The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of bevacizumab in combination with a taxane, having considered evidence on the nature of metastatic breast cancer and the value placed on the benefits of bevacizumab in combination with a taxane by people with metastatic breast cancer, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.
The Committee considered current clinical practice for the treatment of metastatic breast cancer. The Committee noted the manufacturer's clarification response, which stated that approximately 30% of patients receive a taxane in the adjuvant setting, particularly in node positive disease at diagnosis. The clinical specialist stated that in current practice, if metastatic disease subsequently develops, taxanes (that is, weekly paclitaxel or 3-weekly docetaxel) are then offered as first-line treatment for the majority of people in England and Wales. The Committee also heard from the clinical specialist that 3-weekly paclitaxel is no longer routinely used in clinical practice, having been largely replaced by weekly dosing schedules. The Committee heard that the choice between the 2 taxanes is made locally and that weekly paclitaxel and 3-weekly docetaxel are considered to have comparable efficacy. The Committee concluded that the relevant comparators for bevacizumab in combination with a taxane for the first-line treatment of metastatic breast cancer are weekly paclitaxel and 3-weekly docetaxel.
The Committee discussed the clinical effectiveness of bevacizumab in combination with a taxane. It heard that bevacizumab is the first VEGF-targeted therapy for this indication. The Committee discussed the E2100 trial which compared bevacizumab plus paclitaxel with weekly paclitaxel. The Committee heard from the ERG that the trial had several limitations, such as the lack of blinding. The trial demonstrated a statistically significant increase in median progression-free survival of 5.5 months, from 5.8 months in the paclitaxel alone arm to 11.3 months in the bevacizumab plus paclitaxel arm. The Committee explored the value of an increase in progression-free survival with the clinical specialist and patient expert. It heard about the importance and significance of progression-free survival for patients in terms of being able to carry out normal daily activities, as well as being a therapeutic aim of treatment for clinicians.
The Committee then discussed the overall survival results of the E2100 trial and noted a non-statistically significant increase in median survival of 1.7 months, from 24.8 months with paclitaxel alone to 26.5 months with bevacizumab plus paclitaxel. The Committee discussed the possible reasons for the increase in progression-free survival not being reflected in overall survival in the trial. It acknowledged that although it was possible that the relative treatment effect may have been confounded by crossover or other treatments received after disease progression, no data on this had been collected. The Committee heard from the clinical specialist that the response in E2100 to paclitaxel alone was lower than demonstrated in previous studies. The Committee concluded that it was likely that bevacizumab plus paclitaxel improved progression-free survival relative to weekly paclitaxel, but that there was no robust evidence that bevacizumab plus paclitaxel improved overall survival compared with weekly paclitaxel alone.
The Committee discussed the health-related quality of life data for bevacizumab plus paclitaxel compared with weekly paclitaxel. The Committee heard from the primary care trust expert that robust data on the magnitude of quality-of-life improvements were important. The Committee noted concerns about the data presented by the manufacturer. It was aware that a statistically significant improvement in health-related quality of life at 33 weeks was only demonstrated when extreme values were imputed. The Committee also heard from the clinical specialist that the scores for psychological and emotional wellbeing were not explicitly addressed by the manufacturer. The Committee concluded that the magnitude of health-related quality of life benefits with bevacizumab plus paclitaxel compared with paclitaxel alone was uncertain.
The Committee noted the adverse events and the side-effect profile from the E2100 trial as well as from a large uncontrolled study (ATHENA). The Committee noted that the frequency of grade 3 to 5 adverse events was slightly higher with the addition of bevacizumab to paclitaxel. However, the Committee heard from the clinical specialist that many of the adverse events were those expected in cytotoxic regimens, and could be attributed to the taxane. Increased treatment duration would also lead to an increase in the incidence of adverse events. The Committee understood that most adverse events could be satisfactorily managed (for example with dose reductions). Specific adverse events associated with bevacizumab, notably hypertension, were also readily treatable. The Committee concluded that the addition of bevacizumab did not lead to unacceptable toxicity compared with paclitaxel alone, and that adverse effects were manageable.
The Committee noted that evidence from the AVADO study for the clinical effectiveness of bevacizumab plus docetaxel had been provided by the manufacturer after consultation on the appraisal consultation document. The Committee noted the manufacturer's comment that the AVADO dosing regimen of 9 cycles of 100 mg/m2 docetaxel was not routine UK clinical practice as 3-weekly docetaxel was usually given for 6 cycles. The Committee heard from the clinical specialist that 100 mg/m2 was the standard dose used in the absence of contraindications, and that therefore he considered that the trial data were relevant to UK clinical practice. The clinical specialist also highlighted the high methodological quality of the AVADO trial and its placebo-controlled design. The Committee noted that the results from this study demonstrated an approximate 2-month, statistically significant improvement in progression-free survival for bevacizumab at a dose of 15 mg/m2 plus docetaxel. However, the Committee also noted the hazard ratio for death which was 1.03 (95% CI 0.70 to 1.33), indicating a non-statistically significant reduction in median overall survival of 1.7 months from 31.9 months in the docetaxel alone arm to 30.2 months in the bevacizumab plus docetaxel arm. The Committee concluded that bevacizumab plus docetaxel was modestly clinically effective compared with docetaxel alone in terms of progression-free survival. However, its effect on overall survival was uncertain.
