Bevacizumab in combination with oxaliplatin and either 5-fluorouracil or capecitabine for the treatment of metastatic colorectal cancer

The Department of Health has asked the National Institute for Health and Clinical Excellence (NICE) to produce guidance on using bevacizumab in combination with oxaliplatin for the treatment of metastatic colorectal cancer in the NHS in England and Wales. The Appraisal Committee has considered the evidence submitted by the manufacturer and the views of non-manufacturer consultees and commentators, and clinical specialists and patient experts.

This document has been prepared for consultation with the consultees. It summarises the evidence and views that have been considered, and sets out the draft recommendations made by the Committee. NICE invites comments from the consultees and commentators for this appraisal (see appendix B) and the public. This document should be read along with the evidence base (the evaluation report), which is available from www.nice.org.uk

The Appraisal Committee is interested in receiving comments on the following:

Has all of the relevant evidence been taken into account?

• Are the summaries of clinical and cost effectiveness reasonable interpretations of the evidence?
• Are the provisional recommendations sound and a suitable basis for guidance to the NHS?
• Are there any aspects of the recommendations that need particular consideration to ensure we avoid unlawful discrimination against any group of people on the grounds of gender, race, disability, age, sexual orientation, religion or belief?

Note that this document is not NICE's final guidance on this technology. The recommendations in section 1 may change after consultation.

After consultation:

• The Appraisal Committee will meet again to consider the evidence, this appraisal consultation document and comments from the consultees.
• At that meeting, the Committee will also consider comments made by people who are not consultees.
• After considering these comments, the Committee will prepare the final appraisal determination (FAD).
• Subject to any appeal by consultees, the FAD may be used as the basis for NICE’s guidance on using bevacizumab in the NHS in England and Wales.

For further details, see the ‘Guide to the technology appraisal process’ (available at www.nice.org.uk).

The key dates for this appraisal are:

Closing date for comments: 14 December 2009

Second Appraisal Committee meeting: 27 January 2010

Details of membership of the Appraisal Committee are given in appendix A, and a list of the sources of evidence used in the preparation of this document is given in appendix B.

1 Appraisal Committee’s preliminary recommendations

1.1 Bevacizumab in combination with oxaliplatin and either 5−fluorouracil plus folinic acid or capecitabine is not recommended for the treatment of metastatic colorectal cancer.

1.2 People currently receiving bevacizumab in combination with oxaliplatin for the treatment of metastatic colorectal cancer should have the option to continue treatment until they and their clinicians consider it appropriate to stop.

2 The technology

2.1 Bevacizumab (Avastin, Roche Products) is a recombinant humanised monoclonal IgG1 antibody that inhibits the formation of blood vessels (angiogenesis inhibitor). It targets the biological activity of human vascular endothelial growth factor (VEGF), which stimulates new blood vessel formation in the tumour. Bevacizumab in combination with fluoropyrimidine-based chemotherapy has a UK marketing authorisation for treatment of patients with metastatic carcinoma of the colon or the rectum.

2.2 Bevacizumab is contraindicated in pregnant women and people who have hypersensitivity to the active substance or to any of the excipients, to products derived from Chinese hamster ovary cell cultures or other recombinant human or humanised antibodies. The summary of product characteristics (SPC) lists the following conditions that may be associated with the bevacizumab treatment: gastrointestinal perforations, fistulae, wound healing complications, hypertension, proteinuria, arterial and venous thromboembolism, haemorrhage, pulmonary haemorrhage/haemoptysis, congestive heart failure, reversible posterior leucoencephalopathy and neutropenia. For full details of side effects and contraindications, see the SPC.

2.3 Bevacizumab is administered as an intravenous infusion. The recommended dosage for metastatic carcinoma of the colon or rectum is 5 mg/kg or 10 mg/kg of body weight once every 2 weeks or 7.5 mg/kg or 15 mg/kg of body weight given once every 3 weeks. Bevacizumab treatment is given in combination with chemotherapy and is licensed for use until progression of the underlying disease or unacceptable toxicity. Bevacizumab is available in 100-mg and 400-mg vials at net prices of £242.66 and £924.40, respectively (excluding VAT; ‘British national formulary’ [BNF] edition 58). The acquisition cost of bevacizumab (excluding VAT and assuming wastage) for a patient weighing 70 kg is £924.40 at a dosage of 5 mg/kg every 2 weeks and £1409.72 at a dosage of 7.5 mg/kg every 3 weeks. The manufacturer of bevacizumab (Roche Products) has proposed a patient access scheme to the Department of Health for the use of bevacizumab in metastatic colorectal cancer. Costs may vary in different settings because of negotiated procurement discounts.

3 The manufacturer’s submission

The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of bevacizumab and a review of this submission by the Evidence Review Group (ERG; appendix B).

3.1 The manufacturer’s approach to the decision problem compared bevacizumab plus oxaliplatin and 5-flourouracil and folinic acid (B-FOLFOX) or bevacizumab plus oxaliplatin and capecitabine (B-XELOX) with FOLFOX and XELOX without bevacizumab as a first-line treatment. The manufacturer stated that the use of FOLFIRI is decreasing and that it is mainly used in the small minority of patients who cannot tolerate oxaliplatin. This was based on market research analysis, which indicated that combination chemotherapy regimens including oxaliplatin are the most commonly used in UK clinical practice. However, for completeness, the manufacturer performed an economic evaluation comparing bevacizumab and FOLFOX or XELOX with irinotecan in combination with folinic acid and 5-flourouracil (FOLFIRI). The manufacturer stated that the cost-effectiveness of bevacizumab as a second-line treatment could not be demonstrated.

