Colorectal cancer (first line) - cetuximab: appraisal consultation document

Appraisal consultation document

Cetuximab for the first-line treatment of metastatic colorectal cancer

Background
Key dates
Appraisal Committee's preliminary recommendations
The technology
The manufacturer's submission
Consideration of the evidence
Implementation
Proposed recommendations for further research
Related guidance
Proposed date for review of guidance
Appendix A: Appraisal Committee members and NICE project team
Appendix B: Sources of evidence considered by the Committee

Background

The Department of Health has asked the National Institute for Health and Clinical Excellence (NICE or the Institute) to conduct a single technology appraisal (STA) of cetuximab for the first-line treatment of metastatic colorectal cancer and provide guidance on its use to the NHS in England and Wales. The Appraisal Committee has considered the evidence submitted by the manufacturer, the views of non-manufacturer consultees and commentators, clinical specialists and patient experts, and the comments received on the first appraisal consultation document. The Committee has developed preliminary recommendations on the use of cetuximab for the first-line treatment of metastatic colorectal cancer.

This document has been prepared for consultation with the formal consultees. It summarises the evidence and views that have been considered and sets out the preliminary recommendations developed by the Committee. The Institute is now inviting comments from the formal consultees in the appraisal process. This document should be read in conjunction with the evidence base for this appraisal (the evaluation report) which is available from www.nice.org.uk

Note that this document does not constitute the Institute's formal guidance on this technology. The recommendations made in section 1 are preliminary and may change after consultation.

The process the Institute will follow after the consultation period is summarised below. For further details, see the ‘Guide to the single technology appraisal process'.

  • The Appraisal Committee will meet again to consider the original evidence and this appraisal consultation document in the light of the views of the formal consultees.
  • At that meeting, the Committee will also consider comments made on the document by people who are not formal consultees in the appraisal process.
  • After considering feedback from the consultation process, the Committee will prepare the final appraisal determination (FAD) and submit it to the Institute.
  • Subject to any appeal by consultees, the FAD may be used as the basis for the Institute's guidance on the use of the appraised technology in the NHS in England and Wales.

top

The key dates for this appraisal are:

Closing date for comments: 20 February 2009

Fourth Appraisal Committee meeting: 1 April 2009

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. The key dates for this appraisal are:

Closing date for comments: 20 February 2009

Fourth Appraisal Committee meeting: 1 April 2009

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.

Note that this document does not constitute the Institute's formal guidance on this technology. The recommendations made in Section 1 are preliminary and may change after consultation.

top

1 Appraisal Committee's preliminary recommendations
1.1 The Committee is minded not to recommend cetuximab, within its licensed indication, for the first-line treatment of metastatic colorectal cancer.
1,2 The Committee recommends that NICE requests further clarification from the manufacturer, which should be made available for the next Appraisal Committee meeting, on the issues set out in sections 1.3, 1.4 and 1.5.
1.3

The effect of incorporating the following factors into the economic analysis of cetuximab in combination with FOLFOX compared with FOLFOX alone, and of cetuximab in combination with FOLFIRI compared with FOLFOX alone:

  • Stopping treatment with cetuximab at 16 weeks (when people are assessed for curative liver resection) for all people in the analysis, including people who have an unsuccessful liver resection and those who do not undergo liver resection.
  • Alternative relative differences in the rates of resection between the two treatment groups, using liver resection rates of 30%, 35% and 43% for cetuximab plus FOLFOX compared with 22% for FOLFOX alone.
  • The individual and cumulative effect on cost effectiveness of each of these factors should be presented over a lifetime horizon. This should incorporate a 5% failure rate for liver resection in both treatment groups, and include the application of the proposed patient access scheme rebate of 16% of the cost of treatment with cetuximab as available.
1.4 Further clarification should be provided on the identification of the codes used to calculate the costs of liver resection surgery used in the economic analysis.
1.5 The effect on cost effectiveness of using alternative estimates of the costs of liver resection for people with metastatic colorectal cancer that accurately reflect UK clinical practice should be provided. Sensitivity analyses should be performed around this parameter. These analyses should be carried out in combination with the factors detailed in section 1.3.

top

2 The technology
2.1

Cetuximab (Erbitux, Merck Serono) is a recombinant monoclonal antibody that blocks the human epidermal growth factor receptor (EGFR) and therefore inhibits the proliferation of cells that depend on EGFR activation for growth. Cetuximab is indicated for the treatment of patients with EGFR-expressing, Kirsten rat sarcoma (KRAS) wild-type metastatic colorectal cancer:

  • in combination with chemotherapy
  • as a single agent in patients who have failed oxaliplatin- and irinotecan-based therapy and who are intolerant to irinotecan.
2.2 One common adverse effect of cetuximab treatment is the development of skin reactions, which occur in more than 80% of patients and mainly present as an acne-like rash or, less frequently, as pruritus, dry skin, desquamation, hypertrichosis or nail disorders (for example, paronychia). The majority of skin reactions develop within the first 3 weeks of treatment. The summary of product characteristics (SPC) notes that if a patient experiences a grade 3 or 4 skin reaction, cetuximab treatment must be stopped, with treatment being resumed only if the reaction resolves to grade 2. Other common adverse effects of cetuximab include mild or moderate infusion-related reactions such as fever, chills, nausea, vomiting, headache, dizziness or dyspnoea that occur soon after the first cetuximab infusion. For full details of adverse effects and contraindications, see the SPC.
2.3 The acquisition cost of cetuximab is £136.50 for a 5-mg/ml, 20-ml vial (excluding VAT; ‘British national formulary' [BNF] edition 56). The initial dose is 400 mg/m2 body surface area. Subsequent weekly doses are 250 mg/m2 each. Cetuximab treatment is recommended until there is progression of the underlying disease. Assuming vial wastage, an average person with a body surface area of 1.75 m2 would receive seven vials per loading dose and five vials per maintenance dose, equating to a cost of £955.50 for the loading dose and £682.50 for each maintenance dose. Patients in the key clinical trials received cetuximab for approximately 8 months, equating to an average total drug acquisition cost of £22,796 per patient. Costs may vary in different settings because of negotiated procurement discounts.

