ASCO 2012, Chicago, USA
MEK inhibitor, trametinib, improves progression free survival in melanoma
Dr Caroline Robert – Institute Gustave Roussy, Paris, France
We just presented the results of a phase III trial which evaluated the activity of a new MEK inhibitor, the name is trametinib. It inhibits a molecule downstream from the MAP kinase pathway – MEK1 and 2 proteins, they are downstream from BRAF, and this was done in patients with metastatic or advanced unresectable melanoma which were mutant for the V600E or K BRAF protein. We already had some very promising pre-clinical activity with this drug; we also had the results of previous phase I and phase II studies which were quite promising. Here the drug was evaluated versus chemotherapy in patients in first or second line, meaning that they could have received up to one previous line of chemotherapy or immunotherapy. We included 322 patients in this trial and they were randomised 2 to 1, meaning that two out of three patients received trametinib and one out of three received either dacarbazine or paclitaxel because patients who had previously received dacarbazine in second line, they couldn’t receive it again. So the main objective was progression free survival and a cross-over was allowed for the patients who received chemotherapy and progressed, they could receive trametinib secondarily. So we couldn’t have overall survival as an endpoint, as a primary endpoint, because when you authorise a crossover it can reduce the effect, of course, of your overall survival.
So the results are very impressive. PFS very significantly increased with the drug, the median PFS with the drug is 4.8 months, with the chemotherapy it’s 1.5 meaning it’s almost the first evaluation CT scan that doesn’t work in chemotherapy. So here we really increase, we give more than three months additional in terms of progression free survival. The hazard ratio was 0.45 which resulted in a 55 decreased risk of progression or death with this drug compared to chemotherapy.
In terms of response rates it’s significant too. It’s 22% confirmed response rate versus 8% and overall survival is positive, which is quite impressive because almost 50% of the patients in the chemo arm have crossed over, exactly 47%. So in spite of that, we still have a positive overall survival with a hazard ratio of 0.54, which means that we decrease the risk of death by 46%. At six months 81% of the patients are still alive with trametinib versus 68% with chemotherapy, so these are very good results.
Were there any side effects?
The toxicity is quite expected with a MEK inhibitor, that we already knew. The most frequent side effects are cutaneous side effects - we have a papulopustular rash, it’s called acne from dermatitis. It’s very rarely severe, it’s most of the time grade 1 and 2. The two potentially concerning side effects that we know are associated with this class of drug are cardiac side effects. So we were looking at that very carefully and it occurred in only 7% of the patients and in less than 1% of the cases it was grade 3 and no grade 4. It was left ventricular dysfunction or decrease of diffraction of a section of the ventricular. It was mostly asymptomatic, always reversible, so not a big deal. The other side effect that we were really also following very closely was a potential ocular side effect because we know that this class of drug can induce central serous retina and retinitis. We had one case of chorioretinitis, grade 3 reversible. So overall the toxicity was very acceptable, very tolerable.
What is the clinical impact?
We now have another drug that has a very good benefit risk profile to treat melanoma patients with BRAF mutant melanoma. What will be the position of this single agent with regards to anti-BRAF agent that is already on the market? It’s a little bit difficult to anticipate that. For sure, for those patients who do not tolerate BRAF inhibitors it will be a very good option. We already have some information about the fact that when patients have developed resistance against an anti-BRAF agent, probably the anti-MEK trametinib will not be a solution because we already have explored that in more than 30 patients with not a very good response rate. But on the other way round we don’t know, maybe it will be… we know that some patients who received trametinib in the first place, if they relapse or if they reprogress, some of them respond to vemurafenib secondarily. So maybe it can be used like that. But right now we have two drugs with very similar PFS and overall survival it’s difficult to say because we cannot compare it head to head but it seems to be quite close. The fact that there is one difference, it’s the level of the response rate - it’s less elevated with the MEK inhibitor. We have 22% and with the BRAF inhibitor, vemurafenib, it’s more close to 50%. But what does it mean exactly, the response rate? I don’t think it’s a big handicap, I think the most important is overall survival. It’s really the ultimate goal of an anti-cancer agent.
What is very important is that we have another drug that is active and, you know, right now we have a lot of hope in the combination of anti-BRAF and anti-MEK so it’s better for us to know that we are going to combine two active agents. Plus, it seems that when we combine these two agents, not only they are more effective than single agents separately but the toxicities seem to blunt each other, the toxicity of each of the drugs. So I would say it’s a good drug and it gives us even more hope in the combination.