3.2 The manufacturer undertook a systematic review of the literature and identified two randomised controlled trials: one assessed bevacizumab as first-line therapy (NO16966) and one assessed bevacizumab as second-line therapy (E3200). No evidence of bevacizumab used in lines of treatment beyond second-line therapy was provided by the manufacturer.

3.3 The NO16966 study started as a phase III, multinational, two-arm, randomised, open-label study. This study was originally designed to demonstrate the non-inferiority of XELOX compared with FOLFOX-4 (that is, the FOLFOX regimen given every 2 weeks, with two infusions in the first 48 hours) in adult patients with metastatic histologically confirmed metastatic colorectal cancer who had not been treated before with chemotherapy. After randomisation of 634 patients to XELOX or FOLFOX-4, the original protocol design was amended to include a 2 x 2 factorial randomised study where patients were subsequently randomised to either XELOX or FOLFOX plus either bevacizumab or placebo. A further 1401 patients were then recruited (blinded for bevacizumab) and a total of 2035 people were thus randomised in the NO16966 study. The study amendment included a co-primary objective of demonstrating superiority of bevacizumab in combination with chemotherapy (B-XELOX or B-FOLFOX-4) over placebo in combination with chemotherapy (P-XELOX or P-FOLFOX-4). The dosage of bevacizumab was 5 mg/kg every 2 weeks (B-FOLFOX-4) or 7.5 mg/kg every 3 weeks (B-XELOX). Treatment was planned to continue until disease progression, unacceptable toxicity, resection of metastatic disease or for 48 weeks, whichever came first, this being at the discretion of the investigator. Patients who completed the 48-week study treatment phase without progressive disease were eligible to enter the post-study treatment phase and continue treatment until their disease progressed. Patients whose disease became operable, and underwent resection, were eligible to enter the post-study treatment phase. The NO16966 protocol allowed continuation of bevacizumab treatment until disease progression (in line with the SPC) if oxaliplatin treatment was terminated because of adverse events.

3.4 All patients in the study had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The study was stratified to ensure that study arms were balanced with regards to ECOG performance status (0 versus 1), number of metastatic sites (organs) at baseline (1 versus more than 1), alkaline phosphatase level at baseline (within normal range versus above normal range), liver as a site of metastasis (yes versus no) and geographic region. The median follow-up was 28 months. The manufacturer stated that the demographic characteristics and prognostic factors were well balanced between the treatment arms in both parts of the study. However, the manufacturer acknowledged that patients in the study were slightly younger and fitter than people with metastatic colorectal cancer in the UK who are, on average, over 60 years of age.

3.5 The primary pooled analysis of non-inferiority of the NO16966 study (that is, pooling of all XELOX arms compared with pooling of all FOLFOX-4 arms) showed that the XELOX and FOLFOX-4 regimens were equivalent for overall and progression-free survival. The primary pooled analysis of superiority for the NO16966 study (that is, pooling of the initial two-arm study and the 2 x 2 factorial part of the study) showed that the addition of bevacizumab to chemotherapy (B-XELOX and B-FOLFOX-4) significantly improved progression-free survival compared with chemotherapy alone (P-XELOX and P-FOLFOX-4 and XELOX and FOLFOX-4 combined). The median progression-free survival was 7.7 months in the placebo plus chemotherapy group and 9.4 months in the bevacizumab plus chemotherapy group (intention-to-treat analysis, hazard ratio [HR] 0.79; 95% confidence interval [CI] 0.72 to 0.87, p = 0.0001). The median overall survival was 18.9 months in the placebo plus chemotherapy group compared with 21.2 months in the bevacizumab plus chemotherapy group (HR 0.83; 95% CI 0.74 to 0.93, p = 0.0019).

3.6 The manufacturer provided a secondary pooled analysis of superiority based only on the 2 x 2 factorial design (according to the original statistical trial plan, that is B-XELOX and B-FOLFOX-4 combined compared with P-XELOX and P-FOLFOX-4 combined). The median progression-free survival was 8.0 months in the placebo plus chemotherapy group and 9.4 months in the bevacizumab plus chemotherapy group (HR 0.83; 95% CI 0.72 to 0.95, p = 0.0023). The median overall survival was 19.9 months in the placebo plus chemotherapy group and 21.3 months in the bevacizumab plus chemotherapy group (HR 0.89; 95% CI 0.76 to 1.03, p = 0.0769).

3.7 The manufacturer reported that the difference in progression-free survival was statistically significant for bevacizumab versus placebo in the XELOX subgroup (HR 0.80, 97.5% CI 0.66 to 0.96, p = 0.0059) but not in the FOLFOX-4 subgroup (HR0.89, 97.5% CI 0.74 to 1.06, p = 0.1312).The manufacturer stated that this was because bevacizumab delivered no benefit to people in the P-FOLFOX-4 group who had received prior adjuvant treatment (HR 1.75, 97.5% CI 1.15 to 2.65, p value not reported), but delivered a benefit to people in the P-FOLFOX-4 group with no adjuvant therapy (HR 0.72, 97.5% CI 0.58 to 0.90, p value not reported). The manufacturer stated that this difference could be because the time between the end of adjuvant treatment and relapse was longer in the P-FOLFOX-4 group than in the other groups. When people who had received prior adjuvant treatment were excluded from analysis of the factorial study (from all four treatment arms, or from P- and B-FOLFOX-4 groups only or from the P-FOLFOX-4 group only), the hazard ratios for overall survival and for progression-free survival ranged from 0.83 to 0.85 (all p values < 0.03) and from 0.74 to 0.77 (all p values < 0.0001).

