4.1 The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of cetuximab, having considered evidence on the nature of the condition and the value placed on the benefits of cetuximab by people with locally advanced squamous cell cancer of the head and neck, 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 considered that the decision problem described in the manufacturer's submission was reasonable, but noted that the population specified excluded people for whom chemotherapy is suitable. Therefore the decision problem did not reflect the entire population of people with locally advanced squamous cell cancer of the head and neck for whom cetuximab might be considered as a treatment option according to its licensed indication.
4.3 The Committee considered current UK clinical practice in the treatment of locally advanced squamous cell cancer of the head and neck. It heard from the clinical specialist who attended the meeting that chemoradiotherapy is the standard care for patients with stage lll and IV squamous cell cancer of the head and neck. However, there are patients for whom chemoradiotherapy is considered inappropriate (for example, patients with co-existing medical conditions and poor performance status). Chemoradiotherapy carries a high risk of adverse effects and patients should be willing and fit enough to be treated. The clinical specialist and patient experts were of the opinion that for patients whose condition required an alternative to chemoradiotherapy, cetuximab plus radiotherapy was a useful option because of its relatively low toxicity profile compared with chemotherapy.
4.4 The Committee heard from the clinical specialist that there is considerable variation in clinical practice across the UK. There are no clear definitions or criteria for patients for whom chemoradiotherapy is considered inappropriate, and there is variation in the selection of initial treatment modality (surgery or chemoradiotherapy), radiation dose intensities and the means of delivery of chemotherapy. More intensive radiotherapy regimens require suitable infrastructure and patients may need to attend hospital all day (which some are unable to do).
4.5 The Committee considered the evidence on the clinical effectiveness of cetuximab in combination with radiotherapy for the treatment of locally advanced squamous cell cancer of the head and neck. It noted that there was only one relevant RCT that compared cetuximab plus radiotherapy with radiotherapy alone in people with non-resected disease (the Bonner trial). The Committee noted that the trial had started at a time when radiotherapy rather than chemoradiotherapy was the standard treatment. The Committee accepted that cetuximab with radiotherapy had been shown to be more effective than radiotherapy alone in the population represented in the trial.
4.6 The Committee noted that there were no trials that compared cetuximab plus radiotherapy directly with any platinum-based chemoradiotherapy. The Committee understood that chemoradiotherapy is considered to be standard treatment for patients unless there are reasons to contraindicate its use, and that cetuximab plus radiotherapy might have advantages over chemoradiotherapy in terms of reduced toxicity. However, the Committee was not presented with any evidence comparing cetuximab plus radiotherapy with chemoradiotherapy on which an estimate of the clinical and cost effectiveness of cetuximab in combination with radiotherapy could be based. Therefore the Committee was unable to make any recommendations on its use as an alternative to chemoradiotherapy.
4.7 The Committee considered the use of cetuximab in combination with radiotherapy in the population specified in the manufacturer's decision problem, that is, the subgroup of patients for whom chemoradiotherapy was considered to be unsuitable by the manufacturer. The Committee noted that the population in the relevant RCT was relatively fit: more than two thirds had a Karnofsky performance-status score of 90% or above and all had normal haematopoietic, hepatic and renal function. The manufacturer was unable to provide information on the number of patients in the RCT for whom chemoradiotherapy would have been inappropriate, or on the effectiveness of cetuximab plus radiotherapy in this subgroup.
4.8 The Committee considered that patients with lower Karnofsky performance-status scores would form most, if not all, of the population for whom chemoradiotherapy would be considered inappropriate in clinical practice. The Committee discussed the subgroup analyses of the median overall survival data according to Karnofsky performance-status scores provided by the manufacturer and reported in the 'European public assessment report' published by the European Medicines Agency. Although recognising the difficulties in interpreting the subgroup analyses, the Committee noted that no clinical benefit had been demonstrated for cetuximab in combination with radiotherapy in patients with a Karnofsky performance-status score of 80% or less. The Committee concluded that given the absence of clinical benefit (albeit with wide confidence intervals) it could not make the subgroup of patients with Karnofsky performance-status scores of 80% or less the basis for a positive recommendation to use cetuximab in combination with radiotherapy. Indeed, the Committee noted that the 'European public assessment report' stated that the 'overall impression of all subgroup analyses is that the add-on effect of cetuximab tends to be small or absent irrespective of outcome measure in patients with poor prognosis (estimated from median overall survival)'.
4.9 The Committee then considered patients with a Karnofsky performance-status score of 90% or greater and explored situations in which chemoradiotherapy might be unsuitable for them. The Committee reviewed the criteria proposed by consultees for identifying patients with good performance status and for whom cisplatin-based chemoradiotherapy would be inappropriate. It noted from consultees that some patients who are unable to tolerate the nephrotoxicity, ototoxicity and fluid overload from cisplatin-based chemoradiotherapy prefer carboplatin-based chemoradiotherapy. The Committee was made aware by consultees that although carboplatin does not have a UK marketing authorisation for the treatment of locally advanced squamous cell cancer of the head and neck, carboplatin-based combination regimens have been studied in this condition and are sometimes used to treat this condition in UK clinical practice. However, the Committee also heard that carboplatin-based regimens are associated with haematological adverse effects, particularly myelosuppression. The Committee concluded that although carboplatin-based chemoradiotherapy is a treatment option for some patients for whom cisplatin-based chemoradiotherapy is contraindicated, it was possible that there are some patients with good Karnofsky performance-status scores for whom any type of platinum-based chemoradiotherapy is contraindicated. The Committee accepted that the results presented for patients with Karnofsky performance-status scores of 90% or greater indicated that cetuximab in combination with radiotherapy would be more effective than radiotherapy alone in this subgroup.
4.10 The Committee considered the ICER presented by the manufacturer in its original submission and the ERG's original comments. The Committee noted that the ICER of £6400 for cetuximab in combination with radiotherapy versus radiotherapy alone was robust to the main sensitivity analyses. The Committee considered the ICERs presented by the manufacturer for each Karnofsky performance-status score subgroup separately. It noted that the ICERs for patients with a score of 90% or greater were favourable and similar to the overall estimate in the base case. The Committee was persuaded that although there was uncertainty about the number of patients within the subgroups who would have met the criteria to receive chemoradiotherapy, cetuximab in combination with radiotherapy is cost effective for patients with a Karnofsky performance-status score of 90% or greater and for whom chemoradiotherapy is not an option. However, for those with a Karnofsky performance-status score of 80% or less, the HR for survival did not favour cetuximab and therefore the ICERs were unfavourable. The Committee therefore was unable to recommend cetuximab for people with low performance status.
4.11 The Committee concluded that cetuximab in combination with radiotherapy is clinically and cost effective in patients with locally advanced squamous cell cancer of the head and neck who have a Karnofsky performance-status score of 90% or greater and for whom platinum-based chemoradiotherapy treatment is contraindicated.