EADO Congress 2015

Targeting N-RAS mutated tumours

Prof Axel Hauschild - University of Kiel, Kiel, Germany

You are talking here about a topic that isn’t brought up all that often, or at least I haven’t been hearing it so frequently: N-RAS targeting, targeting patients with N-RAS mutated tumours. What is this all about and what are the reasons that you’ve taken an interest in this and indeed done a study?

Yes, the N-RAS mutation is a hot topic because it’s 20% of patients who are carrying N-RAS mutations. So besides the BRAF mutation which is found in 40% of all melanoma patients it’s the second most mutation. We have targeted agents to N-RAS mutation; it’s typically MEK inhibitors. What I present here is an overview on the drugs which are under development for this disease at the moment and there are two phase III randomised clinical trials to approve N-RAS inhibitors. One is on pimasertib, a drug from Merck Serono, which is under development. This is compared to DTIC, it’s a trial which allows a crossover which means if you are treated with DTIC, dacarbazine standard chemotherapy, and you have a progressive disease you can cross over to the MEK inhibitor. The other one is called NEMO, it’s a clinical trial which is testing another drug which was originally called MEK162 and now is binimetinib, a drug from Novartis, which is tested against DTIC but there is no crossover. These two clinical trials are the focus for the N-RAS inhibition at the moment but you know my expectation is also that there is development of combinational treatments and there is a CDK4/6 inhibitor on the way to be combined with binimetinib and the response rate was as high as 41% presented at the recent ECCO meeting.

So what might be the clinical messages emerging for doctors out of the whole concept of N-RAS targeting?

I think that’s a very important question because for melanoma patients who are carrying BRAF mutations you don’t need to investigate the tumour specimen for N-RAS mutations, they are more or less exclusive. Which means that if you are BRAF negative, you have a wildtype, you can be evaluated and this enhances the chance to carry an N-RAS mutation from 20% to 40%. So it’s of relevance for these patients but the results at this point of time are not as good in the absence of phase III clinical trial results. From phase II the data are not as good as the data for BRAF inhibition so the story is not the same.

In clarifying a clinician’s approach to an individual patient right now, how does all of this help at the moment?

The drugs which are currently tested are not approved yet for melanoma, for N-RAS mutated melanoma. But certainly this would be a good offer to include patients to a clinical trial and if the drugs are approved to use these drugs. But there is huge competition and the competition on the table is very clear, it’s the PD1 antibodies which work independently of any mutations. So it’s also a drug which could be considered for patients with N-RAS mutations.

But you’re using MEK inhibitors but this is not synonymous, though, with N-RAS mutation targeting, is it?

It’s interesting because for binimetinib, the MEK inhibitor, there was a clinical trial performed and this clinical trial showed that there is effectiveness in patients with BRAF and the rate was in the range of 25% response rate but also with N-RAS, the same response rate in the range of 25%. So it was a randomised phase II trial treating patients with N-RAS and those with BRAF mutations and this was the first sign that BRAF inhibitors can be used for both diseases.

So can you pull all of this together, if you’re doing targeted therapy, if you’re using targeted therapies you look for the RAF mutation, you look for the N-RAS mutation and you decide on a mix of different inhibitors. How do you go about it potentially in the future?

The dilemma is that the only MEK inhibitor which is currently proved in Europe is the MEK inhibitor which is combined with BRAF inhibition. This trametinib MEK inhibitor has never been tested in N-RAS mutated patients so we simply have no data and I wouldn’t go ahead in using it in patients when I don’t have data on it.

But some of the other agents might in the future give you that important data?

Absolutely. This is what we are expecting.