3.8 The manufacturer also conducted a post-hoc subgroup analysis of the impact of bevacizumab treatment on liver resection rates. This analysis suggested that bevacizumab improved liver resection rates, although this was not statistically significant. No analyses of KRAS or other mutations were submitted.

3.9 The rates of discontinuation in the NO16966 study were higher in the bevacizumab plus chemotherapy groups than in the placebo plus chemotherapy groups. In the 2 x 2 factorial part of the study 29% (203/699) of patients receiving bevacizumab plus chemotherapy and 47% (329/701) of patients receiving chemotherapy alone were treated until progression (despite the protocol allowing treatment to be continued until disease progression, in line with the SPC of bevacizumab).

3.10 In the NO16966 study the most common adverse events specific to bevacizumab were thromboembolic (7.8% venous thromboembolic events and 1.7% arterial thromboembolic events). Grade 3 or 4 hypertension, proteinuria and bleeding were more common in the bevacizumab arms (4% versus 0.8%, 3.5% versus 0.9% and 1.9% versus 1.5%). The incidence of serious and life-threatening (grade 3 and 4) adverse events was higher in the bevacizumab plus chemotherapy group than the placebo plus chemotherapy group and higher with FOLFOX-4 regimens than XELOX regimens (although FOLFOX-4 was associated with different adverse events than XELOX). The manufacturer stated that most adverse events were associated with cytotoxic chemotherapy, and the higher incidence in the bevacizumab arms was likely to be a consequence of a longer duration of chemotherapy for people receiving bevacizumab. No health-related quality of life data were collected in the NO16966 study.

3.11 The E3200 study was a phase III, multicentre, three-arm, randomised, open-label study. It compared B-FOLFOX-4 (n = 293) versus FOLFOX-4 (n = 292) versus bevacizumab alone (n = 244) in adult patients with advanced or metastatic colorectal cancer previously treated with a fluoropyrimidine and irinotecan, either separately or in combination. Following a data monitoring review 18 months after the start of the trial, the bevacizumab-alone arm was terminated because of poorer efficacy. Patients were stratified by ECOG performance status (0 versus 1 or more) and prior radiation therapy (yes versus no). The dosage of bevacizumab was 10 mg/kg every 2 weeks. Median overall survival was 10.8 months in the FOLFOX-4 group and 13 months in the B-FOLFOX-4 group (intention-to-treat analysis, HR 0.751, 95% CI 0.332 to 0.893, p = 0.0012). Median progression-free survival increased from 4.5 months with FOLFOX−4 to 7.5 months with B-FOLFOX-4 (HR 0.518, 97.5% CI 0.416 to 0.646, p < 0.0001).

3.12 The manufacturer produced a Markov model to estimate the cost effectiveness of bevacizumab plus FOLFOX and XELOX compared with FOLFOX and XELOX alone. The model had four distinct health states: first-line treatment, after first-line treatment without progression, progressed disease and death. It was assumed that all patients start in the first health state (first-line treatment)in accordance with the NO16966 study. The model had a cycle length of 1 month and the time horizon was 8 years (equivalent to life expectancy in the population of interest). A half-cycle correction was applied to the model. An NHS and personal social services (PSS) perspective was taken.

3.13 Costs were mainly derived from 2007–2008 national reference costs, BNF 57 and PSSRU (Personal Social Services Research Unit) 2008. FOLFOX-4 was used in the pivotal trial of bevacizumab but the manufacturer stated that FOLFOX-6 (that is the FOLFOX regimen delivered over 2 weeks but with only one infusion in the first 48 hours) is more commonly used in UK clinical practice. Therefore, the economic model was adjusted to include FOLFOX-6 by assuming similar efficacy as FOLFOX-4 but with reduced costs.

3.14 Treatment duration and dose intensity were based on the NO16966 study. Mean and median treatment durations (6 and 7 months respectively) were shorter in the NO16966 study than progression-free survival. Duration of treatment varied between treatment arms and was longer with the addition of bevacizumab and longer in the FOLFOX than in the XELOX arms. However, the model assumed that the treatment duration for oxaliplatin and bevacizumab was the same on the B-FOLFOX and B-XELOX arms. It was also assumed that treatment was given continuously, as in the NO16966 study, rather than intermittently. Kaplan–Meier estimates from the NO16966 study were used for progression-free and overall survival up to a median survival of 28 months. After this point, a Weibull probability distribution for overall survival and an exponential probability distribution of progression-free survival (based on average hazard for months 13–28) were used to model the tails. For overall survival, treatment effect was assumed to continue after the median follow-up period and this was further explored in the sensitivity analysis.

3.15 The manufacturer used utility values from ‘Cetuximab for the first-line treatment of metastatic colorectal cancer’ (NICE technology appraisal guidance 176). These utility values were taken from a randomised controlled trial comparing cetuximab plus FOLFIRI with FOLFIRI alone in first-line treatment of metastatic colorectal cancer and represented mean utility values from 42 people using the EQ–5D questionnaire; however only 37 people fully completed the questionnaires. A utility value of 0.77 was assigned to the first-line treatment health state, the average of all the EQ–5D completed responses over the study period (this assumption was used in NICE technology appraisal guidance 176). A utility value of 0.79 was assigned to the post first-line treatment (without disease progression) health state. This was based on expert opinion that people in this state will experience a higher quality of life than patients on first-line treatment, because of fewer adverse events, and their utility will be similar to a person aged 55–64 in the UK general population. A utility value of 0.68 was assigned to the progressed state, taken from a trial of cetuximab for the third-line treatment of metastatic colorectal cancer and using the Health Utility Index questionnaire (this assumption was used in NICE technology appraisal guidance 176).

