PI3K Inhibitors for HR+ Breast Cancer

Transcript:Adam M. Brufsky, MD, PhD: One last question I think before we summarize this. Is there any role for PI3 kinase inhibitors in this disease?

Hope S. Rugo, MD: Oh, I think so.

Ahmad Awada, MD, PhD: I’m waiting. It’s the last chance for this.

Adam M. Brufsky, MD, PhD: The last chance?

Ahmad Awada, MD, PhD: Yes, it’s selective. It’s called ‘alpha-selective,’ right Hope? If this is really positive, okay, it’s not positive, I think…

Hope S. Rugo, MD: But, I’ve already seen clinical data that suggest that it’s going to be very positive. We’ll see. I think that the toxicity, at least in our early phase trials, has been manageable and the efficacy has been really quite significant and durable even after everolimus.

Michael Untch, MD: I’m a burned kid. We had the experience in Germany. We had to stop that, a lot of toxicity.

Adam M. Brufsky, MD, PhD: Nonspecific?

Michael Untch, MD: Nonspecific buparlisib. So, again, I’m a burned kid.

Hope S. Rugo, MD: I used buparlisib, too, and had significant toxicities, but with alpelisib, I haven’t seen it. Taselisib seems to have a little bit more GI toxicity, but efficacy was shown with both drugs in early studies. So, where they’re both in randomized phase III trials and there are other PI3 kinase inhibitors that are selective coming down the pike, I think we’ll see drugs approved for ER-positive breast cancer that target the alpha subunit.

Adam M. Brufsky, MD, PhD: And do we believe the circulating PI3 kinase mutation as a biomarker?

Ahmad Awada, MD, PhD: You are mentioning the BELLE-2 trial. This was a subgroup analysis which, to some extent, saves the trial.

Adam M. Brufsky, MD, PhD: Right. Well, it saved it potentially. It’s not going to save the drug I don’t think at this point.

Ahmad Awada, MD, PhD: Yes. The whole population is not going to have any difference. That’s with the alpha-selective inhibitor.

Adam M. Brufsky, MD, PhD: So, the alpha-selective, are they using it as selection or as a post-op stratification?

Hope S. Rugo, MD: You have to have a certain number of patients who have PI3 kinase mutations, so you have to have the data in order to randomized because they’re stratified by…. But, the future is really going to be looking at these cell-free DNA in blood because it’s something that we can get over time. We know that PI3 kinase mutations change over time and increase in the metastatic setting. I actually thought that the BELLE-2 data, although a minority of patients, was intriguing. If it had been negative, maybe they wouldn’t have shown it, I don’t know. But, it was negative looking at the tumor when a lot of it was an archival tumor. So, I think that blood is the way to go going forward, that looking at these PI3 kinase mutations might help us in the future.

Michael Untch, MD: What I have learned from you guys, from the United States, is don’t do too much data massage. Go back to the lab.

Adam M. Brufsky, MD, PhD: I agree.

Michael Untch, MD: I have learned this notion or this sentence, so let’s go back to the lab and do some additional work and not too much data massage.

Adam M. Brufsky, MD, PhD: I would agree. That’s a great way to end, on, don’t do too much data massage. I think this has been extremely informative. Before we end the discussion, I’d like to get some final thoughts from each of our panelists. So, Dr. Awada?

Ahmad Awada, MD, PhD: I think really we are living in an exciting time with the clinical results. I think the separation of breast cancer in 3 groups—hormone receptor-positive, HER2-positive, and triple-negative breast cancer—even though we know the heterogeneity of the disease, helped us a lot in understanding and advancing in the treatment of these patients. So, I think this is really, for me, was the major advance; subdividing in clinical trials and studying each group apart. And, we discussed there are a lot of really new options for our patients and we are trying to improve these options. This is a very exciting time.

Adam M. Brufsky, MD, PhD: Hope?

Hope S. Rugo, MD: I think that I agree with everything you said. I think, to add on, where we are now is we have some exciting new drugs. We really can change areas of treatment that we couldn’t before, but it’s critical for us to know, moving forward, what the natural history of disease is. It’s shocking, really, that we don’t understand the natural history of metastatic breast cancer well with various treatments, that there aren’t international registries like that. I think it’s really important for us to know who needs what therapies so that we’re not giving everybody everything, but that we’re trying to really use everything. And if we can’t look at a biomarker yet, we should be looking at the phenotype of a cancer or how it responded to what you gave it before and what it is looking like at the present. And I think that some of the international collaborations, which are just starting to really create either patient-derived registries of what goes on with them in metastatic disease, are looking at collecting blood and tumor tissue. And annotating the cancer are the ways that we’re going to move forward very effectively in the metastatic setting. We’re already doing that in the neoadjuvant setting.

Adam M. Brufsky, MD, PhD: Great. Michael?

Michael Untch, MD: To sum up, I always try to see it from the perspective of our patients. The HER2-positive disease story is not at its end. We have a new beginning, which is good for the patients. In patients with hormone receptor-positive disease, we know that they have a long-lasting risk of recurrence and metastasis. And with the new kids on the block, the CDK4/6 inhibitors, the fulvestrant story, we have more options. You have seen, in our controversial discussion, where to place this treatment first, and second, and third. I think we are old enough to know that 25 years ago we had much less options than today, we have many more options. So, for the patient, it’s a good story and I hope that we follow up on this in the next meetings, and I’m happy to be part of this development. Thank you.

Adam M. Brufsky, MD, PhD: Very good. Again, thank you all. Thank you all for your contributions to the discussion. On behalf of our panel, we thank you for joining us, and we hope you found this Peer Exchange® discussion to be useful and informative. Again, thank you all very much and thank you for listening to us.

Transcript Edited for Clarity