Bevacizumab in combination with oxaliplatin and either fluorouracil plus folinic acid or capecitabine for the treatment of metastatic colorectal cancer

Clinical effectiveness

4.3 The Committee considered the data presented by the manufacturer for the clinical effectiveness of bevacizumab as a first-line treatment for metastatic colorectal cancer. It noted that the data came from a study that included an initial two-arm part and a later 2 x 2 factorial part (six arms in total). Data from the initial two-arm part of the study and the later 2 x 2 factorial part of the study were combined in the primary analysis. The Committee noted that in the primary analysis (that is, pooling of all bevacizumab arms compared with pooling of all placebo arms) statistically significant improvements in progression-free survival of 1.7 months and in overall survival of 2.3 months were reported for bevacizumab. However, the Committee noted an imbalance in prognostic factors between the initial two-arm part of the study and the 2 x 2 factorial part of the study that could bias the results in favour of bevacizumab: the number of patients reported as Caucasian and the proportion of patients with ECOG performance status of 0 were both 10% higher in the 2 x 2 factorial part of the study. Therefore, the Committee considered that the validity of the results from the pooled analysis was not acceptable. The Committee considered the secondary analysis (of the 2 x 2 factorial part of the study only) showing a statistically significant improvement in progression-free survival of 1.4 months, but no statistically significant increase in overall survival, to be more methodologically appropriate. However, the Committee agreed with the ERG that the most appropriate method of analysis would be with the XELOX and FOLFOX arms not pooled and patients with prior adjuvant therapy excluded and noted that this was not provided. The Committee concluded that bevacizumab provided a modest increase in progression-free and overall survival when compared with regimens without bevacizumab but was mindful that there was a significant degree of uncertainty in the clinical evidence.

4.4 The Committee discussed the equivalence of FOLFOX-4 and XELOX regimens. It heard from clinical specialists that FOLFOX-4 regimens are considered to offer equivalent clinical benefits to XELOX regimens. It also heard from patient experts that FOLFOX 4 regimens are associated with fewer and less serious adverse events than XELOX regimens, but XELOX regimens can be more convenient for patients. The Committee agreed that FOLFOX-4 and XELOX could be considered equivalent. The Committee discussed the imbalance observed in the study whereby the improvement in progression-free survival was only significant for the B-XELOX group and not the B-FOLFOX-4 group. The Committee understood that the P-FOLFOX-4 group (placebo and FOLFOX-4) had a greater time between adjuvant treatment and relapse than the other treatment groups and that this represented an important prognostic factor. The Committee noted that exclusion of the 25% of patients who had received prior adjuvant treatment resulted in significant improvement in progression-free survival for the B-FOLFOX-4 group. The Committee concluded that this indicated that there was an imbalance of prognostic factors within the study, but noted that at the time of the study the importance of this prognostic factor was not known.

4.5 The Committee discussed the use of bevacizumab in combination with oxaliplatin-containing regimens as a second-line treatment for metastatic colorectal cancer. The Committee considered the data presented by the manufacturer. It noted that the evidence suggested that both overall survival and progression-free survival were statistically significantly improved by 2 to 3 months (as detailed in section 3.11) in the second-line setting. The Committee concluded that bevacizumab was clinically effective as a second-line treatment. The Committee also noted that the manufacturer did not present any evidence of bevacizumab compared with FOLFIRI as a second-line treatment. It further noted that the manufacturer did not submit any evidence of bevacizumab in lines beyond second-line treatment.

4.6 The Committee noted that a significant percentage of patients withdrew early from the NO16966 study because of adverse events. It heard from clinical specialists that, in general, withdrawals often occur at an early stage for all chemotherapy regimens (including those containing bevacizumab). They further stated that if a patient is tolerant of bevacizumab at the beginning of the treatment, withdrawal is less likely at a later stage because of intolerance. For the chemotherapy agents, however, increased adverse events were likely because of increased time on treatment. The patient experts agreed that although the adverse events experienced with bevacizumab were unpredictable and affected health-related quality of life, they could be tolerated because of the trade-off with the benefits in terms of extension to life.