3.16 The manufacturer submitted details of a patient access scheme for the first-line use of bevacizumab. The scheme involved supplying bevacizumab at a fixed price per cycle of treatment (£800 for 2−weekly cycles and £1200 for 3-weekly cycles), with bevacizumab being provided free after 12 months of treatment and with oxaliplatin being provided free of charge throughout. The manufacturer stated that it will take approximately 5 minutes per cycle for the pharmacist to update the scheme’s registry system. This equates to £4 per cycle. The Department of Health stated that it had concerns around the complexity of the patient access scheme and believed that the administration costs of the scheme would probably be greater than those set out by the manufacturer.

3.17 The manufacturer stated that the incremental cost-effectiveness ratios (ICERs) most relevant to the decision problem were B-XELOX compared with XELOX and B-FOLFOX-6 compared with FOLFOX-6. In the base-case analysis (that is, pooling of the initial two-arm study and the 2 x 2 factorial part of the study), B-XELOX produced an ICER of £34,170 per QALY gained when compared with XELOX (£82,098 per QALY gained without the patient access scheme). The corresponding ICER for B-FOLFOX-6 was £41,388 per QALY gained when compared with FOLFOX-6 (£94,989 per QALY gained without the patient access scheme). In the one-way sensitivity analysis ICERs were most sensitive to variations in the assumed treatment effect after the median follow-up period. In the probabilistic sensitivity analysis, the mean ICER for B-FOLFOX-6 compared with FOLFOX-6 was £41,519 per QALY gained (95% percentiles £31,136 and £67,859) and for B-XELOX compared with XELOX £34,217 (95% percentiles £26,597 and £52,960).

3.18 In response to a request from the ERG, the manufacturer provided a revised base-case analysis. There were 19.7% (n = 256) and 13.7% (n = 96) patients alive after median follow-up in the XELOX/FOLFOX and B-XELOX/B-FOLFOX arms, respectively. The ERG asked the manufacturer to use untruncated data to calculate the estimates of the parameters of the Weibull distribution. The manufacturer used Kaplan–Meier estimates of survival up to month 6 and then a Weibull distribution fitted to untruncated data after month 6 for progression-free survival and a Weibull distribution fitted to untruncated data for overall survival. The model also accounted for oxaliplatin wastage. The revised base-case ICER for B-XELOX was £35,912 per QALY gained when compared with XELOX and for B-FOLFOX-6 was £36,569 per QALY gained when compared with FOLFOX-6. In the one-way sensitivity analysis ICERs were not greatly influenced by variations in any of the parameters. In the probabilistic sensitivity analysis the mean ICER for the comparison of B-FOLFOX-6 with FOLFOX-6 was £36,907 per QALY gained and for the comparison of B-XELOX with XELOX the mean ICER was £36,205 per QALY gained (95% percentiles not provided).

3.19 The manufacturer submitted additional analyses using the revised modelling as suggested by the ERG. Using the 2 x 2 factorial part of the NO16966 study only, B-XELOX compared with XELOX was associated with an ICER of £48,111 per QALY gained. Removing the patients who had received prior adjuvant therapy reduced the ICER to £36,006 per QALY gained. If the XELOX and FOLFOX arms were not pooled then the ICER was £35,662 per QALY gained. Using the 2 x 2 factorial part of the NO16966 study, B-FOLFOX-6 compared with FOLFOX-6 was associated with an ICER of £39,771 per QALY gained. Removing patients who had received prior adjuvant therapy was associated with an ICER of £31,174 per QALY gained. When the XELOX and the FOLFOX arms were not pooled, then the ICER was £62,714 per QALY gained. The manufacturer did not provide an analysis using the 2 x 2 factorial part of the study, with patients who had received prior adjuvant therapy excluded and the XELOX and FOLFOX arms not pooled.

3.20 The manufacturer stated that currently only a minority (12%) of patients in the UK receive FOLFIRI as a first-line treatment for metastatic colorectal cancer and that most of these are people who have contraindications for oxaliplatin treatment. For completeness, the manufacturer provided a cost-effectiveness analysis comparing bevacizumab in combination regimens containing oxaliplatin with FOLFIRI. The efficacy of FOLFIRI was derived from a mixed-treatment comparison. A constant hazard ratio was applied to the extrapolated progression-free survival and overall survival curves of FOLFOX-4 to derive the survival curves for FOLFIRI. The treatment duration and the drug administration and adverse event costs for FOLFIRI were assumed to be equivalent to those for FOLFOX-4. B-XELOX compared with FOLFIRI was associated with an ICER of £9,192 per QALY gained, B-FOLFOX-6 compared with FOLFIRI was associated with an ICER of £38,835 per QALY gained and B-FOLFOX-4 compared with FOLFIRI was associated with an ICER of £58,575 per QALY gained.

3.21 The manufacturer provided a cost-effectiveness analysis of bevacizumab plus regimens including oxaliplatin in the second-line setting. Drug acquisition, administration and pharmacy costs per cycle were taken from the first-line analysis and multiplied by the mean number of cycles reported in the E3200 study. Costs associated with adverse events, third-line treatment and central venous access devices were not included in the second-line analysis and no discounting was applied. As a second-line treatment, B-FOLFOX-4 compared with FOLFOX-4 resulted in an ICER of £102,644 per QALY gained. The manufacturer stated that the larger ICERs reported in the second-line setting were mainly because of the higher doses of bevacizumab used and that bevacizumab could not be considered cost effective for second-line treatment.

