ASCO 2013

Selumetinib, the first effective drug for advanced melanoma of the eye

Dr Richard Carvajal - Memorial Sloan Kettering Cancer Center, New York, USA

Richard, it’s lovely to have you on ecancer television and you’ve been talking here at ASCO about a new MEK inhibitor. Can you tell me what you’ve been doing, why you were interested in uveal cancer and what you’ve been able to do for it? Because you seem to have made quite an impact.

Uveal melanoma has historically been a very difficult disease to treat. This is a disease that, although it arises from melanocytes, just like cutaneous melanoma does, there has really been no effective therapy for this disease unlike the case for cutaneous melanoma. It’s biologically distinct, it responds differently to therapy. What’s been found in 2008 was that these tumours are driven by early oncogenic events affecting something called GNAQ and GNA11. This leads to activation of the MAP-kinase pathway. 

And is that where selumetinib comes in?

Exactly. Selumetinib is a drug that actually turns off that MAP-kinase pathway at the level of MEK and so our hypothesis was that perhaps MEK inhibition in this disease, since it’s driven by those mutations, would be an effective therapy.

In keeping with targeted therapy, individualised therapy that we’re hearing so much about now. What happened, what did you do in the study?

What we did here is we randomised patients to either chemotherapy or the selumetinib drug and overall what we saw is the drug more than doubled the progression free survival for patients that we treated when compared to chemotherapy. We improved the response rate and in fact saw responses that are really not seen or have not been reported with other drugs or other combination therapies. There was actually a trend towards improved survival despite the cross-over design of the trial.

This is quite a tough disease so how much value were you getting in terms of quality of life improvement by getting that extension of PFS?

When patients develop disease progression here oftentimes they have disease in the liver, frequently in the bone, and these can be painful lesions that can lead to fatigue, early satiety and so forth. So by delaying progression we do provide clinical benefit to patients. This is the first time we’ve ever found an agent that’s able to do that.

Where do you think this is going then?

Right now we are in the process of developing a confirmatory trial for regulatory purposes. What we’d like to do is confirm what we found on this trial and, if so, get this drug commercially available for patients with uveal melanoma.

Does it endorse the idea of MEK inhibition perhaps for other cancers?

Absolutely. There are other cancers that are driven by mutations in these G alpha proteins that affect the MAP-kinase pathway as well as others. So this concept very much may apply to other cancers as well.

What should doctors be making of your particular discovery so far then?

What we have here for the first time ever is really a new standard, although the drug is not approved, but a new kind of standard for patients with uveal melanoma. It’s a new benchmark that we can use to design next trials, the next generation of trials. I think we still need to steer patients towards trials, particularly those including a MEK inhibitor and perhaps building upon the efficacy that we’ve seen with new combination trials. Now, if patients do not have access to these trials of course trametinib was just approved recently which is another MEK inhibitor. Although there has not been a great deal of experience of that drug in this disease, that’s something that we’re going to have to discuss within the community as far as whether we should consider treating patients with uveal melanoma with that drug.

So your brief message to doctors right now?

Right now, MEK inhibition, first drug ever to show efficacy of any systemic therapy in this disease. Further trials of MEK inhibition are in the planning process and patients should be steered towards that. This is, again, the first study that has ever been positive in this disease so this offers a great deal of hope to the patients, most importantly, but also to these clinicians who are dealing with these patients for whom we had nothing to offer before.

Richard, thank you for joining us on ecancer.tv.