top

3 The manufacturer's submission
   
  The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of cetuximab and a review of this submission by the Evidence Review Group (ERG; appendix B).
3.1 In the submission, the manufacturer compared a regimen of cetuximab and 5-fluorouracil (5-FU) plus folinic acid plus irinotecan (FOLFIRI) with the FOLFIRI chemotherapy regimen alone, and a regimen of cetuximab and 5-FU plus folinic acid plus oxaliplatin (FOLFOX) with the FOLFOX chemotherapy regimen alone.
3.2

The main evidence on the efficacy of cetuximab in the manufacturer's submission was derived from two randomised controlled trials (RCTs):

  • CRYSTAL (n = 1198), a phase III, multicentre, open-label RCT, which compared cetuximab plus FOLFIRI with FOLFIRI alone, and examined progression-free survival as the primary outcome.
  • OPUS (n = 336), a phase II, multicentre, open-label RCT, which compared cetuximab plus FOLFOX with FOLFOX alone, and examined response rate as the primary outcome.

The participants in both trials were patients with previously untreated metastatic colorectal cancer with non-resectable metastases and an Eastern Cooperative Oncology Group (ECOG) performance-status score of less than or equal to 2 at study entry. The planned treatment duration in both trials was until demonstration of progressive disease by computed tomography (CT) or magnetic resonance imaging (MRI), withdrawal of consent, or occurrence of unacceptable adverse events (CRYSTAL only) or toxicity (OPUS only).

3.3 In the submission, the manufacturer presented data for the full analysis set (people with KRAS wild-type metastatic colorectal cancer and KRAS mutations) for both trials. However, the main data in the submission focused on the post hoc analysis of the KRAS wild-type subgroup (n = 348 for the CRYSTAL trial; n = 134 for the OPUS trial), which was requested by the regulatory agencies and reflects the licensed indication.
3.4 The results of the full analysis set for the CRYSTAL study showed an improved progression-free survival for cetuximab in combination with FOLFIRI compared with FOLFIRI alone (p = 0.0479) with a hazard ratio (HR) of 0.85 (95% confidence interval [CI] 0.726 to 0.998). In the manufacturer's additional evidence, the overall survival (median follow-up 30 months) was 19.9 months (95% CI 18.5 to 21.3) for cetuximab plus FOLFIRI compared with 18.6 months (95% CI 16.6 to 19.8) for FOLFIRI alone (HR = 0.93, 95% CI 0.81 to 1.07). This was not statistically significant (p = 0.30).
3.5 In the OPUS study, for the full analysis set, the best overall response rate for cetuximab in combination with FOLFOX was 45.6% compared with 36.0% for FOLFOX alone. The chance for a best overall response of either complete response (CR) or partial response (PR) increased by 50% in the cetuximab plus FOLFOX group, which was not statistically significant (p = 0.064).
3.6 The results of the CRYSTAL trial for the KRAS wild-type subgroup showed a statistically significant increase in progression-free survival with a median progression-free survival of 9.9 months (95% CI 8.7 to 14.6) for cetuximab plus FOLFIRI compared with 8.7 months (95% CI 7.4 to 9.9) for FOLFIRI alone (HR = 0.684, p = 0.0167). Cetuximab plus FOLFIRI was also associated with a statistically significant increase in response rate compared with FOLFIRI alone (59.3%, 95% CI 51.6 to 66.7 versus 43.2%, 95% CI 35.8 to 50.9, respectively; p = 0.0028). The rate of potentially curative liver metastases resection for cetuximab plus FOLFIRI was 3.5% (n = 6) compared with 2.3% (n = 4) for FOLFIRI alone (statistical significance was not reported for this outcome). In the additional evidence, the overall survival (median follow-up 30 months) was 24.9 months (95% CI 22.2 to 27.8) for cetuximab plus FOLFIRI compared with 21.0 months (95% CI 19.2 to 25.7) for FOLFIRI alone (HR = 0.84, 95% CI 0.64 to 1.11). This was not statistically significant (p = 0.22).
3.7 The OPUS trial results for the KRAS wild-type subgroup also showed a statistically significant increase in progression-free survival, with a median progression-free survival of 7.7 months (95% CI 7.1 to 12.0) for cetuximab plus FOLFOX compared with 7.2 months (95% CI 5.6 to 7.4) for FOLFOX alone (HR = 0.570, p = 0.0163). Cetuximab plus FOLFOX was also associated with a statistically significant increase in response rate compared with FOLFOX alone (60.7%, 95% CI 47.3 to 72.9 versus 37.0%, 95% CI 26.0 to 49.1, p = 0.011). The rate of potentially curative liver metastases resection for cetuximab plus FOLFOX was 11.5% (n = 7) compared with 4.1% (n = 3) for FOLFOX alone (statistical significance was not reported for this outcome).
3.8 The CRYSTAL trial also reported results for people in the KRAS wild-type subgroup who had metastatic disease confined to the liver (n = 67). There was an increase in progression-free survival for cetuximab plus FOLFIRI compared with FOLFIRI alone, with a median progression-free survival of 14.6 months and 9.5 months, respectively. However, this difference was not statistically significant (HR = 0.724, p = 0.437). Cetuximab plus FOLFIRI was associated with a statistically significant increase in response rate compared with FOLFIRI alone (77.1%, 95% CI 59.9 to 89.6 versus 50.0%, 95% CI 31.9 to 68.1, p = 0.0246).
3.9 Quality of life was assessed in the CRYSTAL study using the QLQ‑C30 and the EuroQol (EQ-5D) questionnaires. In the KRAS wild-type subgroup, some measures of the QLQ-C30 showed statistically significant differences between the two treatment arms in favour of the FOLFIRI-only group (mean change from baseline to worst physical functioning score, and dyspnoea scores). Only 37 patients completed evaluable baseline EQ-5D questionnaires; therefore, no formal statistical analyses were performed. A summary utility value was calculated for all patients, pooling all values at each visit. This provided a utility value representative of patients receiving first-line chemotherapy of 0.77 (standard deviation 0.22, n = 128). The OPUS study did not collect any quality of life data.
3.10 The majority of adverse events in the KRAS wild-type subgroup were in line with the existing product labelling for cetuximab or 5‑FU with folinic acid plus irinotecan or oxaliplatin. In the CRYSTAL trial, the adverse events that occurred more frequently in the cetuximab plus FOLFIRI group compared with the FOLFIRI-only group (a difference of 5% or more between groups) were neutropenia, constipation, dyspepsia, dyspnoea, dysgeusia, injection site reaction, erythema, hypotension, hypertrichosis and cheilitis. In the KRAS wild-type population of both the CRYSTAL and OPUS trials, the frequency of palmar-plantar erythrodysaesthesia syndrome was higher in the cetuximab plus FOLFIRI group compared with the FOLFIRI-only group (16.2% versus 2.8% [28 versus 5 patients]) and in the cetuximab plus FOLFOX group compared with the FOLFOX-only group (13.1% versus 4.1% [8 versus 3 patients]).
3.11 The manufacturer developed a semi-Markov model to simulate the disease progression and survival of a cohort of patients with EGFR-expressing, KRAS wild-type metastatic colorectal cancer throughout first and subsequent lines of treatment (second- and third-line) including longer-term survival after successful curative surgery. The model had a cycle length of 1 week and estimated costs and benefits over a lifetime horizon (approximately 23 years).
3.12