3.22 The ERG stated that the manufacturer’s submission generally followed the NICE reference case. It also highlighted that adequate methods of randomisation and allocation concealment were reported in the NO16966 and E3200 studies. However, the ERG noted that the manufacturer focused on a comparison of oxaliplatin regimens with or without bevacizumab as first-line treatment. This differed from the scope, which included irinotecan chemotherapy regimens without bevacizumab as a comparator and bevacizumab as part of second-line treatment.

3.23 The ERG expressed concerns about pooling data from the initial two-arm part and the 2 x 2 factorial part of the NO16966 study. It stated that this was inappropriate because of the different designs of the two parts of the study. The European Medicines Agency (EMEA) in their assessment report for bevacizumab also expressed concerns about the appropriateness of this method of pooling and it noted that this pooled analysis was specified in the protocol in case of borderline significance in progression-free survival in the 2 x 2 study. The EMEA therefore questioned the validity of the results derived from the pooled analysis. The ERG also noted that the number of participants reported as Caucasian and the number of people with ECOG performance status of 0 were 10% greater in the 2 x 2 factorial part of the study than the initial two-arm part. The ERG further highlighted that there was a difference in terms of the overall survival benefit associated with bevacizumab in the primary pooled analysis (overall survival significantly improved) and in the pooled analysis based on the 2 x 2 factorial design only (overall survival not significantly improved). The ERG suggested that this difference might be because of the imbalance of people who have slower rate of progression and the lack of statistical power to assess overall survival.

3.24 Additional analyses were provided by the manufacturer using only the 2 x 2 factorial design (B-XELOX and B-FOLFOX-4 combined compared with P-XELOX and P-FOLFOX-4 combined). The ERG suggested that the most appropriate analysis was one using the 2 x 2 factorial design of the NO16966 study with XELOX and FOLFOX not pooled and people who had received prior adjuvant therapy excluded. However, this analysis was not provided by the manufacturer. The ERG therefore suggested that the next most appropriate ICER was the one using data from the 2 x 2 factorial design of the NO16966 study with the XELOX and FOLFOX arms pooled and people with prior adjuvant therapy excluded, with Kaplan–Meier estimates up to month 6 and then the Weibull distribution used for extrapolating progression-free survival, and Kaplan–Meier estimates up to month 28 with the Weibull distribution then used for extrapolating overall survival. With this analysis the ERG produced an ICER for B-XELOX of £36,354 per QALY gained compared with XELOX and £31,452 per QALY gained for B-FOLFOX-6 compared with FOLFOX-6. The results of the one-way sensitivity analyses showed that the ICERs were not greatly influenced by any of the parameter changes.

3.25 The ERG noted that the duration of chemotherapy treatment was relatively short (6 months) despite the protocol allowing treatment until disease progression or unacceptable adverse events. This was also contrary to the SPC. Although the ERG agreed that the manufacturer’s economic model was an accurate replication of the NO16966 study, the ERG suggested that in clinical practice treatment with drugs other than oxaliplatin (5-fluorouracil, capecitabine, bevacizumab) might continue after oxaliplatin regimens stopped. The ERG conducted an exploratory analysis that examined the impact on ICERs of stopping oxaliplatin 1 month before the other treatment components. Under this scenario, costs in the XELOX and FOLFOX-6 arms were reduced. In the B-XELOX and B-FOLFOX regimens, the cost of oxaliplatin remained the same because oxaliplatin is free for these groups. It was also assumed that no change in incremental survival occurred. In this analysis the ICERs using the 2 x 2 factorial part of the study were increased from £36,354 to £43,511 per QALY gained when B-XELOX was compared with XELOX and from £31,452 to £39,478 per QALY gained when B-FOLFOX-6 was compared with FOLFOX-6. The ERG also examined the impact of increasing the duration of bevacizumab treatment by 1 month on the ICERs using the 2 x 2 factorial part of the study. It was assumed that no change in survival occurred and the treatment duration of the other components remained the same. In this analysis the ICERs increased from £36,354 to £47,312 per QALY gained when B-XELOX was compared with XELOX and from £31,452 to £41,692 per QALY gained when B-FOLFOX-6 was compared with FOLFOX-6.

3.26 The ERG stated that it was not possible to adequately check the sources considered for determining the utility values because the references were incomplete. The ERG suggested that the utility values from the guidance on ‘Cetuximab for the first-line treatment of metastatic colorectal cancer’ (NICE technology appraisal guidance 176) could be relevant to people receiving bevacizumab. However, the ERG also commented that the assumption that the utility value of the health state after first-line treatment (that is, off treatment but not yet progressed) is similar to that of people aged 55–64 in the UK general population is unrealistic. This is because after 6 months of chemotherapy, people are often less mentally and physically fit than those of the same age in the general population. In addition, the ERG noted that the utility value for the health state first-line treatment (that is, 0.77) might be an overestimate. This is because the utility value in the UK general population of the same age group is 0.79.The ERG further noted that the model did not take into account the fact that XELOX regimens might be associated with higher health-related quality of life than FOLFOX regimens because the former are considered more convenient. The ERG performed an exploratory analysis that investigated the impact on ICERs of decreasing the utility values by 20%. This decrease in utility values had a large impact on the ICERs. Using the 2 x 2 factorial part of the study with patients with prior adjuvant therapy excluded, the ICER for B-XELOX increased from £36,354 to £45,433 per QALY gained when compared with XELOX and the ICER for B-FOLFOX-6 increased from £31,452 to £39,315 per QALY gained when compared with FOLFOX-6.

3.27 Full details of all the evidence are in the manufacturer’s submission and the ERG report, which are available from www.nice.org.uk/TAXXX

4 Consideration of the evidence

4.1 The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of bevacizumab, having considered evidence on the nature of metastatic colorectal cancer and the value placed on the benefits of bevacizumab by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.

