ASCO 2011 Annual Meeting, 3—7 June 2011, Chicago

Combining oral targeted therapies shows early anti-tumour activity for advanced melanoma

Dr Jeffrey Infante – Sarah Cannon Research Institute, Nashville, USA

We presented a study of a combination of two therapies which are, it’s a BRAF inhibitor from GSK with a MEK inhibitor from GSK, and we presented data of how we were able to start with dosing of those two drugs together in patients with genetic abnormalities in the BRAF gene so that they all had BRAF mutations. And there was a combination trial.

Just to set the background of why this is important, about half the patients with melanoma have BRAF mutations, which is thought to be one of the drivers for their cancer. We had participated in the initial monotherapy trial, the GSK BRAF inhibitor a year ago, that was presented here by Doctor Kefford, which showed good response rates in the 60% range or so. But the durability was, like other selected BRAF inhibitors, in that 6-9 month range before the tumour figured out a way to get around it. But an active drug by itself.

We also last year presented at ASCO personally the GSK MEK inhibitor in its first in-human trial. We know that BRAF signals directly through MEK, so it makes sense to us that in BRAF mutant tumours a MEK inhibitor may work also. In that first in-human study a year ago we showed that in BRAF mutant patients the response rate was around 40%, so not quite as good but still very active compared to standard therapies in melanoma. And the goal was to give these drugs together in combination, and hopefully get synergy, and really knock down the signalling through that pathway, and really help patients. The way we usually will do that when you have two drugs that are oral pills and you try to give them together is you start at low doses, about half the dose of where you would give each one individually, and that’s what we did. We started with 75mg twice a day of the BRAF inhibitor with 1mg of the MEK inhibitor, which is daily, and then we made sure patients tolerated that. And we ended up going up at four different dose levels until we finally got to the full monotherapy doses of each drug, which is giving the BRAF inhibitor at its full dose of 150mg twice a day in combination with the MEK inhibitor at 2mg daily. So this is continuous dosing of both drugs.

And it turned out the side effects were actually reasonably well tolerated. There are patients that had some fevers and some GI side effects of nausea but usually you don’t have to change the dose for those. And if you look at some of the key skin toxicities, which we knew were troublesome from the single agent experiences with these drugs, we knew that in patients with BRAF inhibitors that were treated with just the BRAF inhibitor by itself that there was a chance that they may develop squamous cell carcinoma of the skin. And this is a kind of paradoxical effect, that you are watching melanomas get better, but they go to the dermatologist and they’re getting frozen or cut, things cut off their skin that may be warts or squamous cell carcinoma. The rate of that squamous cell carcinoma has been in the 7-15% range and, in combination with pre-clinical data, suggesting that we may be able to reduce that with the addition of the MEK inhibitor. So far, of 109 patients that have been treated, there has only been one episode of squamous cell, so that looks like it’s been improved with the combination.

The other side effect that got improved was that with the MEK inhibitor alone, when we presented our data a year ago about 80% of the patients at the 2mg dose are going to have a rash and it’s a very typical acne form like rash, similar to erlotinib. It can be to the point where patients don’t want to take the drug because it can be somewhat disfiguring if it gets really bad. But usually it’s treatable, but still in combination it’s markedly better. And the whole rash rate, not just acne 4 lesions, but any type of rash, is around 27%, so markedly down from 80%.

So the goal was to take two drugs, try to get up to the highest doses of each one by themselves and give it in combination that way and we were able to do that, and we were able to do it with, truthfully, a little bit less toxicity than normally. You expect when you put two drugs together you’re going to get more toxicity; in this case it turned out that some of the most troublesome toxicities got better.

And then from a benefit standpoint, which is the most important thing, how are we helping people, there’s only been two patients of the 109 that the drugs didn’t help at the first three staging scans. So the majority of patients are getting clinical benefit, many of them deep responses. There have been five complete responses so far on the study. That’s of 71 patients that have not had a prior BRAF inhibitor, there’s been five complete responses. And if we look at the duration on study, there’s over 80% of the patients are still on study because this study just began a year ago.

What’s the potential for clinical practice?

I think trials are going to have to bear that out, and that’s a great question of where we are going with this, is that once we found that we can give the two doses together, give it safely, and then showed that we had clinical activity, the idea was to roll into a phase II trial and that trial is on-going. Truthfully, it’s almost completely accrued but it’s a three arm trial. It’s looking at, two arms, well maybe it’s best to say that all three arms, everyone gets the BRAF inhibitor at the full dose, 150mg twice a day; the first arm gets the MEK inhibitor at the full dose of 2mg a day; the second arm gets a little bit lower dose of the MEK inhibitor at 1mg a day, we’re worried about chronic side effects developing potentially, and then the third arm gets the BRAF inhibitor alone. And the idea was to compare the combination therapy up front, to patients that just get the BRAF inhibitor. And if they get the BRAF inhibitor on that third arm, they are allowed to get the combination if it doesn’t work for them.

What is the timescale for that trial?

That trial will be finished, there was 150 patients in that trial, it will have completely accrued by the end of this month, so probably around the beginning of July. So the data hopefully will come out six months after or so.