RTP On Demand — Head & Neck/Thyroid | Research To PracticeMEK1/2 inhibitor selumetinib in differentiated thyroid cancer
4:08 minutes.
TRANSCRIPTION:
DR LOVE: What about selumetinib? What is it, and what do we know about it in thyroid cancer? DR COHEN: Selumetinib is an interesting drug. It’s a MEK1 and 2 inhibitor. And we actually tested it in a Phase II study in thyroid cancer with the hypothesis that because this is a disease that is driven by activation of the MAP kinase pathway, be it through a RET/PTC rearrangement or a RAS mutation or a BRAF mutation, that we may have activity with a single-agent MEK inhibitor. We actually didn’t see activity. We saw 1 patient who had significant tumor shrinkage, a partial response. And interestingly, that patient had a BRAF mutation but really not a lot of activity as a single agent. And that may be peculiar, first of all, to this drug, but it also may be that just inhibiting MEK may not be enough in this population. But that’s not the end of the story. Again, coming from this preclinical work being done, that demonstrated this resensitization to radioactive iodine, the group from Memorial Sloan Kettering actually used that strategy, short-course selumetinib pre and post scans to see if we could reinduce uptake. And, in fact, that’s exactly what we saw. So patients who had new or increased uptake of radioactive iodine, it was 20 patients in the study. Twelve of those actually did have. And what was also interesting is that most of those patients had mutations in the pathway, so either BRAF or RAS mutations, and there were actually some patients who had shrinkage of their disease secondary to the increase in radioactive iodine uptake. So pretty amazing, really, when you think about it. DR LOVE: Any comments on that or where you think things are heading? DR COHEN: Yes, so clearly we see an increase in radioactive iodine uptake. We see, also, tumor shrinkage and even some partial responses. So not only are we seeing what we want to see in the radiographs with the radioactive iodine uptake, but we’re also actually seeing real tumor activity, which, of course, at the end of the day, we want patients to live longer. So I think what we do see is now a Phase III study using exactly this strategy to reinduce radioactive iodine uptake in an effort to really try to control the disease for longer. I don’t think this is going to cure patients of the disease, but what I think it will do is induce either responses or prolong stable disease that can then obviate the need for other systemic therapies for, who knows, maybe several months to even several years. DR LOVE: What kind of tolerability issues are there with the selumetinib? DR COHEN: So selumetinib at full dose for a prolonged period of time is not so easy to take. And we saw that in the Phase II study, skin toxicities, edema, other side effects. However, when we use it in a strategy like this, it’s short-course selumetinib. We’re only giving it for a few weeks. And there, the agent is quite tolerable. DR LOVE: Do you think that this would come before TKIs in the future? DR COHEN: I do. Let’s imagine that the study is positive, the Phase III trial is positive. I think that’s exactly what we’ll see. I think we’ll see patients who become radioactive iodine refractory get a trial of a MAP kinase inhibitor, be it a BRAF inhibitor or a MEK inhibitor, see if we can reinduce radioactive iodine uptake. If we can, they’ll be re-treated with radioactive iodine. If we can’t, then we’ll start to talk about TKIs. And then that will be the paradigm. I don’t think TKIs are going to go away. I think there’s still going to be a role for them, but one can imagine that if this study is positive, that this’ll be the first strategy. |