has relapsed within 24 months. The clinical experts stated that both ibrutinib and idelalisib have been available on the CDF and, wherever possible, treatment with ibrutinib is preferred because of its effectiveness and because of the adverse effects associated with idelalisib. However, the experts agreed that, in the absence of ibrutinib, clinicians would offer idelalisib plus rituximab. The committee agreed that idelalisib plus rituximab is a comparator.

4.8 The committee discussed the other comparators included in the scope and the company submission:

Comparators for the untreated 17p deletion or TP53 mutation population

4.9 The committee heard that alemtuzumab was previously offered to people with a 17p deletion or TP53 mutation, but is difficult to obtain because the company for alemtuzumab has limited the marketing authorisation to multiple sclerosis. The committee concluded that this was not an appropriate comparator.

4.10 The committee noted that NICE's technology appraisal on idelalisib for treating chronic lymphocytic leukaemia recommends idelalisib plus rituximab for untreated CLL in adults with a 17p deletion or TP53 mutation. At its second meeting, the committee was made aware of recent provisional advice by the EMA on idelalisib following a number of serious adverse events in some post-marketing trials. The committee noted that the advice included not starting treatment in people with a 17p deletion or TP53 mutation who had not had previous treatment. At its third meeting, the committee noted that the EMA's Committee for Medicinal Products for Human Use had confirmed that the benefits of idelalisib outweigh the risk of side effects and had now concluded that idelalisib 'can again be initiated in these patients provided they cannot take any alternative treatment and that the measures agreed to prevent infection are followed'. The committee was aware that, in the absence of idelalisib, people with untreated CLL and a 17p deletion or TP53 mutation have no treatment options, and recognised the unmet need in this population. The committee therefore agreed that the relevant comparators for this group were idelalisib plus rituximab or best supportive care.

Clinical effectiveness of ibrutinib compared with ofatumumab (randomised controlled trial evidence)

4.11 The committee considered the clinical evidence that came from the randomised controlled RESONATE trial which compared ibrutinib with ofatumumab. The committee noted that after a positive interim analysis the trial terminated early, when the median time in the trial was 9.4 months. The committee acknowledged that the company had re-analysed the data at a median 16‑month follow-up and at a median of 30 months of follow-up. After a median of 16 months, the median progression-free survival had not been reached with ibrutinib; that is, fewer than half of the people randomised to ibrutinib had progressed disease, while for patients randomised to ofatumumab the median progression-free survival was 8.1 months (hazard ratio 0.106, 95% confidence interval 0.073 to 0.153, p<0.0001). At its second meeting, the committee noted that the company presented data from a median 30‑month follow-up that supported the results in its submission. The committee agreed that the results from RESONATE showed that ibrutinib was a very effective therapy, a conclusion that the clinical experts supported. It was clear that the 'immaturity' of the data reflected the effectiveness of ibrutinib and viewed this positively. However, the committee was mindful that it did mean that a greater proportion of the modelled time horizon depended on extrapolations. The committee agreed that the trial showed ibrutinib extended progression-free survival compared with ofatumumab.

Clinical effectiveness of ibrutinib compared with idelalisib plus ofatumumab (indirect treatment comparison)

4.12 The committee considered the indirect treatment comparisons conducted by the company, and specifically the comparison of overall survival between ibrutinib with idelalisib plus ofatumumab. The common comparator was ofatumumab. The committee noted that the company adjusted the trial results of RESONATE (which compared ibrutinib with ofatumumab) to account for crossover at disease progression. It agreed that this was appropriate, recognising that the unadjusted hazard ratio for death from the RESONATE trial would underestimate ibrutinib's effectiveness relative to ofatumumab. However, the committee noted that the company did not adjust the hazard ratio from the Jones et al. (2015) trial (also known as the 119 trial, and which compared idelalisib plus ofatumumab with ofatumumab) to account for treatment switching to ibrutinib.

4.13 The committee discussed how to account for the effect of the treatment switching that occurred after the 119 trial on the relative effectiveness of ibrutinib and idelalisib. It recognised that the company did not have access to the data from the 119 trial, so could not adjust this data. The committee considered the options available, which were either to adjust the data from the RESONATE trial only, or to adjust neither trial's data. The committee noted that it had not seen any data to quantify the extent to which switching to ibrutinib occurred after the 119 trial. The committee concluded that the true estimates of the clinical benefit of ibrutinib compared with idelalisib plus rituximab would likely be weaker than, but closer to, the company's estimates of clinical effectiveness when adjusting only the RESONATE data for crossover, compared with estimates based on not adjusting data from either trial.

4.14 The committee considered the clinical benefits of treatment with ibrutinib compared with idelalisib. The committee noted the promising results associated with ibrutinib. The committee heard from the patient experts about how ibrutinib had changed their lives, and provides long-lasting progression-free survival for many patients. The committee heard from clinical experts that ibrutinib is very well tolerated in most patients. It noted that some adverse reactions can be serious but are manageable, and are less severe than those seen with other treatments for CLL. It heard from clinicians that, because of the risks associated with idelalisib (see section 4.8), their preference would be to offer ibrutinib. The committee concluded that ibrutinib offered a more preferable toxicity profile, and was likely to offer progression-free and overall survival benefits compared with idelalisib plus rituximab, but was mindful that the extent of this benefit was uncertain.

Idelalisib plus ofatumumab as a proxy for idelalisib plus rituximab

4.15 The committee noted that the scope included idelalisib plus rituximab as a comparator, but that the company presented results for idelalisib plus ofatumumab rather than idelalisib plus rituximab.