4.2 The Committee then discussed possible comparators used in the UK for the first-line treatment of metastatic colorectal cancer in clinical practice. It noted that the manufacturer, based on a market research analysis, and the ERG considered that the standard comparators were combination chemotherapy regimens including oxaliplatin as these are most commonly used in the UK. However, the ERG commented that FOLFIRI could be also considered a relevant comparator because there is previous NICE guidance (NICE technology appraisal guidance 93) recommending its use. However, the Committee heard from clinical specialists that the use of FOLFIRI as a first-line treatment is decreasing in the UK. The clinical specialists highlighted that most patients with metastatic colorectal cancer who are being treated with combination chemotherapy will receive oxaliplatin-containing regimens because these regimens are associated with less marrow suppression and less diarrhoea than FOLFIRI, although there is an increased risk of significant sensory neuropathy. The clinical specialists and patient experts also stated that oxaliplatin-containing regimens are used for patients with liver metastases that are potentially resectable. In addition, the clinical specialists and patient experts highlighted that oral capecitabine is often preferred by patients to intravenous 5-flourouracil. However, the risk of diarrhoea increases when irinotecan is given in combination with capecitabine; therefore if capecitabine is given, it is combined with oxaliplatin (that is, XELOX) rather than with irinotecan. The Committee thus understood that most of the patients who receive first-line FOLFIRI do so because of contraindications to oxaliplatin, such as a pre-existing neuropathy, or a short period elapsing between the end of adjuvant chemotherapy with oxaliplatin and the development of recurrent disease. The Committee therefore concluded that FOLFIRI should be excluded as a comparator to bevacizumab given in combination with oxaliplatin-containing regimens.

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 study and a later 2 x 2 factorial study (6 arms in total). Data from the initial two-arm study and the later 2 x 2 factorial 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 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: the number of participants reported as Caucasian and the proportion of people with ECOG performance status of 0 were 10% higher in the 2 x 2 factorial part of the study. The Committee further noted that the EMEA in their assessment report for bevacizumab also questioned the validity of the results derived using this method of pooling. Therefore, the Committee considered that the validity of the results from the pooled analysis was not acceptable. The Committee then noted that the secondary analysis (of the 2 x 2 factorial part of the study only) showed a statistically significant improvement in progression-free survival of 1.4 months, but that the difference in overall survival was no longer statistically significant.

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 then 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 people 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 unknown.

4.5 The Committee then 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 approximately 3 months in the second-line setting. The Committee also noted that no evidence of bevacizumab compared with FOLFIRI as a second-line treatment had been presented by the manufacturer.

4.6 The Committee noted that a significant percentage of participants 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 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 benefit in terms of effectiveness compared with regimens without bevacizumab. The Committee felt that bevacizumab was clinically effective as a 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 analysis 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 experts that FOLFOX-6 offers similar clinical outcomes to FOLFOX-4. In addition, it heard that FOLFOX-6 is more commonly used in the 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 frequently intermittent treatment and that treatment often restarts 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. Therefore, the Committee concluded that as intermittent treatment is commonly used in the UK, the economic model did not reflect an important part of UK clinical practice in the first-line chemotherapy of metastatic colorectal cancer.

4.10 The Committee then discussed the base-case cost-effectiveness estimate provided by the manufacturer which incorporated the patient access scheme proposed 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 ERG stated that although the manufacturer had not fitted the distributions exactly as suggested, the methods used for the revised base case were appropriate. 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 heard from the ERG that the most plausible model assumption(s) for cost effectiveness would use the 2 x 2 factorial design of the NO16966 study with XELOX and FOLFOX arms not pooled and people who had received prior adjuvant therapy excluded. The Committee noted that this analysis had not been provided by the manufacturer. It considered that this analysis could potentially account for the previously noted imbalance in prognostic factors based on prior adjuvant treatment. The Committee considered that the effect of not pooling the XELOX and FOLFOX arms was unclear, but that it would affect the ICERs. However, the Committee noted this would be a post-hoc analysis. The Committee considered that, of all of the analyses presented, that the ICER with the most plausible assumptions was the one using data from the 2 x 2 factorial design of the NO16966 study with the XELOX and FOLFOX arms pooled, people with prior adjuvant therapy excluded, and with Kaplan–Meier estimates up to month 6 and then the Weibull distribution used for extrapolating progression-free survival, and Kaplan–Meier estimates up to month 28 and then the Weibull distribution used for extrapolating overall survival. With this analysis, B-XELOX compared with XELOX produced an ICER of £36,400 per QALY gained (£92,700 without the patient access scheme) and B-FOLFOX-6 compared with FOLFOX-6 resulted in an ICER of £31,500 per QALY gained (£96,700 without the patient access scheme). See section 4.14 for further details of the Committee’s considerations of the patient access scheme.

4.12 The Committee noted that the ICER 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 experts stated that, if a continuous chemotherapy policy was being practised, treatment with non-oxaliplatin components (such as bevacizumab) may continue after oxaliplatin treatment stops. The Committee noted that stopping oxaliplatin treatment 1 month before the other treatment agents or receiving bevacizumab for 1 month after oxaliplatin treatment had greatly 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 outweigh any additional survival benefits of bevacizumab, given its 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 would be expected to further increase the ICER.