The analysis looked at two treatment strategies: cetuximab plus FOLFIRI compared with FOLFIRI alone, and cetuximab plus FOLFOX compared with FOLFOX alone. The economic evaluation focused on a population with the following characteristics:

  • Good performance-status score (the majority of KRAS wild-type patients in the CRYSTAL and OPUS trials [96% and 90%, respectively] had an ECOG performance-status score of 0 or 1, so this was reflected in the modelled cohort).
  • Suitable for irinotecan- or oxaliplatin-containing chemotherapy.
  • Metastatic disease confined to the liver, excluding people whose liver metastases were resectable at presentation.
3.13 The analysis assessed the impact of cetuximab in combination with FOLFIRI or FOLFOX on the rates of potentially curative resection among people whose tumours became resectable during first-line treatment. The first-line treatment regimens were as set out in the CRYSTAL and OPUS trial protocols and administered as recorded in the trial data sets. The second-line treatment regimens of FOLFIRI or FOLFOX were taken from the published evidence, dependent on first-line treatment. If FOLFIRI was used in the first line, then FOLFOX was used in the second line, and vice versa. In the third-line setting, people received best supportive care. In the model, people were considered tumour free following successful curative resection. Based on other published evidence, people were assumed to have an increase in their estimated mean life expectancy of 4.76 years, with an observed median survival time of 3.23 years.
3.14 Subsequent lines of treatment were modelled because neither clinical trial had generated mature overall survival data at the time of the manufacturer's original submission. Extrapolation techniques were used in the economic model to estimate survival benefits in the base case. These were varied in the scenario analyses.
3.15 The manufacturer considered the liver resection rates from the CRYSTAL and OPUS trials (3.5% [n = 6] for cetuximab plus FOLFIRI versus 2.3% [n = 4] for FOLFIRI alone; 11.5% [n = 7] for cetuximab plus FOLFOX versus 4.1% [n = 3] for FOLFOX alone) to be low compared with current clinical practice in the NHS. Data from a published study were therefore used to estimate possible resection rates for patients with metastatic disease confined to the liver from the response rates. The correlation observed between response rates and resection rates was used to model resection rates in the base case and different scenarios in the model. The resection rates used in the base-case analysis of the CRYSTAL evaluation were 22% for cetuximab plus FOLFIRI and 12% for FOLFIRI alone, and in the OPUS evaluation were 15% for cetuximab plus FOLFOX and 7% for FOLFOX alone. Alternative values used in the scenario analyses were 55% for cetuximab plus FOLFIRI and 35% for FOLFIRI alone, and 42% for cetuximab plus FOLFOX and 26% for FOLFOX alone. The failure rate of liver resection was defined as the proportion of patients whose tumour could not be completely removed. The value for the failure rate of liver resection used in the model was 27.8%, which was taken from the full analysis set from the CRYSTAL trial. This rate was applied to all arms in the model.
3.16 The cost data were taken from the BNF edition 55 (2008) and the NHS National Tariff (2006). The cost of the KRAS test included in the model was £300 per test. This was provided verbally by the manufacturer of the test to the manufacturer of cetuximab, based on ad hoc patient testing. The model took into account testing of the whole patient population.
3.17 Health-related utility weights were applied to the time lived with disease at different stages of disease progression in the Markov model. Heath-related utilities were taken from clinical trials in the first- and third-line settings and estimated for the second-line setting. The utility in the period following curative resection took into account utility in patients free of disease and patients with recurrent disease. It was assumed that patients free of disease had health-related utility equal to that of the general population. In patients with progressive disease, the utility was estimated as the weighted average of utilities in the second- and third-line setting.
3.18 The results of the base-case analysis for cetuximab plus FOLFIRI compared with FOLFIRI alone gave an incremental cost-effectiveness ratio (ICER) of £69,287 per quality-adjusted life year (QALY) gained. The results of the base-case analysis for cetuximab plus FOLFOX compared with FOLFOX alone gave an ICER of £63,245 per QALY gained.
3.19 The manufacturer presented a ‘best-case' scenario analysis which combined the most favourable resection rates (see section 3.15) and extrapolation techniques for estimating survival, and assumed no vial wastage. The best-case scenario analysis for cetuximab plus FOLFIRI compared with FOLFIRI alone gave an ICER of £34,646 per QALY gained. The results of the best-case scenario analysis for cetuximab plus FOLFOX compared with FOLFOX alone gave an ICER of £40,529 per QALY gained.
3.20 The ERG considered there to be a number of limitations with the evidence in the manufacturer's submission. It noted that the KRAS wild-type analysis was carried out post hoc and was likely to have been underpowered. It also noted that the differences in progression-free survival of 1.2 months and 0.5 months for the CRYSTAL and OPUS trials' KRAS wild-type populations, respectively, were statistically significant in favour of cetuximab but not clinically meaningful. The ERG was also uncertain of the accuracy of the KRAS test in clinical practice.
3.21 The ERG identified a number of limitations with the manufacturer's model. It was concerned that the model focused on a much smaller patient population (people with KRAS wild-type metastatic colorectal cancer who had metastases confined to the liver and had a high performance status) than the population defined in the appraisal scope (people with untreated metastatic colorectal cancer) and was therefore concerned about the applicability of the results to clinical practice. The ERG was also concerned that no evidence was provided by the manufacturer to support the assumptions in the model that all patients who are suitable for cetuximab treatment are identified and treated with cetuximab (those who are KRAS wild-type) and that patients who are not suitable for cetuximab treatment (those with KRAS mutations) are not treated with cetuximab. Given the importance of estimating the outcomes for those treated incorrectly in reaching a conclusion on the cost effectiveness of the treatment, the ERG considered that this omission was a flaw in the model design.
3.22 The ERG was uncertain how accurate the effectiveness estimates used within the economic model were, given that they were derived from small post hoc subgroup analyses of trial results.
3.23 The ERG was not certain that all relevant costs had been included within the model, such as the cost of the necessary pretreatment with an antihistamine for people being treated with cetuximab. It also noted that the model did not take account of patients who wished to discontinue treatment as a result of the impact of adverse events, and so could have overestimated the benefits gained from the addition of cetuximab. In addition, the ERG considered that the costs of the scans of the chest, abdomen and pelvis by CT or MRI, which were performed at baseline for eligibility and for a tumour assessment, should have been taken into account.
3.24 In response to the first ACD consultation, the manufacturer submitted additional clinical evidence on the rates of liver resection, updated overall survival data from the CRYSTAL trial (described in sections 3.4 and 3.6) and a revised economic analysis amending the following parameters: the time at which patients are referred for liver resection, liver resection rates, failure rates of liver resection and a revised time horizon.