4.7 In summary, based on the clinical-effectiveness evidence and the opinions of the clinical specialists and patient experts, the Committee concluded that, for the first-line treatment of metastatic colorectal cancer, bevacizumab in combination with oxaliplatin-containing regimens gave a modest clinical benefit compared with regimens without bevacizumab. The Committee concluded that bevacizumab was clinically effective as part of second-line treatment. Benefits from bevacizumab were achieved at the expense of small but definite increases in adverse events.

Cost effectiveness

4.8 The Committee reviewed the results of the economic analyses submitted by the manufacturer. The Committee noted that the manufacturer had assumed that FOLFOX-6 had similar efficacy to FOLFOX-4 but with reduced costs. The Committee heard from clinical specialists that FOLFOX-6 offers similar clinical outcomes to FOLFOX-4. In addition, it heard that FOLFOX-6 is more commonly used in UK clinical practice because it involves only one visit to hospital per therapy cycle rather than the two visits per treatment cycle on consecutive days for FOLFOX-4. The Committee agreed that the assumptions made by the manufacturer with regards to FOLFOX-6 in the economic analysis were appropriate.

4.9 The Committee noted that in the economic model and in the NO16966 study, treatment was continuous. It heard from clinical specialists that current practice in the UK is often intermittent treatment, with treatment restarting when there are signs of disease progression. Although intermittent chemotherapy may be associated with a small survival deficit, it involves shorter durations of treatment and this reduces adverse events such as neuropathy and other side effects of therapy. Intermittent treatment may therefore be associated with better health-related quality of life. However, the Committee noted responses from consultation that, although intermittent treatment is commonly used in the UK, the sole evidence base for the addition of bevacizumab to first-line combination chemotherapy was reflective of a continuous treatment strategy. Therefore, the Committee concluded that the economic model reflected the clinical evidence that was available.

4.10 The Committee discussed the base-case cost-effectiveness estimates originally provided by the manufacturer. It noted that a revised base case was submitted after the ERG suggested that untruncated data should be used to fit alternative distributions when extrapolating the trial data. The Committee noted that the manufacturer's revised base case involved pooling of the initial two-arm part of the study and the 2 x 2 factorial part of the study. As previously noted, the Committee considered that this analysis was inappropriate because of the different designs of the study and the imbalance of demographics between the two parts of the study. Therefore, the Committee concluded that only the 2 x 2 factorial part of the study with the revised modelling of survival should be used in the cost-effectiveness analysis.

4.11 The Committee considered that the most plausible model assumption(s) for cost effectiveness would be to use the 2 x 2 factorial design of the NO16966 study with XELOX and FOLFOX arms not pooled and patients who had received prior adjuvant therapy excluded and noted that this had not been provided by the manufacturer. The Committee heard from the ERG that because no estimates of the effect of treatment in this scenario had been provided it was not possible to demonstrate how the ICERs would be affected. The Committee heard the manufacturer's opinion that removing patients who had received prior adjuvant treatment resulted in similar survival outcomes for XELOX and FOLFOX, and for B-XELOX and B-FOLFOX. The manufacturer stated that the basis of this view was informed by the overall results of the NO16966 study, which showed that XELOX was not inferior to FOLFOX and that there was no interaction between bevacizumab and the chemotherapy regimens used. However, the Committee noted that the analysis that used the 2 x 2 factorial part of the study, with the XELOX and FOLFOX arms pooled and patients who had received prior therapy excluded, resulted in markedly different ICERs than when the XELOX and FOLFOX arms were not pooled and patients who had received prior therapy were included. The ICERs provided by the manufacturer without the patient access scheme for B-XELOX compared with XELOX decreased slightly from £92,700 to £90,800 per QALY gained, and the ICER for B-FOLFOX-6 compared with FOLFOX-6 increased markedly from £96,700 to £240,300 per QALY gained (as detailed in section 3.22). The Committee considered that the analysis that did not pool the XELOX and FOLFOX arms and excluded patients who had received prior adjuvant treatment should have been provided and that the effect of pooling the XELOX and FOLFOX arms was unclear. Additionally, the Committee considered that it was counter-intuitive for the analysis to pool the effects of treatment, but not to pool the duration of treatment in the XELOX and FOLFOX arms. Therefore the Committee concluded that the ICERs were associated with substantial uncertainty.

