We have a new combination of BRAF/MEK inhibitors approved, encorafenib and binimetinib, based on study data of the COLUMBUS trial. This is a study which compared the combination of encorafenib as a BRAF inhibitor and binimetinib as a MEK inhibitor in comparison to monotherapy of encorafenib and a third arm, monotherapy of vemurafenib. This study was done in patients who had metastatic melanoma, first line treatment, who had a BRAF V600 mutation which are roughly 40-45% of the patent population which are suffering from metastatic melanoma.
This study was performed and started roughly in 2015 and we have now seen data on efficacy, response rate, we have seen data on progression free survival, tumour control and overall survival. The data are quite interesting, also in light of the already approved combinations we have in hand already and experience. We have two approved BRAF/MEK combinations – dabrafenib and trametinib and vemurafenib and cobimetinib. What we have now learned inside the COLUMBUS study is that response rates are high, in the range of 75% of patients having a complete or partial response. We have a median progression free survival which is impressively high, in the range of 15 months, and we are seeing a median overall survival which has been reported in Lancet Oncology last month which is more than 33 months which is the highest median overall survival we have seen of all the combinations so far. What is also a part of these results we have seen in the COLUMBUS trial is a direct comparison of the monotherapies, encorafenib and vemurafenib, and we have learned that although this was not the primary goal of the study to compare the monotherapies head to head, this is the first head to head comparison clearly demonstrating that encorafenib seems to be a better BRAF inhibitor than vemurafenib.
In terms of better, does that include all different measures of response rate and toxicity and response and tolerability and including affordability, different levels of toxicity, different interpretations?
We have several aspects which make encorafenib something unique. Obviously there is a high affinity to the kinase it’s binding to and also the time the molecules are sticking together is particularly long so that’s possibly also part of the success of this BRAF inhibitor. It’s contributing possibly also to the clinical benefit we are seeing. The safety profile is actually another interesting aspect. We have, as I have mentioned, quite some experience with two previously registered combinations and the safety profiles are quite different between encorafenib binimetinib on the one hand and dabrafenib trametinib on the other hand and vemurafenib cobimetinib as a third comparator. So choosing the right patients for the right combination, also based not only on efficacy data but also on the side effect profiles, is an interesting option for physicians to have this third combination in hand.
With the follow up for this, you say the head to head comparison finds it better, are there any plans to confirm this with further trials in terms of a head to head that way or introduce it into other combinations to see if it replaces and supplants?
I don’t see that there will be head to head comparisons of BRAF/MEK combinations emerging so we have three combinations of BRAF/MEK inhibitors currently in hand but we have also, and we shouldn’t forget that, checkpoint inhibitors for these patients as well in hand. When we look at two year and three year survival rates of patients, or tumour control rates, we see that BRAF/MEK and also encorafenib and binimetinib, what we have seen now in the COLUMBUS study, the three year survival rate is close to 50% which is in the range of checkpoint inhibitors. It’s still a difficult choice for the investigators to make the choice in first line what to start with, targeted therapy or checkpoint blockade, and obviously safety profiles will help but also, for example, comorbidities will dictate what kind of treatment options you are giving. All the BRAF/MEK inhibitor combinations are oral drug combinations, the checkpoint inhibitors are IV formulations so for that the patients have to come in on a frequent basis. So all that together needs to be discussed with the patients and see what is the best option for the patient.
What we know from BRAF/MEK and also from binimetinib and encorafenib is that the quality of life using these oral drugs is quite high. That’s a very important thing for the patient to know. You can take these oral medications for a long period of time – we have patients on drug now for years and still benefitting.