3.25 The manufacturer submitted data from the CELIM trial (n = 114); a phase II, multicentre, open-label, randomised trial that compared cetuximab plus FOLFOX with cetuximab plus FOLFIRI, and examined tumour response as the primary outcome. Secondary endpoints included liver resection rates, progression-free survival, disease-free survival and overall survival. The participants in the trial were patients with non-resectable colorectal liver metastases (defined as patients with five or more liver metastases, or patients with liver metastases that are technically non-resectable) and a Karnofsky performance-status score of 80 or more. Patients received 8 cycles (approximately 4 months) of treatment.
3.26 The results of the interim analysis of the data from the CELIM trial showed that the liver resection rate for cetuximab plus FOLFIRI (n = 53) was 43% compared with 40% for cetuximab plus FOLFOX (n = 52). For all patients in the trial (n = 105) the liver resection rate was 42%, and for the KRAS wild-type subgroup (n = 67) it was 43%. For those patients who had technically non-resectable liver metastases at baseline (n = 57) the liver resection rate was 40%. The liver resection rate for the KRAS wild-type subgroup (43%) was used in the new base-case analysis for both cetuximab plus FOLFIRI and cetuximab plus FOLFOX.
3.27 The CELIM trial did not include FOLFIRI or FOLFOX alone as a direct comparator. Therefore, in the revised economic analysis the manufacturer assumed a liver resection rate of 9% for FOLFIRI alone and 22% for FOLFOX alone (taken from published evidence [GERCOR study]), based on the recommendation of clinical specialists as being the most robust data for resection rates for FOLFIRI and FOLFOX. The model was also adjusted so that patients were referred for curative liver resection surgery at 16 weeks rather than 12 weeks, to reflect the data from the CELIM trial.
3.28 In addition, the manufacturer obtained clinical opinion on the 27.8% liver resection failure rate used in the original analysis. Clinical advice suggested that this rate was high for patients who have a liver resection in a specialist centre, and suggested that this rate was more likely to be 5%. The manufacturer used the original value of 27.8% for the new base-case analysis; however it also ran a best-case scenario analysis using a 5% failure rate of liver resection. The revised economic analysis was run over a 10-year time horizon for the base case.
3.29 The results of the new base-case analysis (27.8% liver resection failure rate and 10-year time horizon) for cetuximab plus FOLFIRI compared with FOLFIRI alone gave an ICER of £36,117 per QALY gained. The new base-case results for cetuximab plus FOLFOX compared with FOLFOX alone gave an ICER of £41,938 per QALY gained.
3.30 The results for the best-case scenario (5% failure rate of liver resection) for cetuximab plus FOLFIRI compared with FOLFIRI alone gave an ICER of £28,024 per QALY gained. The results for the best-case scenario for cetuximab plus FOLFOX compared with FOLFOX gave an ICER of £33,780 per QALY gained.
3.31 A scenario analysis examined the impact of running the model over a lifetime horizon. The results of this scenario analysis (27.8% failure rate of liver resection and lifetime horizon) for cetuximab plus FOLFIRI compared with FOLFIRI alone gave an ICER of £30,546 per QALY gained. The results for cetuximab plus FOLFOX compared with FOLFOX alone gave an ICER of £37,571. Combining the best-case scenario (5% failure rate of liver resection) and a lifetime horizon gave an ICER of £23,456 per QALY gained for cetuximab plus FOLFIRI compared with FOLFIRI alone, and of £29,891 per QALY gained for cetuximab plus FOLFOX compared with FOLFOX alone.
3.32 Details of a patient access scheme were provided by the manufacturer based on a 16% rebate of the costs of cetuximab when used in combination with FOLFOX for people with KRAS wild-type metastatic colorectal cancer who have metastases confined to the liver. The scheme requires that patients are treated according to the final NICE guidance and that data should be provided to the manufacturer to show that the NICE guidance has been followed. Cetuximab would be rebated in the form of free stock at a rate of 16% for all patients in the scheme on a per patient basis. When the patient access scheme was incorporated into the economic analysis for the comparison of cetuximab plus FOLFOX compared with FOLFOX alone (5% liver resection failure rate, 10‑year time horizon) the ICER reduced from £33,780 to £29,327 per QALY gained.
3.33 The ERG identified a number of limitations with the evidence taken from the CELIM study. It was concerned that the study was not a randomised assessment of cetuximab compared with no cetuximab. Therefore the ERG was uncertain whether the higher rates of resection were because of cetuximab treatment or other factors in the study such as those associated with patient care, surgical practice and patient characteristics. The ERG noted that inclusion criteria for the study specified patients with non-resectable liver metastases, however only 55% of patients had technically non-resectable metastases at baseline. In addition, the ERG commented that the sample size in the trial was relatively small, with approximately 55 patients in each arm.
3.34 The ERG also identified a number of limitations with the additional economic analysis provided by the manufacturer. It noted that the new liver resection rates for the combination of cetuximab with chemotherapy were higher than those considered likely by the clinical specialists at the first Committee meeting. The ERG also expressed concern over the reliability of the figure of 5% used for the failure rate of liver resection because it was gathered from the opinion of only two experts in a non-systematic manner. The ERG noted that this outcome was not included in the probabilistic sensitivity analysis.
3.35 The ERG was asked by the Committee to confirm the following modelling assumptions used in the additional manufacturer analysis: liver resection failure rates for both cetuximab plus chemotherapy and chemotherapy alone, duration of treatment with cetuximab for all patients, costs of liver resection surgery and the number of liver resections in the model. The ERG was also asked to complete a sensitivity analysis around the liver resection rates for cetuximab plus chemotherapy.
3.36 The ERG confirmed that the same liver resection failure rates were used in the cetuximab plus chemotherapy groups and the chemotherapy-alone groups. It was noted that following a successful curative liver resection, people did not receive any further treatment with cetuximab. However, people who had an unsuccessful liver resection or did not undergo a liver resection were treated with cetuximab until disease progression. The ERG confirmed that the model used a weighted average cost per liver resection surgery of £2271 calculated from four liver healthcare resource groups: G02 (liver – complex procedures), G03 (liver – very major procedures), G04 (liver – major procedures, patient aged over 69 years with complications and/or comorbidities) and G05 (liver – major procedures, patient aged under 70 years without complications and/or comorbidities). This cost is assumed to occur only once, at 16 weeks.
3.37 The ERG performed a sensitivity analysis around the liver resection rate for the cetuximab plus chemotherapy groups in the model using a 5% failure rate of liver resection and a lifetime horizon. The ICERs for cetuximab plus FOLFIRI compared with FOLFIRI alone using liver resection rates of 30% and 35% in the cetuximab group and 9% in the FOLFIRI group were £36,461 and £30,913 per QALY gained, respectively. The ICERs for cetuximab plus FOLFOX compared with FOLFOX alone using resection rates of 30% and 35% in the cetuximab group and 22% in the FOLFOX group were £51,598 and £40,515 per QALY gained, respectively.
3.38 Full details of all the evidence are in the manufacturer's submission and the ERG report.