4.13 The Committee then 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 are inconsistent and there is a paucity of data. The Committee noted that the utility values assigned to the health states first-line treatment and post first-line treatment without disease progression (0.77 and 0.79, respectively) were high because they were similar to the utility values of people in the UK general population aged 55–64 and 65–74 rather than people with metastatic colorectal cancer . The Committee heard from the clinical specialists and patient experts that the adverse events associated with chemotherapy, although manageable, would continue for at least 4–6 weeks after stopping treatment and that this would affect health-related quality of life. The Committee agreed that the utility values seemed to be high and this further increased the uncertainty associated with the base-case ICER.

4.14 The Committee then discussed the details of the patient access scheme. The Committee understood that intermittent treatment is commonly used in UK clinical practice and chemotherapy treatment is often restarted if there are signs of disease progression. The Committee understood that in these circumstances (that is with any signs of disease progression) the patient access scheme would no longer apply. The Committee then considered the impact of the patient access scheme on the ICERs. It noted that when the patient access scheme was applied then the ICERs (as detailed in section 4.11) were decreased from £92, 700 to £36,400 per QALY gained for B-XELOX compared with XELOX and from £96,700 to £31,500 per QALY gained for B-FOLFOX-6 compared with FOLFOX-6. Nevertheless, the Committee understood from the ERG that the ICERS for both B-XELOX and B-FOLFOX increased if bevacizumab treatment continued beyond that of oxaliplatin. It also noted that it was not clear how the three components of the patient access scheme contributed to the reduction in the ICERs. Thus with all the considerations set out above, especially in relation to current clinical practice in the UK, it was not clear whether the patient access scheme would result in such an apparent improvement in cost effectiveness. The Committee also noted that there was uncertainty around the administration costs of the scheme. It 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. This therefore meant that the administrative costs were likely to be significantly greater than those presented by the manufacturer. The Committee agreed that the impact of the scheme in practice was uncertain and that incorporating higher administration costs would increase the ICER estimates.

4.15 The Committee further noted that the administration costs of B−FOLFOX and B-XELOX were assumed to be very similar to the administration costs of FOLFOX and XELOX. The Committee considered that the addition of a bevacizumab infusion to either XELOX or FOLFOX would incur greater additional administration costs than those assumed by the manufacturer. The Committee concluded that if the higher administration costs were included, then this would result in an increase in the ICER estimates. This increased the Committee’s uncertainty surrounding the ICERs presented.

4.16 The Committee concluded that the cost-effectiveness estimates of bevacizumab as a first-line treatment of metastatic colorectal cancer (£36,400 and £31,500 per QALY gained) were at the lowest end of a range and plausible adjustments to the key model inputs would increase these ICERs substantially. The ICERs were therefore associated with a great deal of uncertainty. The Committee therefore concluded that bevacizumab in combination with oxaliplatin-containing regimens could not be recommended as a cost-effective use of NHS resources for the first-line treatment of metastatic colorectal cancer.

4.17 The Committee then reviewed the cost-effectiveness analysis of bevacizumab in combination with oxaliplatin-containing regimens as 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 as acceptable uses of NHS resources. In addition, the manufacturer stated that a cost-effective case for bevacizumab as a second-line treatment could not be presented. The Committee therefore concluded that bevacizumab in combination with oxaliplatin-containing regimens could not be recommended as a cost-effective use of NHS resources.

5 Implementation

5.1 The Secretary of State and the Welsh Assembly Minister for Health and Social Services have issued directions to the NHS on implementing NICE technology appraisal guidance. When a NICE technology appraisal recommends use of a drug or treatment, or other technology, the NHS must provide funding and resources for it within 3 months of the guidance being published. If the Department of Health issues a variation to the 3-month funding direction, details will be available on the NICE website. The NHS is not required to fund treatments that are not recommended by NICE.

5.2 NICE has developed tools to help organisations put this guidance into practice (listed below). These are available on our website (www.nice.org.uk/TAXXX). [NICE to amend list as needed at time of publication]

• Slides highlighting key messages for local discussion.
• Costing report and costing template to estimate the savings and costs associated with implementation.
• Implementation advice on how to put the guidance into practice and national initiatives that support this locally.
• A costing statement explaining the resource impact of this guidance.
• Audit support for monitoring local practice.

6 Related NICE guidance

Published

• Cetuximab for the first-line treatment of metastatic colorectal cancer. NICE technology appraisal 176 (2009). Available from www.nice.org.uk/TA176
• Cetuximab for the treatment of metastatic colorectal cancer following failure of oxaliplatin-containing chemotherapy (terminated appraisal). NICE technology appraisal 150 (2008). Available from www.nice.org.uk/TA150
• Bevacizumab and cetuximab for the treatment of metastatic colorectal cancer. NICE technology appraisal guidance 118 (2007). Available from www.nice.org.uk/TA118
• Capecitabine and oxaliplatin in the adjuvant treatment of stage III (Dukes’ C) colon cancer. NICE technology appraisal guidance 100 (2006). Available from www.nice.org.uk/TA100
• Irinotecan, oxaliplatin and raltitrexed for the treatment of advanced colorectal cancer (review of technology appraisal 33). NICE technology appraisal guidance 93 (2005). Available from www.nice.org.uk/TA93
• Improving outcomes in colorectal cancers - manual update. NICE cancer service guidance (2004). Available from www.nice.org.uk/csgcc
• Guidance on the use of capecitabine and tegafur with uracil for metastatic colorectal cancer. NICE technology appraisal guidance 61 (2003). Available from www.nice.org.uk/TA61

Under development

NICE is developing the following guidance (details available from www.nice.org.uk):

• Diagnosis and management of colorectal cancer. NICE clinical guideline (publication expected July 2011).

7 Proposed date for review of guidance

7.1 NICE proposes that the guidance on this technology is considered for review by the Guidance Executive in November 2012. NICE welcomes comment on this proposed date. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.

