I want to ask you about the COMBI-V study because you’ve been combining MEK inhibition with BRAF inhibition and you’re getting quite an interesting result. Now, tell me what is the study, what were you trying to do?
This is a phase III study; the main goal of this study is to demonstrate an overall survival benefit with the combination of anti-BRAF dabrafenib plus anti-MEK trametinib versus anti-BRAF vemurafenib.
Now these specifically were patients with melanoma who were positive for BRAF.
Exactly, who have a BRAF mutation, it can be BRAF V600E for 90% of them or V600K for 10% of the patients and this is a first line treatment. Patients have not been treated previously for their metastatic melanoma.
Now you had the combination arm and the single agent arm, what did you find?
We found that the survival was increased with the combination with a hazard ratio of 0.69. That translates into a reduction of the risk of dying of 31% with the combination compared with the dabrafenib.
What were the toxicities when you were using both MEK inhibition and BRAF inhibition?
Surprisingly enough, the toxicity is not increased by combining two drugs. Actually if you look at the grade 3 it’s a little bit decreased – we have around 48 versus 50 something with the single agent. But if we look in detail into the adverse events the spectrum is slightly different; some adverse events are more frequent with the combination, like pyrexia, chills and vomiting, and some other adverse events are decreased by the combination, mostly skin adverse events. Interestingly, among the skin adverse events we have the skin proliferation because we know that BRAF inhibitors can favour the emergence of some skin cancers that are less serious than melanoma but still some keratinocyte skin cancers or skin benign lesions. This is due to a paradoxical activation of the MAP kinase pathway by the BRAF inhibitor and when you put in the additional MEK inhibitor then you decrease this activation and you see almost none of these tumours on the skin.
So it’s a kind of negative synergy in terms of toxicity, you’re protecting?
Exactly. That’s very interesting.
Now, if you were to put months and years on it, what broadly would the figures be in terms of progression free survival and overall survival, which you have got a signal on, haven’t you?
We have a very strong signal. We have a signal in overall survival, as I said. We don’t yet have the median overall survival of the combination because it has not been reached after a median follow-up of eleven months so we’ll see later. We have an increase of the progression free survival – in median it goes from 7.3 months with vemurafenib to 11.4 months with the combination and the hazard ratio, which is actually the most important thing to remember, the hazard ratio, is showing that there is a decrease of the risk of progression or death of 44%. In terms of response rate it’s also very much increased; we have 64% of overall response rate with 13% of complete response with the combination versus 51% response rate with the vemurafenib and 8% of complete response.
So what is the clear message for cancer doctors?
The clear message is that the combination of BRAF plus MEK inhibitor, dabrafenib plus trametinib, is more effective than BRAF inhibitor vemurafenib only. What is really very strong is that it’s not the first trial to demonstrate that, we have a randomised phase II trial, we have another phase III that was comparing with dabrafenib, we have this phase III and we also have the results from the Roche study, with also a combination of anti-BRAF plus anti-MEK. All these trials go in the same direction so I really think that the combination will become the drugs to use instead of anti-BRAF only in this population of patients.
And in fifteen or twenty seconds the take home bottom line, bearing in mind the other new therapies in melanoma too?
We live in an incredible time with melanoma. We now have combination anti-BRAF plus anti-MEK that is stronger than the already very effective anti-BRAF treatment. On the other side we have immunotherapy with anti-PD1 monoclonal antibodies, that’s really stronger than ipilimumab that was already effective. So it’s very good for our patients.