top

4 Consideration of the evidence
4.1 The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of cetuximab for the first-line treatment of metastatic colorectal cancer, having considered evidence on the nature of the condition and the value placed on the benefits of cetuximab by people with metastatic colorectal cancer, those who represent them, and clinical specialists. It was also mindful of the need to take account of the effective use of NHS resources.
4.2 The Committee noted that the marketing authorisation for cetuximab limits its use to people with KRAS wild-type metastatic colorectal cancer, a narrower indication than outlined in the scope. The Committee acknowledged that the scope pre-dated the marketing authorisation for cetuximab, which placed this restriction on use. It heard from the clinical specialists that the marketing authorisation for cetuximab reflects increasing evidence that KRAS mutation status is predictive of response to treatment and that people whose tumours have KRAS mutations are unlikely to respond to treatment with cetuximab. The Committee also heard from the clinical specialists that KRAS testing accurately identifies people with wild-type KRAS status. The test can be carried out on 95% of tissue samples and is currently conducted in two NHS centres (Leeds and Cardiff), although limited capacity means it may not be immediately available for all people with metastatic colorectal cancer. Commercial companies offer KRAS testing, but these are more expensive than the tests carried out within the NHS.
4.3 The Committee reviewed the clinical-effectiveness results from the two clinical trials that compared cetuximab plus FOLFIRI with FOLFIRI alone and cetuximab plus FOLFOX with FOLFOX alone in the KRAS wild-type subgroup. It noted the statistically significant improvements in progression-free survival and response rates associated with cetuximab. However, it was aware that the improvement in median progression-free survival was 1.2 months and 0.5 months in the two trials and concluded that the effectiveness of cetuximab in improving progression-free survival was therefore limited. In addition, the Committee noted that the difference in the overall survival of 3.9 months from the CRYSTAL trial was not statistically significant. The Committee was also concerned that the KRAS subgroup analysis was based on small sample sizes and was carried out post hoc (at the request of the European Medicines Agency; EMEA). However, the Committee was reassured by the clinical specialists that differential response based on KRAS status had biological plausibility given current understanding of the pathology of metastatic colorectal cancer.
4.4 The Committee heard from the clinical specialists that cetuximab had an important potential role in shrinking secondary liver metastases, to enable potentially curative surgical resection in people with KRAS wild-type metastatic colorectal cancer. The clinical specialists reported that, of the people whose disease responds sufficiently to cetuximab to enable resection of liver metastases, approximately 90% would do so within 12 weeks of treatment with cetuximab. The duration of treatment with cetuximab in clinical practice for KRAS wild-type metastatic colorectal cancer patients with liver-only metastases would not normally exceed 12–16 weeks. Patients for whom liver resection was not possible (for example, because of the distribution of liver metastases) or who were not fit enough for potentially curative liver resection would not be treated with cetuximab, and would receive standard chemotherapy only.
4.5 The Committee considered the evidence for the effect of treatment with cetuximab on potentially curative resection of liver metastases. The results of the clinical trials showed that very few patients with KRAS wild-type metastatic colorectal cancer went on to receive potentially curative resection (cetuximab plus FOLFIRI 3.5%, FOLFIRI alone 2.3%; cetuximab plus FOLFOX 11.5%, FOLFOX alone 4.1%) and the Committee noted that no statistical significance was reported for these differences. It heard from the clinical specialists that the number of patients receiving potentially curative liver resection in the CRYSTAL and OPUS trials was lower than that seen in UK clinical practice, which is based on management by multidisciplinary teams involving highly specialised liver surgical services. The clinical specialists stated that a more realistic rate for potentially curative resection with chemotherapy in current practice was approximately 12–15%, which could rise to approximately 30–35% with the addition of cetuximab. The Committee also heard from the clinical specialists that the current UK standard chemotherapy approach for shrinking liver metastases was to use the FOLFOX regimen, which in practice enables a resection rate of approximately 20%. The Committee acknowledged the importance of liver resection rates as an endpoint in assessing the effectiveness of cetuximab.
4.6 The Committee reviewed the additional clinical data submitted by the manufacturer on the liver resection rates. It noted that the CELIM trial was not a randomised assessment of cetuximab plus chemotherapy compared with chemotherapy alone, had a relatively small sample size and had not been peer-reviewed. The Committee was also concerned that only 55% of patients had technically non-resectable liver metastases at baseline. It noted that the subgroup analysis for this group of patients indicated a liver resection rate of 40%, but that this subgroup analysis was for all patients and not just those with KRAS wild-type metastatic colorectal cancer. The Committee heard from the clinical specialists that the 43% liver resection rate for patients with KRAS wild-type metastatic colorectal cancer who were treated with cetuximab was an encouraging result, but it also noted that this was higher than the 30–35% rate originally considered likely by the clinical specialists (see section 4.5). The Committee was concerned that the 22% liver resection rate for FOLFOX was taken from an older study (GERCOR, Tournigand et al. 2004), but noted that the clinical specialists suggested that a liver resection rate of approximately 20% for FOLFOX was appropriate for current UK clinical practice (see section 4.5).
4.7 The Committee discussed the failure rate of liver resection. It noted that the 27.8% failure rate used in the original analysis appeared high for current practice. The Committee heard from the clinical specialists that a 5% failure rate of liver resection was a more appropriate reflection of current practice in UK specialist centres. The Committee agreed that this low rate reflected improvements in preoperative assessment and surgical technique and was appropriate to be used in the model.
