Negative draft decision for Zelboraf (vemurafenib) highlights challenges facing future value-based pricing implementation and UK access to medicines.
Roche is extremely disappointed with the preliminary decision that NICE is not planning to recommend Zelboraf (vemurafenib) to be available on the NHS for the treatment of BRAF mutation positive unresectable or metastatic melanoma.
While NICE recognises vemurafenib to be a ‘step-change’ in the management of advanced metastatic melanoma, acknowledges that it meets its end of life criteria and agrees it is a significant innovation for a disease with a high unmet clinical need, it still has made the decision to deny patients access through routine NHS channels. As these are the key factors that will constitute a value-based pricing system, this preliminary negative decision suggests that NICE methodology is not suitable for its introduction in 2014. NICE has now turned down nine out of the last ten end of life cancer drugs at final guidance stage.
The decision is all the more disappointing as since its launch in February 2012, vemurafenib has been widely used by clinicians through the cancer drugs fund, who have seen the benefit it can make to the lives of patients, in turn quickly making it the new standard of care for BRAF mutation positive metastatic melanoma. One of just two breakthrough treatments in the last 30 years in this disease area, vemurafenib is the first licenced personalised medicine to extend the lives of patients with BRAF V600 mutation positive unresectable or metastatic melanoma to over a year.
John Melville, Managing Director, Roche UK said, “Zelboraf ticks all the boxes when considering the types of medicines that value-based pricing aims to encourage pharmaceutical companies to develop, and in addition we strongly believe it is cost effective. NICE themselves acknowledge that Zelboraf is innovative and addresses an unmet need. The draft recommendation that results from the use of the existing NICE methodology highlights a need for change in order for value-based pricing to meet the Government’s stated access to medicines objectives. Whilst patients can continue to access Zelboraf through the Cancer Drugs Fund, the fact the CDF was only intended as a bridge to value-based pricing, the outcome of this NICE decision causes me great concern in relation to long term patient availability.”
A key factor in NICE’s recommendation was its assertion that there are uncertainties about the long term benefits of vemurafenib. This has occurred partly because Roche, on compassionate grounds and at the request of regulatory authorities, allowed patients who were not receiving vemurafenib on the trial to access the drug once its benefits became clear. Referred to as cross-over, this commonly happens in cancer clinical trials where true benefit is demonstrated by new medicines, despite the fact that cross-over can underplay the true long term benefits of the drug, as patients on both arms of the trial can end up receiving the treatment.
Roche feels it has been penalised for the decision to ethically ensure patients benefit from true advances in medicine. Additionally, Roche believes it is unsatisfactory that a treatment with acknowledged short term benefits to a group of patients with great need for an effective therapy should be rejected because of a lack of information on the impact of the drug five to 10 years after starting treatment. Although this information will emerge with time, it will be too late for most of those patients needing treatment today and who will, typically, live for less than a year with existing therapies.
Roche urges NICE to take into account its concerns about the methodology used to make its decision, and consider the views of clinical experts at centres of excellence.
Vemurafenib will continue to be available to patients in England via the Cancer Drugs Fund, although there is no similar access for patients in Wales, Scotland and Northern Ireland.
The most frequent grade 3 adverse events with vemurafenib were skin related and included cutaneous squamous cell carcinoma, a common skin cancer treated by local excision. Additionally, generally mild and reversible increases in liver enzymes (GGT, ALT, AST, alkaline phosphatase, and bilirubin) were observed in some patients. The most common adverse events reported with vemurafenib include arthralgia, fatigue, rash, photosensitivity reaction, nausea, alopecia and pruritus. Cutaneous Squamous Cell Carcinoma (CuSCC) was very commonly reported and was most commonly treated by local excision.
About Metastatic Melanoma and BRAF
Metastatic (or advanced) melanoma is the deadliest and most aggressive form of skin cancer. A person with advanced melanoma typically has a short life expectancy that is measured in months. There are an estimated 2,000 deaths annually in the UK from malignant melanoma, with young people disproportionately affected by the disease.12 Over the last 25 years, rates of malignant melanoma in Britain have risen faster than any other common cancer.12 If current trends continue, it is anticipated that there will be around 15,500 cases of malignant melanoma diagnosed per year within the next 15 years.12 Until recently there has been no major advance in treatment for 30 years and patients with advanced melanoma have had very few treatment options.
The BRAF protein is a key component of the RAS-RAF pathway involved in normal cell growth and survival. Activating mutations in the BRAF gene cause this pathway to be overactive, which may lead to excessive growth and cancer. Mutations in the BRAF protein are found in about 50 percent of melanomas and it is estimated that approximately eight percent of all solid tumours contain BRAF mutations.
Vemurafenib is an oral medicine that is designed to selectively inhibit a cancer-causing mutated form of the BRAF protein. Vemurafenib is indicated in monotherapy for the treatment of adult patients with BRAF V600 mutation-positive unresectable or metastatic melanoma. It was co-developed under a 2006 licence and collaboration agreement between Roche and Plexxikon. A polymerase chain reaction-based companion diagnostic, the cobas® 4800 BRAF V600 Mutation Test, was co-developed by Roche Molecular Diagnostics and Plexxikon in parallel to identify people whose tumours carry the BRAF V600 mutation.
About clinical trials and patient cross-over
Clinical trials are designed to find out if a new treatment or procedure is safe, has side effects, works better than the currently used treatment and if it makes patients feel better.14 Cross-over in clinical trials occurs when patients are moved from the control arm of the trial, on to the treatment arm. In the case of vemurafenib, in the BRIM3 (phase III) clinical trial, some patients moved from receiving standard chemotherapy to vemurafenib, making it difficult to determine the clear impact of treatment. As such it is possible to underestimate the longer term benefit of the drug.
Source: Roche in the UK