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The Emerging Role of PI3K Inhibition in Breast Cancer

Panelists:Adam M. Brufsky, MD, PhD, University of Pittsburgh Cancer Institute;Carlos L. Arteaga, MD, Vanderbilt University;Kimberly L. Blackwell, MD, Duke University Medical Center;Joyce A. O’Shaughnessy, MD, Baylor Charles A. Sammons Cancer Center;Sunil Verma, MD, MSEd, FRCPC, University of Calgary
Published: Tuesday, Jul 19, 2016


Transcript:

Adam M. Brufsky, MD, PhD:
Speaking about monitoring for somatic changes, I think that we’ve seen some data—at least for other tumors from liquid biopsy—on the Guardant assay. I think that, going forward, is that how we’re going to be doing things, a more circulating tumor DNA as opposed to actually rebiopsying the tumor itself? What are your guys’ thoughts about that?

Kimberly L. Blackwell, MD: I don’t think we’re going to be using any of these in the clinic until we get the bioinformatics caught up with the data that are being derived. So, Carlos’s points about following the tumor sequentially is so important. But then, when I go home from this year’s ASCO meeting and I’ve seen all this great science, does it still mean I’m not going to use everolimus in the second-line setting? Probably not, because it’s a targeted therapy that’s been shown to improve progression-free survival. I think we need the bioinformatics to catch up with the science to help us poor clinicians trying to figure out what to do with patients.

Adam M. Brufsky, MD, PhD: That’s a great question. Right now, you have someone—thankfully it may take 2 years—but you have someone who now progresses on a CDK4/6 inhibitor and, say, letrozole. A lot of people in the community, a lot of people everywhere, really will go to a cytotoxic chemotherapy. What would you guys do? Would you go to exemestane and everolimus?

Sunil Verma, MD, MSEd, FRCPC: Or single-agent endocrine therapy is still an option on the table, as well.

Adam Brufsky, MD, PhD: Right, absolutely.

Sunil Verma, MD, MSEd, FRCPC: I don’t think necessarily the fact that they had a cell cycle inhibitor means that they need to go to another one, destroy it with chemotherapy. I think endocrine treatment alone is an option, endocrine plus an mTOR inhibitor is an option, and, of course, chemotherapy—if they have significant visceral disease—is an option. But I would not take endocrine treatment off the table for those patients.

Joyce A. O’Shaughnessy, MD: My clinical experience, so far, is patients who still have disease that we would otherwise give endocrine therapy to—looking at sites of disease, tempo of disease—I have had very good responses with everolimus and exemestane or tamoxifen and everolimus after a CDK4/6 inhibitor. I’ve had a number of patients with those ER-(estrogen receptor) driven sites, if you will, not the kind that are calling out for chemotherapy.

Kimberly L. Blackwell, MD: I think people have kind of forgotten about everolimus, honestly, and I think we need to bring it back up on our radar screen. I think we have to be very cautious about jumping from one targeted therapy lily pad to the other. I think these are great to have these options, especially with the targeted agents.

Adam M. Brufsky, MD, PhD: I agree. One last thing before we go off the subject: we have all these great new targeted agents. Where does this leave the PI3 kinase inhibitors? We know we’ve had the BELLE trial, but now we have the alpha-specific agents. What are your thoughts on those, and where do you think they’re going?

Sunil Verma, MD, MSEd, FRCPC: There are two large phase III trials, the SOLAR-1 study and the SANDPIPER trials, which are being done. Again, probably most likely that these agents are going to be more specifically active in a PI3 kinase mutation-positive patient population rather than all-comers. So, it remains to be seen. We probably won’t see data until late 2017, mid-2018, for some of this, and it will give us time to pause and at least reflect on what we have been able to achieve with CDK4/6 and adjust to that before we start looking at how that data fits in. But I think my bet is going to be that it’s going to be more specific in the PI3 kinase mutation-positive patients rather than all-comers.

Adam M. Brufsky, MD, PhD: Any other comments, Joyce?

Joyce A. O’Shaughnessy, MD: No. The only thing that I’ll mention is with the BELLE-2 clinical trial with the buparlisib—the more pan-PI3 kinase inhibitor, fulvestrant plus/minus—it met its primary endpoint, but it was only a 6-week improvement in PFS, which was not really clinically meaningful in the context of the toxicities. But what was interesting is that the PIK3CA mutation status of the primary cancers did not predict for response. It was the cell-free DNA, the circulating tumor DNA, that had PIK3CA mutations at the time of study entry onto trial. That’s where the benefit of buparlisib was seen specifically in those patients. So, the Darwinian evolution and the outgrowth of these clones, at that point in metastatic disease, really predicted for benefit. Because sometimes, obviously, lots of years go by between the primary diagnoses by the time they’re getting these agents.

Carlos L. Arteaga, MD: I agree that the window for PI3 kinase inhibitors may have shrunken a bit, and I’m happy that patients are being stratified based on PIK3CA mutations—which is the group where PI3 kinase alpha inhibitors are likely to work. But there’s going to be a group of patients that may require triple therapy, anti-estrogens, CDK 4 inhibitors, and PI3K inhibitors. I don’t expect them to be that many, but there’s going to be a group, and there are data that suggest that both pathways may be yin-yang, ER/CDK4 and PI3 kinase.