4.8 The Committee discussed the adverse effects related to cetuximab. The clinical specialists advised the Committee that cetuximab is associated with an increase in an acne-like rash affecting a person's upper trunk, gastrointestinal adverse effects such as diarrhoea, and fatigue. The clinical specialists and patient experts explained that the acne-like rash may be indicative of response to cetuximab treatment and would not usually cause admission to hospital. Therefore, it is often interpreted by people as a positive effect because it suggests that the drug is working, outweighing any negative effects of the rash.
4.9 The Committee considered the results of the economic analysis submitted by the manufacturer. The Committee noted that the manufacturer had not provided an economic analysis that included the entire population for which cetuximab is licensed. The economic model focused on a subgroup of patients with a good performance-status score and metastatic disease confined to the liver. The Committee was persuaded that, in this group of patients, the aim of treatment with cetuximab was to reduce the size of metastases so they were resectable. Therefore the most appropriate comparator was FOLFOX, considered over a lifetime horizon. In addition, the Committee agreed that an analysis of cetuximab in combination with FOLFIRI compared with FOLFOX alone should be undertaken and recommended that this be requested from the manufacturer.
4.10 The Committee was aware that in the manufacturer's new analysis, in the best-case scenario (5% failure rate of liver resection) using a lifetime horizon, the incremental cost per QALY gained for cetuximab plus FOLFOX compared with FOLFOX alone was £29,900 (see section 3.31). The Committee noted that the liver resection rate for cetuximab plus FOLFOX assumed in the manufacturer's new analysis (43%) was higher than that reported in the OPUS clinical trial and was higher than that originally considered plausible by the clinical specialists (see section 4.5). The Committee was concerned about the limited methodology used for estimating the resection rates in the model, in that single arms from two separate studies were used to provide the data for the two groups in the model; the CELIM study for cetuximab plus FOLFOX and the GERCOR study for FOLFOX alone. The Committee considered that exploration of the different populations and evaluation of possible selection biases between the trials had not been done to a satisfactory level. Therefore, the Committee expressed caution about the results produced by the new analysis as the relative difference in resection rates was assumed from unrelated studies without any adjustments. In addition, the Committee noted the sensitivity analysis undertaken by the ERG, which used resection rates of 30% and 35% for cetuximab plus FOLFOX (assuming a 22% resection rate for FOLFOX alone), resulted in ICERs of £51,600 and £40,500, respectively. On the basis of the sensitivity of the ICER to the relative resection rates between the two groups, and the quality of the clinical evidence used, the Committee agreed that the ICER for cetuximab of £29,900 per QALY gained presented by the manufacturer was associated with a high degree of uncertainty.
4.11 The Committee discussed the cost of liver resection included in the economic analysis. It noted that the manufacturer had used a weighted average of a range of healthcare resource groups for all liver procedures giving an average cost of approximately £2300 for liver resection surgery, and that this only occurred once in the model. The Committee considered that this cost could be low compared with current UK clinical practice because a proportion of patients may undergo more than one operation to achieve complete resection of metastases. In addition, the Committee heard from the clinical specialists that liver resection costs approximately £7000 per case. The Committee was not persuaded that the manufacturer's approach to calculating the costs of liver resection using a weighted average of the healthcare resource groups was the most appropriate. Therefore, the Committee recommended that further clarification be requested from the manufacturer on the identification of the codes used to calculate the costs of liver resection incorporated in the economic analysis. Alternative estimates of the costs of liver resection surgery for people with metastatic colorectal cancer that accurately reflect UK clinical practice should then be incorporated in the economic analysis, and sensitivity analyses performed around this parameter.
4.12 The Committee discussed the duration of treatment with cetuximab used in the manufacturer's model. It noted that the model assumed that patients who underwent a successful liver resection did not receive any further treatment with cetuximab after the first 16 weeks. However, patients who either had an unsuccessful liver resection or had no liver resection were treated with cetuximab until disease progression. The Committee heard from the clinical specialists that in current UK clinical practice, all patients would normally stop receiving treatment with cetuximab at the time of the assessment for possible liver resection, that is, after approximately 12–16 weeks. The Committee considered that modelling this scenario could have a significant impact on the ICER. Compared with the scenario of patients receiving treatment with cetuximab until disease progression (median progression-free survival in the OPUS trial was 7.7 months for cetuximab plus FOLFOX), they would only receive treatment for 16 weeks, therefore substantially reducing the costs of cetuximab treatment. The Committee agreed that this was a scenario that should be explored in the economic analysis and recommended that this be requested from the manufacturer.
4.13 The Committee discussed the details of the patient access scheme provided by the manufacturer and the impact of the scheme on the results of the economic analysis. The Committee noted that the analysis that included the scheme used a 10-year time horizon, and this reduced the ICER for cetuximab plus FOLFOX compared with FOLFOX alone from £33,800 to £29,300 per QALY gained. As the Committee agreed that the lifetime horizon was the most appropriate for the analysis, it felt that this scenario should be requested from the manufacturer, in addition to the other scenarios.
4.14 The Committee took into consideration the manufacturer's cost-effectiveness estimates, the associated uncertainty in the analysis, (in particular the sensitivity of the model to the relative differences between the rates of liver resection with cetuximab plus FOLFOX and FOLFOX alone), the cost of liver resection surgery and the limitations of the clinical evidence used to obtain the rates of liver resection. On the basis of the evidence presented, the Committee was unable to conclude that cetuximab was a cost-effective use of NHS resources for the first-line treatment of metastatic colorectal cancer.
4.15 The Committee concluded that further clarification should be requested from the manufacturer to address the various areas of uncertainty and alternative approaches to the economic analysis, including an analysis of cetuximab plus FOLFIRI compared with FOLFOX alone.

