Cetuximab and panitumumab for previously untreated metastatic colorectal cancer

The appraisal committee recognised that this appraisal reviewed the NICE technology appraisal guidance on:

• Cetuximab for the first-line treatment of metastatic colorectal cancer, which before this review recommended up to 16 weeks of treatment with cetuximab only in a subgroup of people with metastases confined to the liver.

• Panitumumab in combination with chemotherapy for the treatment of metastatic colorectal cancer, which did not recommend treatment with panitumumab because the company did not submit evidence.
  
  The committee understood that the guidance was being reviewed because the marketing authorisations for cetuximab and panitumumab had changed since the previous appraisal. The change narrows the marketing authorisation to exclude a genotype that responds poorly to cetuximab and panitumumab. The committee also understood that cetuximab and panitumumab had been available on the Cancer Drugs Fund. The committee reviewed the data available on the clinical and cost effectiveness of cetuximab and panitumumab, having considered evidence on the nature of previously untreated metastatic colorectal cancer and the value placed on the benefits of cetuximab and panitumumab by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.

The committee discussed the current management of metastatic colorectal cancer and considered the population relevant for this appraisal. The committee heard from NHS England at the fourth appraisal committee meeting that managing colorectal cancer with liver-only metastases has evolved over the course of this appraisal. It heard that clinicians continue to offer surgical resection, which may improve prognosis, to people with metastases confined to the liver and that treatment with cetuximab or panitumumab makes it easier for surgeons to resect tumours. The committee heard from the clinical experts, that if the metastases are not resectable after treatment, the person would be offered up to 3 lines of chemotherapy. It heard that few people have successful resection, meaning that there is a greater emphasis on using cetuximab and panitumumab palliatively for people with liver-only metastases. The committee noted that this was in line with palliative use of these treatments in people with widespread metastases, who have a biological treatment (such as cetuximab or panitumumab) with chemotherapy and then up to 2 further lines of chemotherapy alone. It heard that the aim of palliative treatment is to slow disease progression early, and to prolong life. The committee concluded that there are 2 purposes of treatment: to shrink tumour tissue for surgical resection and to palliate.

The committee was aware that previous guidance recommended cetuximab only in a subgroup of patients with metastases confined to the liver and included a stopping rule at 16 weeks (see section 4.1). During this appraisal, commentators and consultees, including NHS England, stated that people with metastases confined to the liver no longer represent a distinct subgroup in clinical practice and that resection was likely to be done after the best response to treatment, rather than at 16 weeks as with the stopping rule. The committee also heard that the stopping rule is difficult to implement in practice, because it can mean withdrawing a palliative treatment from people. The committee concluded that people with metastases confined to the liver were no longer a distinct subgroup in current clinical practice and did not further consider this subgroup separately from the overall population. In addition, it concluded that it was inappropriate to implement a stopping rule in people with metastatic colorectal cancer.

The committee considered the most appropriate comparators for cetuximab and panitumumab for treating RAS wild-type tumours in people with metastatic disease. It heard from the clinical experts that they use combinations including oxaliplatin (for example, FOLFOX) and irinotecan (for example, FOLFIRI). The committee understood that there are 2 different delivery schedules for FOLFOX treatment, FOLFOX4 and FOLFOX6, and heard from the clinical experts that FOLFOX6 is more commonly used in clinical practice in England. The committee heard that cetuximab is usually given with FOLFIRI and that panitumumab is usually given with FOLFOX, because there is a stronger evidence base for these combinations than for cetuximab plus FOLFOX or panitumumab plus FOLFIRI. The committee was aware that other chemotherapy regimens, such as XELOX (oxaliplatin and capecitabine), were listed among the comparators in the scope but heard from the clinical experts and the assessment group that these drugs were not routinely offered in clinical practice in the NHS. The committee concluded that the appropriate comparators for this appraisal were FOLFOX and FOLFIRI for both cetuximab and panitumumab.

The committee considered how frequently cetuximab is administered in clinical practice. It was aware the summary of product characteristics for cetuximab recommends a weekly dose of 250 mg/m² body surface area. However, the committee heard from the clinical experts and from NHS England that in practice a dose of 500 mg/m² body surface area is given every 2 weeks, which reduces administration costs. The committee was concerned that cetuximab given every 2 weeks may not have the same effectiveness as cetuximab given weekly, as done in the trials. At the fourth appraisal committee meeting, the committee heard from the company that a study (CECOG/CORE2) in a similar population showed that the effectiveness of cetuximab given every 2 weeks or weekly may be the same and that the Cancer Drugs Fund chose to offer cetuximab every 2 weeks on the basis of this evidence. The committee was aware that NICE's guide to the methods of technology appraisal states that the committee 'does not normally make recommendations regarding the use of a drug outside the terms of its marketing authorisation'. It noted that the guide also states that evidence relating to using the technology under appraisal outside the terms of its marketing authorisation may inform deliberations. The committee concluded that it would take into account the lower costs of administration in clinical practice.

