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PI3K Inhibitors in HR+ Metastatic Breast Cancer

Panelists: Adam M. Brufsky, MD, PhD, University of Pittsburgh School of Medicine; Mark E. Robson, MD, Memorial Sloan Kettering Cancer Center; Aditya Bardia, MD, MPH, Massachusetts General Hospital Cancer Center; Kimberly L. Blackwell, MD, Duke Cancer Institute
Published: Friday, Mar 03, 2017



Transcript:

Adam M. Brufsky, MD, PhD:
Let’s switch again. The last thing we want to talk about are PI3-kinase inhibitors. I know you participated in BELLE-3 or BELLE-2.

Aditya Bardia, MD, MPH: BELLE-2.

Adam M. Brufsky, MD, PhD: What do you think of BELLE-3, which was presented last year? Then we had taselisib presented this year. What do you think of where we’re going? What do you think of those trials? Will you let our audience know what they’re about?

Aditya Bardia, MD, MPH: Buparlisib, or BKM120, is a pan-PI3-kinase inhibitor. So, BELLE-2 was a clinical trial very similar to BOLERO-2, where patients who had received a prior AI were randomized to receive fulvestrant versus fulvestrant plus a PI3 kinase inhibitor, buparlisib. And BELLE-3 was even an extension of that. These were patients who had received prior AIs, including an AI plus mTOR, and were randomized to receive fulvestrant alone versus fulvestrant plus buparlisib. And the trial did show a statistically significant benefit. Patients who received fulvestrant plus the PI3-kinase inhibitor had an improvement in progression-free survival compared to fulvestrant alone. But if you look at the data, the control arm did not do very well, and that’s to be expected in a patient population that has received multiple prior lines of therapy, including an mTOR inhibitor. In that patient population, giving fulvestrant would not be that helpful, and the trial did show that the control arm did not do that well. But the addition of the PI3-kinase inhibitor did have an improvement in progression-free survival that was clinically significant, and one could potentially argue that it was clinically meaningful as well.

The challenge with the PI3-kinase inhibitor, buparlisib, is the potential toxicity. It does cause effects on the CNS system. So, some patients had an increase in depression, concern for suicide, and also LFT abnormalities. There is interest in PI3-kinase inhibitors that are more selective, like taselisib or alpelisib—which is another drug by Novartis—that are alpha-selective PI3-kinase inhibitors. So, the idea is that you inhibit the alpha component of PI3-kinase, which is what drives tumor progression, but you don’t affect the other components—the beta, gamma, delta—which can contribute to the side effects. You have a very selective PI3-kinase inhibitor that can essentially achieve the same result with lower toxicity. It reminds us of the CDK4/6 story as well. When pan-CDK4/6 inhibitors were developed in the 2000s, they were abandoned because of toxicity. But when CDK4/6 selective inhibitors were developed, that is when we saw the success. So, it’s about selectivity towards the tumor while lowering the side effects.

Adam M. Brufsky, MD, PhD: But the issue is with taselisib, we got a phase III trial. It was, in my understanding, very similar to the BELLE trial—taselisib and placebo with a second-line endocrine therapy—and there was a PFS of 1 to 2 months. It was statistically significant. But really, what do you do? It sounds like if I’m a pharma, I’m probably not going to develop taselisib based on that, just like we’re not going to develop BKM120, I assume. What do we do now?

Kimberly L. Blackwell, MD: The BKM120 studies are interesting. Baselga went back and looked at activating mutations in the PI3-kinase, and that’s truly what drives the difference in PFS. In patients who had cell-free DNA PI3-kinase mutations, there’s a 3.6-month absolute difference, roughly, in PFS for the addition of the PI3-kinase inhibitor versus where the mutation wasn’t found in cell-free DNA. Those curves are right on top of one another, I absolutely agree. It’s like the fine tuning, which is not only do you get a more specific drug, but I think it also is going to be what’s going on in the tumor itself. I’m really coming to a very optimistic place that cell-free DNA, alongside with some of the other things that we’re doing in the genomics world, might help “Big Pharma” get the right drugs to the right patients.

Adam M. Brufsky, MD, PhD: And we may come up with doing cell-free DNA assays at an earlier point. There seems to be a lot of targeted therapies we can now potentially use and figure out the therapy.