The Committee discussed the indirect treatment comparison presented by the manufacturer for bevacizumab plus weekly paclitaxel compared with docetaxel alone and gemcitabine plus 3-weekly paclitaxel. The Committee noted the ERG's comments related to the reliability of the indirect treatment comparison. The quality of the included studies was variable, and the trials included variable numbers of patients receiving second-line treatment, where the prognosis may be worse than for first-line chemotherapy. Also, it was not clear that the selection criteria for included studies had been consistently applied, with the AVADO trial being excluded on the grounds of the docetaxel dose used, while another study using the same dose of docetaxel was included. The Committee concluded that the indirect treatment comparison was not robust and that the results were not considered reliable.
The Committee discussed the additional data presented by the manufacturer for the triple negative subgroup in response to consultation on the appraisal consultation document. The Committee explored whether bevacizumab might be more clinically effective in this subgroup. The Committee heard from the clinical specialist that for the subgroup of women with triple negative cancers (that is, cancers that do not have receptors for oestrogen, progesterone or HER2) there may be worse outcomes. The Committee noted, however, that while it was plausible that bevacizumab could be more effective in some tumour types than others, there was no proposal of a biologically plausible specific mechanism of effect for bevacizumab having an increased benefit for this subgroup. The Committee discussed the results of the manufacturer's meta-analysis that demonstrated that the progression-free survival and overall survival hazard ratios for the triple negative subgroup (0.63 and 0.96) were indistinguishable from those of the intention-to-treat population (0.64 and 0.97). Moreover, the results for the overall survival difference were not statistically significant (95% CI 0.79 to 1.16). The Committee concluded that there was no evidence of any greater clinical benefit in the triple negative subgroup than in the intention-to-treat population.
The Committee then discussed the additional data provided by the manufacturer for the prior taxane-treated subgroup. It heard from the clinical specialist that this was an area of clinical need as 30% to 40% of patients, usually those with lymph node involvement, would have received taxanes in the adjuvant setting. These patients would generally have a worse prognosis and might need different treatment options if the disease progressed after treatment. The Committee noted that although there could be taxane resistance in this subgroup, there were no specific biological markers or other hypotheses to suggest why VEGF agents would work more effectively in this subgroup compared with the intention-to-treat population. The Committee discussed the results provided for this subgroup, noting that these were based on post hoc analyses. The Committee noted that the hazard ratio for death in the E2100 trial for the prior taxane-treated subgroup was 0.67 (95% CI 0.45 to 0.99), indicating a statistically significant increase from 17.6 months in the paclitaxel alone arm to 26.3 months in the bevacizumab plus paclitaxel arm, and that the hazard ratio for death in the meta-analysis for the prior taxane-treated subgroup was 0.73 (95% CI 0.55 to 0.97), indicating a statistically significant increase from 21.3 in the taxane only arm to 26.9 months in the bevacizumab plus taxane arm. However, the Committee identified a number of concerns that questioned the robustness of the data. It noted that the E2100 trial was unblinded and did not stratify for prior taxane-treated patients, and the AVADO study, though stratified, had a very small number of patients (n=78). Further, although the results for this subgroup were statistically significant for both progression-free survival and overall survival, there was no indication of the hazard ratios for the group who did not receive prior taxane treatment in the adjuvant setting and there were no statistical tests for interaction. The clinical specialist, while expressing interest in the findings, agreed on their exploratory nature. The Committee also noted the manufacturer's comment in its submission that although in the meta-analysis these differences appear to be statistically significant, it should be noted that this analysis is exploratory only.
Consequently, the Committee considered that although the results of the prior taxane-treated subgroup analyses were interesting in terms of possible clinical benefit, they were not sufficiently robust to use for the development of guidance. The Committee concluded that the results needed to be confirmed in larger, well-designed studies, and that the estimates of effectiveness could not be considered suitable as the basis of a cost-effectiveness analysis. The Committee discussed whether there were any subgroups other than those presented by the manufacturer that may have an increased benefit from bevacizumab treatment. It heard from the clinical specialist that the groups identified by the manufacturer were key subgroups. The Committee noted the clinical specialist's comment that further research into whether there are any clinical or biological subgroups (such as subgroups by biological markers) for whom bevacizumab is particularly beneficial would be useful. The Committee concluded that no robust evidence on subgroups was currently available and that the data that were available were not reliable and could not be carried forward as the basis for a cost-effectiveness analysis.
