Dabrafenib and trametinib combo shows significant survival benefit in melanoma

Prof Caroline Robert - Institute Gustave Roussy, Villejuif, France

You’ve been looking at the COMBI-b study, a phase III study. You were trying two different approaches head to head on this, what were you doing? And this is for patients with melanoma.

It’s patients with melanoma, advanced melanoma, but also with a mutation of B-RAF which is about 40% of our patients with melanoma, a somatic mutation of B-RAF. We already knew that these patients can benefit from a treatment with a B-RAF inhibitor, this was shown some years ago, and now we are evaluating the combination of an anti-B-RAF plus anti-MEK, namely dabrafenib plus trametinib versus single agent anti-B-RAF.

A quick question, why didn’t you go for dabrafenib in both arms for the anti-RAF?

There is a study which is COMBI-d where we have the combination versus dabrafenib but this one was versus vemurafenib.

And what did you get from this? It’s now two years, isn’t it?

Now we present the update of the results. You know the study was stopped at the interim analysis because the results were so good. The overall survival was good at the first interim analysis and it was not ethical to continue; we could crossover other patients and they could all receive the combination. Now we have the update, so we have an additional eleven months of follow-up but for the patients it’s eight months of median follow-up. We can estimate the two year overall survival, so we know that after two years we have 51% of the patients in the combination arm who are alive versus 38% in the vemurafenib arm. We have the two curves, on the Kaplan-Meier curves we have the two curves really nicely separated and the median overall survival in the combination arm is 25.6 months, which is actually the longest overall survival that we ever reached in a randomised trial in patients with metastatic melanoma.

Overall survival is looking good, what about progression free survival?

It’s also very good, very different in between the two arms. We have a little bit more than one year in PFS, median PFS, in the combination arm and seven point something months with the vemurafenib arm.

You’re using a combination of two innovative approaches, does this add toxicity?

No. We already have this very good surprise which in fact was not a surprise if you know exactly the mechanism of action. In fact, you have a combination that has more efficacy but less toxicity on some adverse events. If you compare the absolute number of adverse events it’s very similar; the spectrum is slightly different, we have more chills and more fever with the combination because of the dabrafenib effect and we have all the adverse events that are linked to the paradoxical activation of the pathway which are much more frequent with vemurafenib. But interestingly, with this update we see that we don’t have any other adverse events. With this additional follow-up we have the same percentage of patients who have interrupted the treatment for safety issues.

What are the clinical messages coming out of this for doctors, then?

It’s very important, this is a very important result. This is actually the longest median overall survival in patients with advanced melanoma. So it’s very important also to know that in the patients with low LDH, which is the best population of patients, whatever treatment we do, it can be immunotherapy or targeted therapy, it’s a good prognosis marker. We see that we have in this population of patients a bigger benefit. So it’s very important because right now everybody thinks about immunotherapy all the time and this treatment is something that can be really compared to immunotherapy in this population of patients.

And these patients have the B-RAF mutation, how important is that to the efficacy of this approach?

You would never give a B-RAF inhibitor to a patient who is not mutated for B-RAF.

So now the message is clear, is it clear between vemurafenib and dabrafenib though?

It has not been tested head to head, of course it’s never going to be done because it’s not interesting now at the point where we are. It’s quite equivalent, we have less paradoxical adverse events with dabrafenib but we have more fever and more chills so it’s not exactly the same but in terms of efficacy it’s not very different.

So what brief message would you distil for doctors at this point to summarise?

The combination of dabrafenib and trametinib is a treatment that should be a standard of care for patients with a B-RAF mutant metastatic melanoma.