4.12 The Committee noted that the ICERs presented by the manufacturer represented the treatment durations observed in the trial (that is, bevacizumab was stopped at the same time as FOLFOX and XELOX and before disease progression). The Committee noted that the trial protocol and the SPC allowed bevacizumab treatment until disease progression, even if oxaliplatin was stopped early because of adverse events. The ERG and the clinical specialists stated that, if a continuous chemotherapy policy was being practised, treatment with non-oxaliplatin components (such as bevacizumab) would be likely to continue after oxaliplatin treatment had stopped. The Committee noted that stopping oxaliplatin treatment 1 month before the other treatment agents or receiving bevacizumab for 1 month after oxaliplatin treatment had stopped, increased the ICERs. It noted that both analyses assumed no increase in progression-free or overall survival. However, the Committee considered that if such increases in progression-free and overall survival were accounted for, the extra bevacizumab costs would be likely to outweigh any additional survival benefits of bevacizumab, given the previously noted modest impact on progression-free and overall survival. The Committee concluded that, although the economic model was an accurate replication of the study (in terms of treatment duration), in practice bevacizumab treatment would be expected to continue until disease progression in patients treated with a continuous therapy policy. This could potentially increase the ICERs.

4.13 The Committee noted the manufacturer's comments in response to consultation that it was plausible that with an increase in the treatment duration the ICERs might increase but that they might also decrease. The Committee heard from the manufacturer that this could be because patients who do not progress and continue to receive treatment are those that may receive the greatest benefit. The manufacturer thought it was possible that the additional benefits would not be outweighed by the additional costs of treatment. However, the ERG commented that ICERs were more likely to increase because the incremental cost of taking bevacizumab for 1 month after stopping oxaliplatin (that is, bevacizumab costs versus no oxaliplatin costs) is higher than the incremental cost of treatment with bevacizumab and oxaliplatin (that is, bevacizumab and oxaliplatin costs versus oxaliplatin costs). Therefore, the additional costs would outweigh any additional benefits and the ICERs would be likely to increase. The Committee agreed that there was uncertainty as to how the ICERs would be affected if bevacizumab was given until progression because of the lack of clinical evidence but noted the ERG's view that the ICERs were likely to increase. Therefore, the Committee concluded that the ICERs may not reflect the way in which bevacizumab would be used in UK clinical practice, and were therefore associated with additional uncertainty but were more likely to increase.

4.14 The Committee considered the utility values used in the economic model. The Committee noted that no health-related quality-of-life data were collected in the study and that the utility values were taken from 'Cetuximab for the first-line treatment of metastatic colorectal cancer' (NICE technology appraisal guidance 176). The ERG stated that the reporting of utility values in metastatic colorectal cancer was inconsistent and there is a paucity of data. The Committee noted that the manufacturer had adjusted the utility value associated with the health state after first-line treatment (that is, without disease progression) to 0.77 in the revised analyses. However, the Committee agreed that the utility value of 0.77 was still high because it was similar to the utility values of people in the UK general population rather than people with metastatic colorectal cancer. The Committee also noted that the utility values were obtained from a small study of patients with metastatic colorectal cancer receiving cetuximab and chemotherapy using the EQ-5D. In addition, the utility values in the economic model were not regimen-specific. It further noted that decreasing the utility values by 20% increased the ICERs substantially. The Committee concluded that these issues also increased the uncertainty associated with the base-case ICERs.