The Committee discussed the pair wise cost-effectiveness estimates of bevacizumab plus paclitaxel as presented by the manufacturer. The Committee noted that the manufacturer had provided 2 base cases, 1 of which was based on average prices paid by NHS trusts for paclitaxel over a 4-month period and a patient access scheme for bevacizumab. The Committee was aware that no patient access scheme had been approved by the Department of Health and that therefore the scheme could not be taken into account in the consideration of cost effectiveness. The Committee was also aware that it was not in accordance with the NICE methods guide for the manufacturer to use average prices paid by NHS trusts for paclitaxel over a 4-month period rather than a nationally agreed discounted price that is consistently available to the NHS. However, the Committee noted the confirmation from the Department of Health Commercial Medicines Unit that discounts for paclitaxel are in a range greater than 95% from the BNF list price of the branded presentation and that prices within these ranges are available to all NHS hospital trusts in England. The Committee concluded that it would consider the range of the ICERs based both on the list prices and the average prices paid by NHS trusts for paclitaxel.
The Committee was aware that the manufacturer's analysis used a series of pair wise comparisons for bevacizumab plus paclitaxel relative to each separate comparator regimen. The Committee accepted comments from the ERG that the correct methodological approach would have been a fully incremental analysis. The Committee noted that the incremental analysis carried out by the ERG resulted in ICERs that were similar to the pair wise ICERs. The Committee therefore concluded that, taking this into account, together with the fact that the ERG's exploratory analyses had been conducted using the pair wise ICERs, these were appropriate for consideration in this instance.
The Committee noted that the manufacturer's base case assumed that the clinical effectiveness of all the comparators (that is, 3-weekly docetaxel, gemcitabine plus paclitaxel and 3-weekly paclitaxel) were the same as weekly paclitaxel. The manufacturer subsequently conducted revised analyses substituting the clinical effectiveness results from the indirect comparison. The Committee noted its earlier conclusions that the results of the indirect comparison were not reliable and that there were only 2 relevant comparators. In addition, the Committee heard from the clinical specialist that weekly paclitaxel and 3-weekly docetaxel were not considered to demonstrate clinically meaningful differences in effectiveness. The Committee concluded that the cost-effectiveness estimates derived from assuming comparators had equivalent effectiveness to weekly paclitaxel were acceptable.
The Committee discussed the way in which the manufacturer had modelled overall survival in the economic model provided in the original submission. It noted that a key assumption made by the manufacturer was that patients would have the same risk of dying per unit time once disease progressed, regardless of the first-line treatment they had received. This resulted in improvements in observed progression-free survival being carried over to projected improvements in overall survival. The Committee was aware that there are various ways of modelling that would result in different estimates of overall survival. The Committee noted that the manufacturer's model (whereby overall survival was independent of previous treatments received) resulted in mean life years of 2.68 years in the bevacizumab plus paclitaxel arm and 2.33 years in the paclitaxel alone arm (an incremental benefit of 0.35 years) and a pair wise ICER of £118,000 per QALY gained, using the list price for paclitaxel. The manufacturer indicated that this represented an optimistic scenario compared with the trial data. The manufacturer did not provide results for a scenario including the average price for paclitaxel paid by NHS trusts without the patient access scheme; however, an analysis of this by the ERG indicated an ICER of £110,500 per QALY gained. The Committee also examined the exploratory analyses carried out by the ERG that attempted to calibrate overall survival in the model with that directly observed in the E2100 trial by using an area under the curve method. These analyses resulted in mean life years of 2.16 years in the bevacizumab plus paclitaxel arm and 2.13 years in the paclitaxel alone arm (an incremental benefit of 0.03 years) and a pair wise ICER of £259,000 per QALY gained, based on the list price for paclitaxel. Using the average price for paclitaxel paid by NHS trusts, the ERG reported that the ICER remained over £200,000 per QALY gained. The ERG acknowledged that this represented a pessimistic scenario. The Committee therefore concluded that the true ICER for bevacizumab plus paclitaxel compared with weekly paclitaxel probably lay between £110,000 and £259,000 per QALY gained.
The Committee noted that the ICER for bevacizumab plus paclitaxel versus docetaxel alone presented by the manufacturer was £115,000 per QALY gained, based on list prices for paclitaxel. Although the ERG did not conduct a further exploratory analysis for this comparison, the Committee considered that it would also have resulted in a substantially higher ICER. The Committee concluded that the true pair wise ICER for bevacizumab plus paclitaxel compared with 3-weekly docetaxel was over £115,000 per QALY gained.