Clinical effectiveness of ibrutinib compared with best supportive care (using physician's choice as a proxy for best supportive care)

4.16 The committee was aware the company had not compared ibrutinib with best supportive care for people who cannot take idelalisib plus rituximab. The committee discussed whether physician's choice could be considered a proxy for best supportive care in people who cannot have idelalisib plus rituximab. However, the committee considered that this was problematic because bendamustine plus rituximab comprises 35% of physician's choice. The committee noted that taking bendamustine out of the mix would lower the cost, but also the effectiveness, of physician's choice. Without formal analyses, it concluded that it could not judge the impact this would have on clinical and cost effectiveness. The committee discussed whether ofatumumab would be a proxy for best supportive care. It noted that, in the Osterborg et al. trial, in the intention-to-treat analyses, patients randomised to ofatumumab lived longer than patients randomised to physician's choice (despite patients crossing over from the physician's choice arm) and therefore ofatumumab was unlikely to reflect best supportive care. The committee concluded that it was not presented with any evidence which compared ibrutinib with best supportive care. However, it concluded that it was likely that ibrutinib would be more effective compared with best supportive care than when compared with idelalisib plus rituximab.

Using ibrutinib after idelalisib in the treatment pathway

4.17 The committee noted that, in clinical practice, ibrutinib could be used after idelalisib. It heard from clinical experts that they would be keen to offer ibrutinib if idelalisib failed, or if patients had stopped idelalisib because of adverse events. The committee, however, was not presented with any data for using ibrutinib after idelalisib. The committee concluded that it could not consider ibrutinib for this setting.

Time horizon

4.21 The committee considered the time horizon used by the company in its modelling. The committee noted that the company used a 20‑year horizon in its base case, and conducted sensitivity analyses varying this to 10 years and 30 years. The committee noted that the ICERs were sensitive to the time horizon chosen, and the ICER increased with shorter time horizons. The ERG commented that 20 years may be too short a time horizon because, according to the company model, people treated with ibrutinib would still be alive at the end of this time period. By contrast, the committee heard from clinical experts that a time horizon of 20 years might be too long because the population had a mean starting age of 67 years. The committee concluded that, although there was some uncertainty about the most appropriate time horizon, it accepted that the 20‑year time horizon was suitable for decision-making.

Treatment duration

4.22 The committee understood that time to progression determines treatment duration, which in turn determines the cost of treatment. Having heard that clinicians in the NHS may continue to offer ibrutinib after disease progression, the committee considered that this could contribute to costs higher than those modelled by the company. The committee considered that it might also contribute to greater benefits than stopping treatment at disease progression, but did not see any evidence to support this. The committee noted that the summary of product characteristic states that treatment should continue only until disease progression or when it is no longer tolerated by the patient. The committee therefore concluded to consider only the costs and benefits of treatment until progression in the modelling.

Modelling the level of response to treatment

4.23 The committee noted that for patients in the progression-free health state, costs of routine follow-up were determined by disease response to treatment as measured in RESONATE. The committee heard from clinical experts that patients whose disease has responded to treatment would not be followed up at different intervals depending on the level of response to treatment. After consultation on the first appraisal consultation document, the company maintained that response level should determine routine follow-up and inpatient costs. The ERG agreed with the company that it may be more reasonable to equalise costs at the level of partial response, but stated that the company had not shown that rates of admission to hospital differ by response status. The committee concluded that, after consultation on the first appraisal consultation document, the company had corrected most imbalances in the costs, and that the costs of routine follow-up had a negligible impact on the ICERs.

Utility values

4.24 The committee considered the evidence on health-related quality of life presented by the company. The committee noted that the company had collected EQ‑5D data in RESONATE. The committee noted that the quality-of-life values collected at baseline before treatment did not differ much from those collected during either treatment. The clinical experts commented that this did not reflect their clinical experience, stating that symptoms improve immediately with ibrutinib and patients usually have a good quality of life unless they have an adverse event. Having heard the positive experience of patients with ibrutinib, particularly with regard to energy levels and few side effects, the committee was concerned that benefits may not have been appropriately captured, noting that the EQ‑5D does not directly measure fatigue. After consultation on the first appraisal consultation document, the company applied a utility increment for ibrutinib. The committee heard from the ERG that this increment was derived from EQ‑5D data, so did not resolve the committee's concerns about the sensitivity of the EQ‑5D. Also, this increment was based on the quality-of-life difference between idelalisib and rituximab treatment. The ERG noted that it was not appropriate to apply this as an additional increment to the EQ‑5D quality-of-life estimate for ibrutinib. The committee was aware that this had a minor impact on the results. The committee concluded that the EQ‑5D may not have captured the experience of people with CLL, and the base case may have underestimated the quality-of-life benefit with ibrutinib.

4.25 The committee considered the utility value for post-progression applied in the company's model. The committee heard from the clinical experts that they would not expect utility in the post-progression health state to be as high as assumed by the company. The committee was also aware that the company did not age-adjust the utilities. After consultation on the first appraisal consultation document, the company provided age-adjusted utility values, and chose a lower utility value in the post-progression state (0.60). The committee noted that this had a small impact on the ICERs. The committee agreed with these 2 changes.

Cost-effectiveness results

4.26 The committee considered the cost effectiveness of ibrutinib based on the evidence available. The committee reiterated that these ICERs were associated with uncertainty relating to efficacy estimates, utility values and long-term outcomes. The committee noted that the company's results did not reflect all its preferred assumptions, but was aware that exploratory analyses conducted by the ERG addressing many of these assumptions. These included:

4.27 The committee considered the ICERs including the updated ibrutinib patient access scheme and the patient access scheme for idelalisib. It noted that the ERG scenario without adjusting for crossover in the RESONATE trial was around £50,000 per quality-adjusted life year (QALY) gained, and the scenario adjusting for crossover was below £50,000 per QALY gained.