4.15 The Committee noted that disutility due to adverse events was not included in the economic model. The manufacturer stated that because the utility values were obtained using the EQ-5D, then disutility due to adverse events would be included implicitly within this measure. The Committee noted that a higher incidence of grade 3 and 4 adverse events associated with bevacizumab had been reported in the trial. It considered that there would be disutility (that is, the quality-of-life estimates were likely to have been overestimated) and additional costs associated with the toxicity of bevacizumab. The Committee heard from the manufacturer that the majority of grade 3 and 4 adverse events are due to hypertension, which in most cases is readily treatable and likely to have a small impact on the health state utility of the patient. However, the Committee considered that, in some cases, the adverse effects of bevacizumab could be serious and that the disutility due to adverse events specific to bevacizumab treatment should have been incorporated into the model. The Committee further noted that the utility values used by the manufacturer could not have accounted for the adverse effects of bevacizumab because they were obtained from a study that examined cetuximab. The Committee therefore concluded that the ICERs would increase if the disutility due to adverse events related to bevacizumab treatment was included.

4.16 The Committee noted that in the revised analyses provided by the manufacturer in response to consultation, the treatment administration costs of B-FOLFOX and B-XELOX were stated to have been overestimated in the original submission. The Committee noted the ERG's concerns about the time-and-motion study conducted by the manufacturer; in particular, the sources of the unit costs were unclear and the study was based on data from one small private hospital. The Committee considered that the addition of a bevacizumab infusion to either XELOX or FOLFOX could incur greater additional treatment administration costs than those stated by the manufacturer. The Committee concluded that if these higher administration costs were included, then this would result in an increase in the ICER estimates.

4.17 The Committee discussed the details of the patient access scheme and the impact of the patient access scheme on the ICERs. It noted that when the amended patient access scheme was applied the ICERs decreased from £105,000 to £30,000 per QALY gained for B-XELOX compared with XELOX, and from £108,000 to £24,600 per QALY gained for B-FOLFOX-6 compared with FOLFOX-6. The Committee noted that there was uncertainty expressed by the Department of Health around the operating costs of implementing the scheme. The Committee had concerns about the complexity of the scheme and considered that hospital trusts were likely to involve clinical staff and finance departments as well as pharmacists in its implementation. It noted the revised analyses presented by the manufacturer that incorporated higher operating costs of the patient access scheme. However, the Committee considered that the scheme was complex, with requirements for a number of financial transactions between the manufacturer, healthcare providers and commissioners. Therefore, the operating costs of the scheme were still likely to be greater than those presented by the manufacturer. The Committee noted the ERG's exploratory analysis showing that when the administration costs of the patient access scheme were increased to £100 the ICERs increased slightly. In addition, the Committee noted its earlier conclusions that all of the ICERs with and without the patient access scheme were associated with substantial uncertainty and could be underestimated.

4.18 The Committee considered how the four components of the patient access scheme contributed to the reduction in the ICERs. It noted that the provision of free oxaliplatin was the key component in reducing the ICERs. The Committee noted that the price of oxaliplatin in the economic model was based on the BNF 57 non-proprietary price of £313.50 per 100 mg. The Committee heard from the manufacturer that the list price of oxaliplatin had been used in accordance with the NICE methods guide. However, the Committee noted that the methods guide also states that when the acquisition price paid for a resource differs from the public list price then a sensitivity analysis should be conducted to assess the implications of variations from this price. The Committee acknowledged that generic versions of oxaliplatin have recently become available and that the list price was decreasing, with the list price in BNF 60 reduced to £299.50 per 100 mg. The Committee also noted information provided by the Commercial Medicines Unit of the Department of Health which stated that oxaliplatin is widely available in the NHS through procurement contracts at a discount of more than 90% off the list price. The Committee noted the ERG's exploratory analyses, which showed that when the oxaliplatin list price was discounted by 90% the ICERs with the patient access scheme were greatly increased to £68,100 per QALY gained for B-XELOX compared with XELOX, and to £70,500 per QALY gained for B-FOLFOX compared with FOLFOX-6. The Committee considered that it was more appropriate to use the discounted cost of oxaliplatin when assessing the impact of the patient access scheme on cost effectiveness and therefore did not accept the manufacturer's estimates that ICERs of £105,000 and £108,000 per QALY gained were reduced to £30,000 and £24,600 respectively with the amended patient access scheme.

