The US and European approval of Bristol-Myers Squibb's Yervoy earlier this year followed by the prompt FDA approval of Roche's Zelboraf last week has been welcomed; European approval of Zelboraf is anticipated in the next few months. However, the reality is that there will remain a substantial proportion of patients that will not be impacted by these new drugs. The oncology team at Decision Resources Group has engaged in much cogitation, debate, discussion and analysis to determine how the dynamic malignant melanoma market will play out over the next few years.
The BRAF inhibitor - a success story of a targeted therapy where the target was identified initially through the human genome project (Davies H., 2002), is precisely that - targeted, albeit to a large proportion, 47% of patients with the mutated BRAF gene (Chapman PB, 2011; Jakob JA, 2011; Menzies AM, 2011; Long GV, 2011). The aim will be for the majority of patients with BRAF mutated disease to receive Zelboraf as soon as they are diagnosed with metastatic disease, it should prolong the time before their disease progresses, and current data shows a superior 6 month overall survival rate (84% versus 64% for dacarbazine (Chapman PB, 2011): experts are optimistic that median overall survival benefits will be realized when data mature. Patients with wild-type BRAF will be eligible for Yervoy - won't they. Well yes, in the U.S., and yes, eventually - on failure of a traditional, largely ineffectual treatment, in Europe - if the current label for previously treated advanced melanoma is strictly adhered to.
Yervoy should be celebrated as the first drug to demonstrate an overall survival benefit, 3.7 months over control arm, in a previously treated population and 2.1 months better than dacarbazine in a first-line trial. However, this does not reveal the entire story as there is a proportion of patients who experience long, durable responses extending towards two years. Typically, the pay-off with Yervoy is the side-effect profile, and many patients may either be ineligible for treatment, or not complete the planned four injection course of Yervoy, with the consequence of compromised efficacy. In addition, and in contrast to Zelboraf, precisely which patients will derive benefit is difficult to predict.
And of course to price; many melanoma patients are young, and, in the US, will not be covered by Medicare so the uninsured will face reimbursement hurdles. It seems unlikely that Yervoy with an anticipated UK price tag of £75,000 a course ($123,000 exchange rate 24th August 2011) even in the light of an overall survival benefit, will jump the NICE barrier unless a cost-sharing or reimbursement structure is agreed. The UK has melanoma patients aplenty who may not be able to access this treatment.
So despite these exciting, novel new agents there remains ample room for more drugs to make even more gains, and increase treatment options, in this deadly indication. GlaxoSmithKline are steaming ahead with the clinical development of their BRAF and MEK inhibitors, dabrafenib and trametinib respectively, and the data from the trial that combines the two drugs are particularly eagerly anticipated. And of course there is the adjuvant setting - a much larger, and therefore commercially attractive, patient population, with in Europe in particular, low treatment rates due to a dearth of effective therapies, and high rates of recurrence to locoregional, in-transit, and metastatic disease. Yervoy is currently being explored in the adjuvant setting, and vaccines currently explored by Amgen and GSK amongst others, as always are the great hope in this low tumor burden setting. So let's celebrate these important advances, but let's also hope more buses come along soon.