Kimberly L. Blackwell, MD: And we see that in the HER2 space, as well. If we look at BOLERO-1 and BOLERO-3, the subgroup analysis where everolimus really made a difference in the first-line metastatic was actually in the PI3 kinase mutation. So, I agree with you. I think our brains think very linear, and I think we’ve got to start thinking in parallel processing.

Transcript Edited for Clarity
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Transcript:

Adam M. Brufsky, MD, PhD:
Speaking about monitoring for somatic changes, I think that we’ve seen some data—at least for other tumors from liquid biopsy—on the Guardant assay. I think that, going forward, is that how we’re going to be doing things, a more circulating tumor DNA as opposed to actually rebiopsying the tumor itself? What are your guys’ thoughts about that?

Kimberly L. Blackwell, MD: I don’t think we’re going to be using any of these in the clinic until we get the bioinformatics caught up with the data that are being derived. So, Carlos’s points about following the tumor sequentially is so important. But then, when I go home from this year’s ASCO meeting and I’ve seen all this great science, does it still mean I’m not going to use everolimus in the second-line setting? Probably not, because it’s a targeted therapy that’s been shown to improve progression-free survival. I think we need the bioinformatics to catch up with the science to help us poor clinicians trying to figure out what to do with patients.

Adam M. Brufsky, MD, PhD: That’s a great question. Right now, you have someone—thankfully it may take 2 years—but you have someone who now progresses on a CDK4/6 inhibitor and, say, letrozole. A lot of people in the community, a lot of people everywhere, really will go to a cytotoxic chemotherapy. What would you guys do? Would you go to exemestane and everolimus?

Sunil Verma, MD, MSEd, FRCPC: Or single-agent endocrine therapy is still an option on the table, as well.

Adam Brufsky, MD, PhD: Right, absolutely.

Sunil Verma, MD, MSEd, FRCPC: I don’t think necessarily the fact that they had a cell cycle inhibitor means that they need to go to another one, destroy it with chemotherapy. I think endocrine treatment alone is an option, endocrine plus an mTOR inhibitor is an option, and, of course, chemotherapy—if they have significant visceral disease—is an option. But I would not take endocrine treatment off the table for those patients.

Joyce A. O’Shaughnessy, MD: My clinical experience, so far, is patients who still have disease that we would otherwise give endocrine therapy to—looking at sites of disease, tempo of disease—I have had very good responses with everolimus and exemestane or tamoxifen and everolimus after a CDK4/6 inhibitor. I’ve had a number of patients with those ER-(estrogen receptor) driven sites, if you will, not the kind that are calling out for chemotherapy.

Kimberly L. Blackwell, MD: I think people have kind of forgotten about everolimus, honestly, and I think we need to bring it back up on our radar screen. I think we have to be very cautious about jumping from one targeted therapy lily pad to the other. I think these are great to have these options, especially with the targeted agents.

Adam M. Brufsky, MD, PhD: I agree. One last thing before we go off the subject: we have all these great new targeted agents. Where does this leave the PI3 kinase inhibitors? We know we’ve had the BELLE trial, but now we have the alpha-specific agents. What are your thoughts on those, and where do you think they’re going?

Sunil Verma, MD, MSEd, FRCPC: There are two large phase III trials, the SOLAR-1 study and the SANDPIPER trials, which are being done. Again, probably most likely that these agents are going to be more specifically active in a PI3 kinase mutation-positive patient population rather than all-comers. So, it remains to be seen. We probably won’t see data until late 2017, mid-2018, for some of this, and it will give us time to pause and at least reflect on what we have been able to achieve with CDK4/6 and adjust to that before we start looking at how that data fits in. But I think my bet is going to be that it’s going to be more specific in the PI3 kinase mutation-positive patients rather than all-comers.

Adam M. Brufsky, MD, PhD: Any other comments, Joyce?

Joyce A. O’Shaughnessy, MD: No. The only thing that I’ll mention is with the BELLE-2 clinical trial with the buparlisib—the more pan-PI3 kinase inhibitor, fulvestrant plus/minus—it met its primary endpoint, but it was only a 6-week improvement in PFS, which was not really clinically meaningful in the context of the toxicities. But what was interesting is that the PIK3CA mutation status of the primary cancers did not predict for response. It was the cell-free DNA, the circulating tumor DNA, that had PIK3CA mutations at the time of study entry onto trial. That’s where the benefit of buparlisib was seen specifically in those patients. So, the Darwinian evolution and the outgrowth of these clones, at that point in metastatic disease, really predicted for benefit. Because sometimes, obviously, lots of years go by between the primary diagnoses by the time they’re getting these agents.

Carlos L. Arteaga, MD: I agree that the window for PI3 kinase inhibitors may have shrunken a bit, and I’m happy that patients are being stratified based on PIK3CA mutations—which is the group where PI3 kinase alpha inhibitors are likely to work. But there’s going to be a group of patients that may require triple therapy, anti-estrogens, CDK 4 inhibitors, and PI3K inhibitors. I don’t expect them to be that many, but there’s going to be a group, and there are data that suggest that both pathways may be yin-yang, ER/CDK4 and PI3 kinase.

Kimberly L. Blackwell, MD: And we see that in the HER2 space, as well. If we look at BOLERO-1 and BOLERO-3, the subgroup analysis where everolimus really made a difference in the first-line metastatic was actually in the PI3 kinase mutation. So, I agree with you. I think our brains think very linear, and I think we’ve got to start thinking in parallel processing.

Transcript Edited for Clarity
View Conference Coverage
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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