Peter Clark
Chair, Appraisal Committee
November, 2009

Appendix A: Appraisal Committee members and NICE project team

A Appraisal Committee members

The Appraisal Committee is one of NICE’s standing advisory committees. Its members are appointed for a 3-year term. A list of the Committee members who took part in the discussions for this appraisal appears below. The Appraisal Committee meets four times a month except in December, when there are no meetings. There are four Appraisal Committees, each with a chair and vice chair. Each Committee considers its own list of technologies, and ongoing topics are not moved between Committees.

Committee members are asked to declare any interests in the technology to be appraised. If it is considered there is a conflict of interest, the member is excluded from participating further in that appraisal.

The minutes of each Appraisal Committee meeting, which include the names of the members who attended and their declarations of interests, are posted on the NICE website.

Dr Brian Buckley
Lay member

Professor Usha Chakravarthy
Professor of Ophthalmology and Vision Sciences, Queen’s University Belfast

Professor Peter Clark
Consultant Medical Oncologist, Clatterbridge Centre for Oncology, Liverpool

Dr Ian Davidson
Lecturer in Rehabilitation, The University of Manchester

Dr Martin Duerden
Medical Director, Conwy Local Health Board

Dr Alexander Dyker
Consultant Physician, Wolfson Unit of Clinical Pharmacology, Newcastle

Dr Jon Fear
Consultant in Public Health Medicine, Head of Healthcare Effectiveness NHS Leeds

Miss Paula Ghaneh
Senior Lecturer and Honorary Consultant Surgeon, University of Liverpool

Alison Hawdale
Lay member

Professor John Hutton
Professor of Health Economics, University of York

Professor Peter Jones
Pro Vice Chancellor for Research and Enterprise, Professor of Statistics, Keele University

Dr Steven Julious
Senior Lecturer in Medical Statistics, University of Sheffield

Dr Vincent Kirkbride
Consultant Neonatologist, Regional Neonatal Intensive Care Unit, Sheffield

Professor Jonathan Michaels
Professor of Vascular Surgery, University of Sheffield

Dr Neil Milner
General Medical Practitioner, Tramways Medical Centre, Sheffield

Professor Oluwafemi Oyebode
Professor of Psychiatry and Consultant Psychiatrist, The National Centre for Mental Health, Birmingham

Mr Mike Pinkerton
Chief of Business Development, Rotherham NHS Foundation Trust

Dr Phillip Rutledge
General Practitioner and Consultant in Medicines Management, NHS Lothian

Mr Paddy Storrie
Lay member

Mr Mike Wallace
Health Economics and Reimbursement Director, Johnson & Johnson Medical Ltd

Dr Lok Yap
Consultant in Acute Medicine and Clinical Pharmacology, Whittington Hospitals NHS Trust, London

B NICE project team

Each technology appraisal is assigned to a team consisting of one or more health technology analysts (who act as technical leads for the appraisal), a technical adviser and a project manager.

Panagiota Vrouchou
Technical Lead

Rebecca Trowman
Technical Adviser

Philip Higham
Project Manager

Appendix B: Sources of evidence considered by the Committee

A The Evidence Review Group (ERG) report for this appraisal was prepared by School of Health and Related Research (ScHARR), The University of Sheffield:

• Whyte S, Pandor A, Stevenson M, et al., Bevacizumab in combination with fluoropyrimidine-based chemotherapy for the first-line treatment of metastatic colorectal cancer, September 2009

B The following organisations accepted the invitation to participate in this appraisal as consultees and commentators. They were invited to comment on the draft scope, the ERG report and the appraisal consultation document (ACD). Organisations listed in I were also invited to make written submissions. Organisations listed in II and III had the opportunity to give their expert views. Organisations listed in I and II also have the opportunity to appeal against the final appraisal determination.

I Manufacturer/sponsor:

• Roche Products

II Professional/specialist and patient/carer groups:

• Association of Surgeons of Great Britain and Ireland
• Cancer Research UK
• Royal College of Nursing
• Royal College of Physicians, Medical Oncology Joint Special Committee
• Beating Bowel Cancer
• Bowel Cancer UK
• Macmillan Cancer Support

III Other consultees:

• Department of Health
• NHS Manchester
• Welsh Assembly Government

IV Commentator organisations (did not provide written evidence and without the right of appeal):

• Department of Health, Social Services and Public Safety for Northern Ireland
• Medicines and Healthcare products Regulatory Agency
• NHS Quality Improvement Scotland
• Scottish Medicines Consortium
• Medac UK
• Merck Serono
• Pfizer
• Roche Products
• Sanofi-Aventis
• Institute of Cancer Research
• MRC Clinical Trials Unit
• National Institute for Health Research Health Technology Assessment Programme
• School of Health and Related Research (ScHARR)
• National Collaborating Centre for Cancer

C The following individuals were selected from clinical specialist and patient expert nominations from the non-manufacturer/sponsor consultees and commentators. They gave their expert personal view on bevacizumab in combination with oxaliplatin and either 5-fluorouracil or capecitabine for the treatment of metastatic colorectal cancer by attending the initial Committee discussion and providing written evidence to the Committee. They are invited to comment on the ACD.

• Professor Daniel Hochhauser nominated by the Royal College of Physicians on behalf of NCRI/RCP/RCR/ACP/JCCO – clinical specialist
• Dr Rob Glynne-Jones nominated by Bowel Cancer UK – clinical specialist
• Ian Beaumont (Director of Communications, Bowel Cancer UK) nominated by Bowel Cancer UK
• Barbara Moss nominated by Bowel Cancer UK – patient expert