The Committee noted that the manufacturer did not provide any clinical or cost-effectiveness data related to bevacizumab plus docetaxel, even though it was specified in the scope. The Committee considered the manufacturer's statement that it can be inferred from the high ICERs in the model that bevacizumab plus docetaxel (the more expensive taxane) is unlikely to provide a more cost-effective outcome than the analysis presented in the submission and, hence, a full economic analysis of bevacizumab plus docetaxel was not warranted. The Committee agreed that the ICER for bevacizumab plus docetaxel would be higher than the ICER for bevacizumab plus paclitaxel compared with weekly paclitaxel and 3-weekly docetaxel.
The Committee discussed the estimates of the ICERs given by the manufacturer using subgroup data from the E2100 study. For the triple negative subgroup, the cost per QALY for bevacizumab plus paclitaxel ranged from £64,100 to £87,900 per QALY gained depending on the comparator and whether the list price for paclitaxel was used or the average price for paclitaxel paid by NHS trusts was used. For the prior taxane-treated subgroup, the corresponding range was £57,400 to £74,600 per QALY gained. The Committee noted that these estimates remained above the conventional levels normally considered cost effective, and would be further increased if alternative techniques were used to model overall survival. The Committee considered that because of the uncertainty around the subgroup clinical effectiveness estimates, those estimates could not be carried forward to form the basis of a cost-effectiveness analysis and guidance to the NHS. The Committee concluded that the estimates of cost effectiveness for the intention-to-treat population represented the most plausible estimate of cost effectiveness for bevacizumab.
The Committee discussed whether there were any equality issues relating to population groups protected by equality legislation. It noted information from the manufacturer's submission relating to the potential for worse outcomes in lower socioeconomic groups or by ethnicity. The Committee heard from the clinical specialist that there may be differences in overall treatment outcomes between these groups, but that they are likely to result from factors such as lower uptake of screening or later presentation of disease rather than differences in treatment. The Committee noted that the triple negative subgroup may be over-represented in some ethnic groups. The Committee concluded that there was no evidence of differences in access to treatment or response to treatment by socioeconomic status or ethnicity in patients with disease at the metastatic stage.
The Committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of people with a short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met:
The treatment is indicated for patients with a short life expectancy, normally less than 24 months.
There is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3 months, compared with current NHS treatment.
The treatment is licensed or otherwise indicated for small patient populations.
In addition, when taking these criteria into account the Committee must be persuaded that the estimates of the extension to life are robust and the assumptions used in the reference case economic modelling are plausible, objective and robust.
The Committee discussed whether bevacizumab in combination with a taxane for the first-line treatment of metastatic breast cancer fulfilled the criteria for a life-extending, end-of-life treatment. The Committee noted that the E2100 trial data indicated that median overall survival in the paclitaxel alone arm was 24.8 months. The Committee considered the fact that this was just above the defined limit of life expectancy of less than 24 months in the end-of-life criteria. The Committee also noted that the change in median overall survival was an increase of 1.7 months with bevacizumab plus paclitaxel compared with paclitaxel alone. The Committee accepted that, although it was possible that this increase had been underestimated (because of the possibility of crossover or additional treatments), there was no robust evidence that bevacizumab plus paclitaxel offers an extension to life of an additional 3 months, compared with paclitaxel alone. The Committee agreed that the robustness of evidence for the subgroups was not convincing; therefore, the Committee did not discuss whether the subgroups presented fulfilled the criteria for consideration as a life-extending, end-of-life treatment. The Committee also noted that bevacizumab is licensed for a relatively large population across a range of indications, such as colorectal cancer, non-small-cell lung cancer and renal cell carcinoma, and hence does not meet the third criterion that the treatment should be licensed for small populations. The Committee concluded that bevacizumab in combination with a taxane did not fulfil the criteria for special consideration as a life-extending, end-of-life treatment.
In summary, the Committee concluded that the most plausible ICER for bevacizumab plus paclitaxel versus weekly paclitaxel was between £110,000 and £259,000 per QALY gained and that the ICER for bevacizumab plus paclitaxel versus docetaxel would be greater than £115,000 per QALY gained. The Committee accepted the manufacturer's statement that the ICER for bevacizumab plus docetaxel would be higher than that for bevacizumab plus paclitaxel since docetaxel is the more expensive taxane. The Committee considered that although the subgroup results were promising in terms of potential clinical benefit, they were not sufficiently robust to develop guidance and could not be carried forward as the basis for a cost-effectiveness analysis. The Committee concluded that bevacizumab in combination with a taxane as a first-line treatment for metastatic breast cancer was not a cost-effective use of NHS resources.