The committee discussed the clinical trial evidence for cetuximab and panitumumab in people with RAS wild-type metastatic colorectal cancer. The assessment group included 3 main randomised clinical trials of cetuximab and panitumumab in its base-case model: OPUS (cetuximab plus FOLFOX compared with FOLFOX alone), CRYSTAL (cetuximab plus FOLFIRI compared with FOLFIRI alone), and PRIME (panitumumab plus FOLFOX compared with FOLFOX alone).

• The committee heard that the evidence for cetuximab and panitumumab in patients with RAS wild-type colorectal cancer was based on post-hoc subgroup analyses. Although based on small data sets, it understood from the clinical experts that knowledge about metastatic colorectal cancer and biomarkers has changed. The committee agreed that it was appropriate to use data from post-hoc subgroup analyses for its decision-making.

• The committee heard from the assessment group that the survival data were likely confounded by different second and further lines of treatment across the trial arms. These treatments are associated with prolonged survival and are not widely available in the NHS. The committee noted that, in response to the appraisal consultation document, the assessment group adjusted for subsequent treatments (see section 4.12).
  
  The committee concluded that, for the purpose of this appraisal, the populations in the clinical trials of cetuximab and panitumumab were broadly generalisable to clinical practice in the NHS.

The committee considered the cost-effectiveness results for cetuximab and panitumumab in all patients. The committee recalled its preferred assumptions to consider cetuximab given 2‑weekly and to adjust survival for subsequent treatments (see section 4.13). The committee noted that the assessment group's ICERs for cetuximab plus FOLFIRI compared with FOLFIRI alone and panitumumab plus FOLFOX compared with FOLFOX alone were all below £50,000 per quality-adjusted life year (QALY) gained. The exact ICERs are not reported to prevent calculation of the discount associated with the patient access scheme and commercial access agreement.

The committee noted that it had not been presented with ICERs consistent with its preferred assumptions for some comparisons:

• Cetuximab plus FOLFOX compared with FOLFOX alone: It noted that ICERs adjusted for subsequent treatments were not presented because of limited data. It recalled hearing that the clinical experts considered FOLFOX and FOLFIRI to be broadly equivalent (see section 4.8). The committee concluded that the ICER for cetuximab plus FOLFOX compared with FOLFOX alone was likely to be similar to that for cetuximab plus FOLFIRI compared with FOLFIRI alone (see section 4.16).

• Panitumumab plus FOLFIRI compared with FOLFIRI alone: It noted that ICERs were not presented because of a lack of relevant clinical evidence (see section 4.9). It recalled its earlier conclusion that the effectiveness of panitumumab plus FOLFIRI was likely to be similar to that of panitumumab plus FOLFOX. The committee concluded that the ICER for panitumumab plus FOLFIRI compared with FOLFIRI alone was likely to be similar to that for panitumumab plus FOLFOX compared with FOLFOX alone (see section 4.16).

The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's final Cancer Drugs Fund technology appraisal process and methods. Having previously concluded that the end-of-life criteria were met for the overall population, but not for the subgroup of people with metastases confined to the liver, the committee limited its discussion to the overall population at the fourth appraisal committee meeting. The committee concluded that the end-of-life criteria were met in the overall population based on the following discussions:

• The committee considered the life expectancy of people with RAS wild-type metastatic colorectal cancer with either FOLFOX or FOLFIRI, using estimates from the assessment group's model. For the overall population, it noted that mean life-expectancy estimates were below 24 months for FOLFIRI when adjusted for subsequent treatments. The committee noted that the estimates for FOLFOX were slightly above 24 months. It recalled its earlier conclusion that FOLFOX and FOLFIRI were likely to be broadly equivalent (see section 4.8) and was aware that there was uncertainty about the estimates. The committee concluded that the criterion for short life expectancy was met.

• The committee considered how long, on average, cetuximab and panitumumab extended life in the whole population, based on the estimates in the assessment group's model. It noted that estimates were above a mean of 3 months for both cetuximab with FOLFIRI and panitumumab with FOLFOX when adjusted for subsequent treatments. The committee was aware that estimates adjusted for subsequent treatments were not available for cetuximab with FOLFOX but recalled its earlier conclusion that FOLFOX and FOLFIRI were likely to be broadly equivalent (see section 4.8). The committee concluded that both cetuximab and panitumumab met the criterion of extension to life when considering the whole population.

The committee heard from the companies that they consider cetuximab and panitumumab to be innovative treatments and a step-change in managing metastatic colorectal cancer, because their targeted mechanisms of action mean that those people with colorectal cancer that is most likely to respond (that is, RAS wild-type) have treatment. The committee concluded that it had not been presented with any additional evidence of benefits that were not captured in the measurement of QALYs.

The committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of any of the technologies in this appraisal.