top

5 Implementation
5.1 The Healthcare Commission assesses the performance of NHS organisations in meeting core and developmental standards set by the Department of Health in ‘Standards for better health' issued in July 2004. The Secretary of State has directed that the NHS provides funding and resources for medicines and treatments that have been recommended by NICE technology appraisals normally within 3 months from the date that NICE publishes the guidance. Core standard C5 states that healthcare organisations should ensure they conform to NICE technology appraisals.
5.2 ‘Healthcare standards for Wales' was issued by the Welsh Assembly Government in May 2005 and provides a framework both for self-assessment by healthcare organisations and for external review and investigation by Healthcare Inspectorate Wales. Standard 12a requires healthcare organisations to ensure that patients and service users are provided with effective treatment and care that conforms to NICE technology appraisal guidance. The Assembly Minister for Health and Social Services issued a Direction in October 2003 that requires local health boards and NHS trusts to make funding available to enable the implementation of NICE technology appraisal guidance, normally within 3 months.
5.3

NICE has developed tools to help organisations implement this guidance (listed below). These are available on our website (www.nice.org.uk/TAXXX). [Note: tools will be available when the final guidance is issued]

  • 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 which support this locally.
  • Audit support for monitoring local practice.

top

6 Proposed recommendations for further research
6.1

The Committee noted the following ongoing clinical trial related to this appraisal:

  • NCT00182715 is a phase III RCT evaluating first-line use of cetuximab for metastatic colorectal cancer (COIN trial). It aims to determine whether the addition of cetuximab to continuous oxaliplatin plus fluoropyrimidine chemotherapy improves overall survival when compared with either continuous or intermittent oxaliplatin plus fluoropyrimidine chemotherapy.

top

7 Related guidance
 

Published

 

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).

top

8 Proposed date for review of guidance
8.1 The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider whether the technology should be reviewed. This decision will be taken in the light of information gathered by the Institute, and in consultation with consultees and commentators.
8.2 It is proposed that the guidance on this technology is considered for review in January 2012. The Institute would particularly welcome comment on this proposed date.
  David Barnett
Chair, Appraisal Committee
January 2009

top

Appendix A. Appraisal Committee members and NICE project team
A. Appraisal Committee members

The Appraisal Committee is a standing advisory committee of the Institute. 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 three times a month except in December, when there are no meetings. The Committee membership is split into three branches, each with a chair and vice chair. Each branch considers its own list of technologies, and ongoing topics are not moved between the branches.

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.

