Breast Cancer Update, Issue 2, 2016 (Video Program) - Video 22Novel PI3K inhibitors under investigation in mBC: Alpelisib and taselisib
4:22 minutes.
TRANSCRIPTION:
DR LOVE: I see that you’re involved with research on PI3 kinase inhibitors and a couple I never heard of before. Taselisib and alpelisib are a couple of them that are out there, but how do these agents work? Are they utilized more with ER-positive disease? And what do we know about them? DR DICKLER: Right. So let’s back up a little bit and think about everolimus. And we know everolimus is an mTOR inhibitor. So I’m just going to simplify it. But when you think about it’s the PI3K, AKT, mTOR pathway, which is really important in ER-positive breast cancer, and we know that adding an mTOR inhibitor, everolimus, to exemestane in the second- or third-line setting improves progression-free survival. That was shown by José Baselga in the BOLERO-2 trial. But we do worry that when we inhibit mTOR, which is distal, as you say, we know that mTOR negatively feeds back on the PI3 kinase, which is more proximal. And when you inhibit mTOR, we interfere with that negative feedback loop. My colleague Sarat Chandarlapaty has shown that we really get more activity down the proximal part of the pathway. So the thought is that if we give an inhibitor earlier and inhibit PI3K, particularly PI3K alpha, that we may get better downregulation down the pathway. And there’s a number of PI3K inhibitors in development in ER-positive breast cancer. There’s also preclinical data to suggest that when you inhibit PI3K, you get increased expression of ER. So it’s thought that you want to give 2 of these drugs together. You want to downregulate both PI3K and ER. And that’s why they’re being looked at in combination. So there’s been a number of Phase I studies, Phase I and II studies. And now there are large randomized Phase III trials that are testing PI3K inhibitors. There are 2 other Phase III studies that are enrolling. One of them is the SANDPIPER trial, which is a study of fulvestrant with or without taselisib, okay? The GDC-0032. And then there’s another study, the SOLAR-1 trial, which is the same backbone of fulvestrant with or without BYL719, or alpelisib. So these are 2 large randomized Phase III studies with 2 different agents that are currently enrolling. And they will be designed to look at the benefit of these agents both in the general population and then specifically in patients that have PIK3CA mutations. DR LOVE: And what about tolerability, for example, of these 2 agents, taselisib and alpelisib? DR DICKLER: So some of the side effects that we see are, actually, the drugs are a little bit different. For taselisib, we’ve seen sometimes diarrhea and colitis that develops 3 to 4 months into treatment. And it’s thought to be immune-mediated colitis. DR LOVE: That sounds like idelalisib from lymphoma. DR DICKLER: Correct. Correct. And that’s potentially due to some, I think, delta inhibition, whereas that’s not really seen with the alpelisib. But alpelisib can cause skin rash. Both of these drugs and these classes of drugs in general can cause hyperglycemia, just like everolimus, and, actually, that’s an on-target effect. We know when we’re seeing hyperglycemia from these agents that we are inhibiting the pathway. And it’s something that needs to be monitored closely and treated. And often, metformin is a useful addition. I know with everolimus, we also have to watch the triglycerides. That’s something else that has to be monitored, not so much with these PI3K inhibitors. |