NICE published on 26 October 2016 a Technology appraisal guidance [TA414] with next recommendation: Cobimetinib in combination with vemurafenib is not recommended within its marketing authorisation for treating unresectable or metastatic melanoma in adults with a BRAF V600 mutation.
This guidance is not intended to affect the position of patients whose treatment with cobimetinib in combination with vemurafenib was started within the NHS before this guidance was published. Treatment of those patients may continue without change to whatever funding arrangements were in place for them before this guidance was published until they and their NHS clinician consider it appropriate to stop.
Cobimetinib (Cotellic, Roche) is an inhibitor of MEK 1 and MEK 2 kinases. Vemurafenib (Zelboraf, Roche) is an inhibitor of the BRAF protein. Both are taken as tablets. The BRAF protein and MEK 1 and 2 kinases are part of the same cell-signalling pathway. Inhibiting these proteins stops proliferation and survival of melanoma cells.
The appraisal committee reviewed the data available on the clinical and cost effectiveness of cobimetinib in combination with vemurafenib, having considered evidence on the nature of advanced (unresectable or metastatic) BRAF V600 mutation-positive melanoma and the value placed on the benefits of cobimetinib plus vemurafenib 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 noted that people with BRAF V600 mutation-positive advanced melanoma could have an immunotherapy agent (ipilimumab, pembrolizumab or nivolumab) or a targeted BRAF inhibitor (vemurafenib or dabrafenib). The clinical expert stated that about 70% of people with BRAF V600 mutation-positive disease have immunotherapy in first line because of the long-term benefit that has been shown in trials. BRAF inhibitors would usually be used in first line only for people with rapidly progressing disease, high disease burden or elevated lactate dehydrogenase (LDH) levels, when a rapid onset of action is needed. BRAF inhibitors are considered to be equally effective whether given before or after immunotherapy. The committee concluded that most people with BRAF V600 mutation-positive melanoma would have a targeted therapy at some point in their treatment.
For most people with BRAF V600 mutation-positive melanoma, the combination of cobimetinib plus vemurafenib will be taken after an immunotherapy agent and as an alternative treatment option to a BRAF inhibitor (vemurafenib or dabrafenib).
Data from the coBRIM trial (comparing cobimetinib plus vemurafenib with vemurafenib alone) were considered to be the most robust clinical data for decision-making. This was because there were no head-to-head data comparing cobimetinib plus vemurafenib with dabrafenib, the company's indirect comparison was based on a network with a small number of trials, and potential differences between the trials had not been fully explored.
The relative clinical effectiveness of cobimetinib plus vemurafenib compared with dabrafenib was uncertain because no trials had directly compared these treatment options. However, the relative clinical effectiveness of cobimetinib plus vemurafenib compared with dabrafenib was expected to be similar to the clinical effectiveness of cobimetinib plus vemurafenib compared with vemurafenib because the committee had heard that vemurafenib and dabrafenib monotherapies are considered to be of similar clinical effectiveness.
Cobimetinib plus vemurafenib extends overall survival by 4.9 months compared with vemurafenib alone.
The following common adverse reactions affect more than 1 in 5 people: diarrhoea, rash, nausea, vomiting, fever, light sensitivity reaction, abnormal liver function tests, and abnormal results for creatine phosphokinase. Less common adverse reactions include retinopathy or reduced left ventricular ejection fraction. People taking cobimetinib plus vemurafenib should be monitored for new and worsening visual disturbances, and for cardiac function.
In all of the analyses presented to the appraisal committee, the incremental cost-effectiveness ratios (ICERs) were over 100,000 GBP per quality-adjusted life year (QALY) gained. This is substantially over the range usually considered a cost-effective use of NHS resources.