4.19 The Committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with 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:

4.20 The Committee discussed whether bevacizumab in combination with oxaliplatin and either fluorouracil plus folinic acid or capecitabine for the treatment of metastatic colorectal cancer fulfilled the criteria for consideration as a life-extending, end-of-life treatment. The Committee noted that life expectancy with XELOX or FOLFOX was unlikely to be greater than 24 months and was potentially as low as 20 months and 11 months in the first-line and second-line settings respectively. In the first-line setting, the Committee noted from the 2 x 2 analysis of the clinical trial that bevacizumab increased overall survival by 1.4 months compared with XELOX and FOLFOX-4. However, the Committee considered the design of the trial was complex and that the most appropriate method of analysis (that is, with the XELOX and FOLFOX arms not pooled and patients with prior adjuvant therapy excluded) was not provided and therefore the Committee had concerns about the robustness of the evidence. The Committee further noted that bevacizumab as a second-line therapy (E3200 study) statistically significantly increased overall survival by 2.2 months compared with FOLFOX-4. The Committee was aware that the total number of patients currently presenting with metastatic colorectal cancer in England and Wales is approximately 16,000. In addition, the Committee understood that it should take into account the cumulative population for each product in considering the strength of any case, for justifying decisions which employ, in whole or part, the supplementary criteria for appraising life-extending, end-of-life treatments. It noted that bevacizumab was licensed for a number of other indications also involving large patient groups. In summary, the Committee concluded that bevacizumab in combination with oxaliplatin and either fluorouracil plus folinic acid or capecitabine for the treatment of metastatic colorectal cancer did not meet all of the criteria for a life-extending, end-of-life treatment.

4.21 The Committee concluded (on the basis of the submitted evidence) that the most appropriate cost-effectiveness estimates of bevacizumab as a first-line treatment for metastatic colorectal cancer available were those using the 2 x 2 factorial part of the study, with the XELOX and FOLFOX arms pooled and with patients who had received prior therapy excluded, giving ICERs of £105,000 per QALY gained for B-XELOX and £108,000 per QALY gained for B-FOLFOX-6 (without the patient access scheme) and £68,100 per QALY gained for B-XELOX and £70,500 per QALY gained for B-FOLFOX-6 (with the patient access scheme applied and the discounted price of oxaliplatin used). However, the Committee agreed that these ICERs (both without and with the patient access scheme) were associated with substantial uncertainty and that plausible adjustments to the key model inputs could increase these ICERs. The Committee recognised the novel mode of action of bevacizumab but did not consider it to be a substantially innovative technology in the treatment of metastatic colorectal cancer. The Committee concluded that bevacizumab in combination with oxaliplatin and either fluorouracil plus folinic acid or capecitabine could not be recommended as a cost-effective use of NHS resources for the first-line treatment of metastatic colorectal cancer.

4.22 The Committee reviewed the cost-effectiveness analysis of bevacizumab in combination with oxaliplatin-containing regimens as a second-line treatment for metastatic colorectal cancer. The Committee noted that the base-case ICER presented by the manufacturer was £103,000 per QALY gained. The Committee noted that this ICER was substantially higher than those normally considered an acceptable use of NHS resources. In addition, the manufacturer stated that a cost-effective case for bevacizumab as a second-line treatment could not be made. The Committee further noted that no evidence of bevacizumab given after second-line treatment was submitted by the manufacturer. Therefore, the Committee concluded that bevacizumab in combination with oxaliplatin-containing regimens could not be recommended as a cost-effective use of NHS resources for second-line or later treatment of metastatic colorectal cancer.

4.23 The Committee considered whether there were issues related to equality to be taken into account in its considerations. It noted that no equality issues had been raised during the scoping, evidence submissions or consultation stages. Therefore, it concluded that there were no specific issues relating to equality that needed to be taken into account.