DR CAREY: Temsirolimus is a very similar drug to everolimus, in most respects. But, unlike the everolimus studies, both the Phase III and the Phase II, there was exactly no impact on progression-free survival. And the question is, why would there be discordance between the everolimus studies and this one very large, 1,000-patient temsirolimus study — it was first-line. The emergence is that everolimus may, in fact, be a very good salvage for acquired AI resistance, if you’re giving it first line. These patients are typically not needing to be salvaged. This is de novo, so the first-line setting and the drug were the main ones.
DR LOVE: Edith, what were your thoughts about this? I really like the argument you made there about first line — the idea that somehow, when you develop resistance to endocrine therapy, this makes more sense. What are your thoughts?
DR PEREZ: What a great question. I was the chair of the IDMC for BOLERO-2. I remember the night in which we saw the data for the first time of efficacy and the dramatic difference in that trial. And we immediately thought about the temsirolimus data. How can we put these two things together? And then we started thinking: Are there some mechanisms of resistance to endocrine therapy that somehow sensitize the cells to enter inhibition? But we need to wait to see whether there will be enough tumor specimens collected in BOLERO-2 to really be able to address that issue.
At the same time, everolimus has been moved right to the adjuvant setting, though we think that the refractoriness, if I may mention, of hormonal therapy may be a factor. I think the magnitude of improvements seen in BOLERO-2 really warrant moving this drug into the first line and the adjuvant setting.
DR LOVE: Any thoughts, Hope, about how everolimus is going to play out in the adjuvant setting in terms of toxicity?
DR RUGO: Well, in terms of toxicity, I think it’s going to be important for us to get an idea about this prophylaxis against mouth sores. I think that in my experience it is critical to actually prevent the mouth sores from happening, to have very good patient education and then to have patients hold the drug before they call in when they start getting mouth sores and reduce it in the appropriate way.