Professor Keith Abrams
Professor of Medical Statistics, University of Leicester

Dr Ray Armstrong
Consultant Rheumatologist, Southampton General Hospital

Dr Jeff Aronson
Reader in Clinical Pharmacology, University Department of Primary Health Care, University of Oxford

Dr Darren Ashcroft
Reader in Medicines Usage and Safety, School of Pharmacy and Pharmaceutical Sciences, University of Manchester

Professor David Barnett (Chair)
Professor of Clinical Pharmacology, University of Leicester

Dr Peter Barry
Consultant in Paediatric Intensive Care, Leicester Royal Infirmary

Professor John Cairns
Public Health and Policy, London School of Hygiene and Tropical Medicine

Dr Mark Chakravarty
External Relations Director - Pharmaceuticals & Personal Health, Oral Care Europe

Professor Jack Dowie
Health Economist, London School of Hygiene and Tropical Medicine

Ms Lynn Field
Nurse Director, Pan Birmingham Cancer Network

Dr Fergus Gleeson
Consultant Radiologist, Churchill Hospital, Oxford

Ms Sally Gooch
Independent Nursing and Healthcare Consultant

Mrs Eleanor Grey
Lay member

Mr Sanjay Gupta
Former Service Manager in Stroke, Gastroenterology, Diabetes and Endocrinology, Basildon and Thurrock University Hospitals Foundation NHS Trust

Mr Terence Lewis
Lay Member, Mental Health Consultant, National Institute for Mental Health in England

Professor Gary McVeigh
Professor of Cardiovascular Medicine, Queens University, Belfast

Dr Ruairidh Milne
Senior Lecturer in Public Health, National Coordinating Centre for Health Technology

Dr Neil Milner
General Practitioner, Tramways Medical Centre, Sheffield

Dr Rubin Minhas
General Practitioner, CHD Clinical Lead, Medway PCT

Dr John Pounsford
Consultant Physician, Frenchay Hospital, Bristol

Dr Rosalind Ramsay
Consultant Psychiatrist, Adult Mental Health Services, Maudsley Hospital

Dr Stephen Saltissi
Consultant Cardiologist, Royal Liverpool University Hospital

Dr Lindsay Smith
General Practitioner, East Somerset Research Consortium

Mr Roderick Smith
Finance Director, West Kent Primary Care Trust

Mr Cliff Snelling
Lay Member

Professor Ken Stein
Professor of Public Health, Peninsula Technology Assessment Group (PenTAG), University of Exeter

Professor Andrew Stevens
Professor of Public Health, Department of Public Health and Epidemiology, University of Birmingham

Dr Rod Taylor
Associate Professor in Health Services Research, Peninsula Medical School, Universities of Exeter and Plymouth

Ms Nathalie Verin
Health Economics Manager, Boston Scientific UK and Ireland

Dr Colin Watts
Consultant Neurosurgeon, Addenbrookes Hospital

Mr Tom Wilson
Director of Contracts and Information Management and Technology, Milton Keynes PCT

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.

Helen Knight
Technical Lead

Helen Chung / Zoe Garrett
Technical Advisers

Jeremy Powell
Project Manager

 

top

Appendix B. Sources of evidence considered by the Committee
A

The Evidence Review Group (ERG) report for this appraisal was prepared by West Midlands Health Technology Assessment Collaboration – University of Birmingham:

  • Meads C, Round J, Tubeuf S, et al. Cetuximab for the first-line treatment of metastatic colorectal cancer, July 2008
B

Additional evidence for this appraisal was prepared by West Midlands Health Technology Assessment Collaboration – University of Birmingham:

  • Critical appraisal of additional material on the CELIM RCT submitted by Merck Serono for the Cetuximab STA
  • Comment on additional material submitted by Merck Serono in relation to cetuximab for metastatic colorectal cancer
  • Cetuximab CRC STA - Additional briefing document required for third committee meeting
C

The following organisations accepted the invitation to participate in this appraisal. 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, II and III also have the opportunity to appeal against the final appraisal determination.

I Manufacturer/sponsor:

  • Merck Serono

II Professional/specialist and patient/carer groups:

  • Association of Coloproctology of Great Britain and Ireland
  • Beating Bowel Cancer
  • Bowel Cancer UK
  • British Association of Surgical Oncology
  • Cancer Research UK
  • Macmillan Cancer Relief
  • Royal College of Nursing
  • Royal College of Pathologists
  • Royal College of Physicians, Medical Oncology Joint Special Committee
  • UK Oncology Nursing Society

III Other consultees:

  • Department of Health
  • Islington PCT
  • Nottinghamshire County PCT
  • 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
  • Institute of Cancer Research
  • National Collaborating Centre for Cancer
  • NHS Quality Improvement Scotland
  • Pfizer
  • Roche Diagnostics
  • Roche Products
  • Sanofi-Aventis 
D

The following individuals were selected from clinical specialist and patient advocate nominations from the non-manufacturer/sponsor consultees and commentators. They gave their expert personal view on cetuximab by attending the initial Committee discussion and providing written evidence to the Committee. They are invited to comment on the ACD.

  • Mr Ian Beaumont, nominated by Bowel Cancer UK - patient expert
  • Dr Rob Glynne-Jones, Clinical Oncologist, Mount Vernon Hospital, nominated by Bowel Cancer UK - clinical specialist
  • Professor Timothy Maughan, Consultant Clinical Oncologist and Professor of Cancer Studies, Cardiff University, nominated by the Royal College of Physicians - clinical specialist
  • Mr Goff Norrington, nominated by Beating Bowel Cancer - patient expert
  • Mr Graeme Poston, nominated by the British Association of Surgical Oncology - clinical specialist

top

This page was last updated: 30 March 2010

Accessibility | Cymraeg | Freedom of information | Vision Impaired | Contact Us | Glossary | Data protection | Copyright | Disclaimer | Terms and conditions

Copyright 2014 National Institute for Health and Care Excellence. All rights reserved.

Selected, reliable information for health and social care in one place

Accessibility | Cymraeg | Freedom of information | Vision Impaired | Contact Us | Glossary | Data protection | Copyright | Disclaimer | Terms and conditions

Copyright 2014 National Institute for Health and Care Excellence. All rights reserved.