EADO Congress 2015

Latest from the CoBRIM study

Prof Grant McArthur - Peter MacCallum Cancer Centre, Melbourne, Australia

You’ve been looking at patients with melanoma and using a combination therapy. Tell me about this therapy, we’ve heard a little bit about its success but it is now maturing, isn’t it?

Yes, so we’ve known for a while that the combination of a BRAF and MEK inhibitor gives high response rates and better progression free survival compared to mono-BRAF therapy. So what I’m talking about here is vemurafenib and cobimetinib or dabrafenib and trametinib versus the single agent BRAF inhibitors, that is either vemurafenib alone or dabrafenib alone. So we’ve known for a while that you definitely have superior progression free survival and superior response rate but what is really emerging with this maturing data in 2015 is the impact on overall survival. For me the 2015 take-home message has been the overall survival is looking better with maturing data than I had first anticipated. We now have at three years over 30% of patients with BRAF mutant melanoma alive following treatment with a combination of a BRAF and MEK inhibitor.

Right, they have to have the appropriate markers like the BRAF V600 mutated factor, don’t they?

It is absolutely clear that one requires a BRAF mutation at the V600 position to get the benefit from BRAF inhibitors, either alone or in combination with the MEK inhibitor. So even with the combination therapy for BRAF and MEK inhibitor, one requires a BRAF mutation to get the clinical benefit.

So a subset of patients are doing well out of this, what are the implications of that?

The other very interesting data that’s emerging in 2015 is the role of prognostic markers that help define how patients are going to do when they’re treated with targeted therapy for BRAF mutant melanoma. What is emerging, an old test but now turning out to be quite a discriminatory test, is the lactate dehydrogenase level at baseline. If this is normal then the overall survival of these patients treated with a combination of BRAF and MEK inhibitors is really a quite impressive; median overall survival has yet to be estimated accurately in that group, it’s likely to be in the order of three years, maybe even better. So this group are doing extremely well with targeted therapy. However, what is also clear is if at baseline the lactate dehydrogenase is elevated the overall survival is poor, median overall survival is less than twelve months. Certainly better than old-fashioned chemotherapy, no question this is a beneficial treatment for those patients, but we’re not getting long-term benefits of even the combination of a BRAF and MEK inhibitor for those patients.

So that’s one biomarker that could help you individualise therapy, are there others?

We’ve had an explosion in knowledge about the mechanisms of resistance to BRAF inhibitors and the combination of BRAF and MEK inhibitors with fantastic laboratory studies. New biomarkers to predict who is going to do well and who may not do so well are under investigation. Some data presented here at the European Association of Dermato Oncology meeting in Marseilles is very intriguing because what we have done is to analyse for mutant sub-clones within the melanoma. So these are cells that at the baseline, before any treatment, harbour mutations that should give resistance in a fraction of the cells. So you would expect those patients to have worse progression free survival. It turns out they don’t, which is very surprising, very surprising indeed. In other words there’s not this selection for the mutant cells early to give very short progression free survival. That heartens me; why does it hearten me? It says that if we can really get effective therapy up front for our patients, even if there are some resistant mutant sub-clones sitting there they may die, potentially in an unfavourable tumour environment, in a responding tumour, if we get the best treatment up-front for our patients. So that’s now our goal – get the best treatment up front for your patients.

Because you now understand some of these predictive and prognostic markers, do you think you can consider using the c word, cure?

This is very interesting. Of course we, as oncologists, often say to our patients we are very conservative about the use of the word cure. With ipilimumab in advanced melanoma we know that 20% of patients are becoming long-term survivors. I like the term clinical cure; some of those patients still have abnormalities on their scans but they don’t progress. So what about the targeted therapies? What I’m very hopeful with now with high complete response rates, 15% of patients getting complete response now with BRAF plus MEK inhibition, potentially sequencing targeted therapies and immune therapies together, looking at novel combinations. I actually think that we could reduce the total mortality from the disease of melanoma with these systemic therapies. More research needed, more clinical trials, but I think we’re on the path to actually getting clinical cure for a greater proportion of patients.

Of course these therapies are very costly, they’re not attainable by many centres. What do you think is the practical advice to doctors right now?

This is one of the frustrations of our practice, that one is limited by reimbursement of these new drugs. We need to continue to do the science, we need to continue to do clinical trials and to find the best way of improving overall survival and getting those clinical cures. But also we need to look at working collaboratively, particularly with our patient advocacy groups, to try to bring down the cost of these drugs. Because patients need access, particularly in more developing countries, to such wonderful drugs that are improving survival for patients with advanced melanoma.