Transcript Edited for Clarity

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Transcript:

Adam M. Brufsky, MD, PhD:
Let’s switch again. The last thing we want to talk about are PI3-kinase inhibitors. I know you participated in BELLE-3 or BELLE-2.

Aditya Bardia, MD, MPH: BELLE-2.

Adam M. Brufsky, MD, PhD: What do you think of BELLE-3, which was presented last year? Then we had taselisib presented this year. What do you think of where we’re going? What do you think of those trials? Will you let our audience know what they’re about?

Aditya Bardia, MD, MPH: Buparlisib, or BKM120, is a pan-PI3-kinase inhibitor. So, BELLE-2 was a clinical trial very similar to BOLERO-2, where patients who had received a prior AI were randomized to receive fulvestrant versus fulvestrant plus a PI3 kinase inhibitor, buparlisib. And BELLE-3 was even an extension of that. These were patients who had received prior AIs, including an AI plus mTOR, and were randomized to receive fulvestrant alone versus fulvestrant plus buparlisib. And the trial did show a statistically significant benefit. Patients who received fulvestrant plus the PI3-kinase inhibitor had an improvement in progression-free survival compared to fulvestrant alone. But if you look at the data, the control arm did not do very well, and that’s to be expected in a patient population that has received multiple prior lines of therapy, including an mTOR inhibitor. In that patient population, giving fulvestrant would not be that helpful, and the trial did show that the control arm did not do that well. But the addition of the PI3-kinase inhibitor did have an improvement in progression-free survival that was clinically significant, and one could potentially argue that it was clinically meaningful as well.

The challenge with the PI3-kinase inhibitor, buparlisib, is the potential toxicity. It does cause effects on the CNS system. So, some patients had an increase in depression, concern for suicide, and also LFT abnormalities. There is interest in PI3-kinase inhibitors that are more selective, like taselisib or alpelisib—which is another drug by Novartis—that are alpha-selective PI3-kinase inhibitors. So, the idea is that you inhibit the alpha component of PI3-kinase, which is what drives tumor progression, but you don’t affect the other components—the beta, gamma, delta—which can contribute to the side effects. You have a very selective PI3-kinase inhibitor that can essentially achieve the same result with lower toxicity. It reminds us of the CDK4/6 story as well. When pan-CDK4/6 inhibitors were developed in the 2000s, they were abandoned because of toxicity. But when CDK4/6 selective inhibitors were developed, that is when we saw the success. So, it’s about selectivity towards the tumor while lowering the side effects.

Adam M. Brufsky, MD, PhD: But the issue is with taselisib, we got a phase III trial. It was, in my understanding, very similar to the BELLE trial—taselisib and placebo with a second-line endocrine therapy—and there was a PFS of 1 to 2 months. It was statistically significant. But really, what do you do? It sounds like if I’m a pharma, I’m probably not going to develop taselisib based on that, just like we’re not going to develop BKM120, I assume. What do we do now?

Kimberly L. Blackwell, MD: The BKM120 studies are interesting. Baselga went back and looked at activating mutations in the PI3-kinase, and that’s truly what drives the difference in PFS. In patients who had cell-free DNA PI3-kinase mutations, there’s a 3.6-month absolute difference, roughly, in PFS for the addition of the PI3-kinase inhibitor versus where the mutation wasn’t found in cell-free DNA. Those curves are right on top of one another, I absolutely agree. It’s like the fine tuning, which is not only do you get a more specific drug, but I think it also is going to be what’s going on in the tumor itself. I’m really coming to a very optimistic place that cell-free DNA, alongside with some of the other things that we’re doing in the genomics world, might help “Big Pharma” get the right drugs to the right patients.

Adam M. Brufsky, MD, PhD: And we may come up with doing cell-free DNA assays at an earlier point. There seems to be a lot of targeted therapies we can now potentially use and figure out the therapy.

Transcript Edited for Clarity
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Online CME Activities
TitleExpiration DateCME Credits
34th Annual Miami Breast Cancer Conference® Clinical Case Vignette Series™May 25, 20182.0
Community Practice Connections™: CDK4/6 Inhibitors With the Experts: The Role of Emerging Agents for the Management of Metastatic Breast CancerMay 30, 20182.0
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