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Other Novel Targets and Future Outlook in Breast Cancer

Panelists: Joyce A. OShaughnessy, MD, Baylor Charles A. Sammons Cancer Center; Sara A. Hurvitz, MD, UCLA Jonsson Comprehensive Cancer Center; Komal Jhaveri, MD, FACP, Memorial Sloan Kettering Cancer Center; Hope S. Rugo, MD, UCSF Helen Diller Family Comprehensive Cancer Center; Debu Tripathy, MD, The University of Texas MD Anderson Cancer Center
Published: Tuesday, Aug 28, 2018



Transcript: 

Joyce A. O’Shaughnessy, MD: Our last target of great interest in triple-negative breast cancer is AKT, which is so important since so many triple-negatives have lost PTEN and INPP4B, and have activated AKT. Can you update us on what’s going on there, Komal?

Komal Jhaveri, MD, FACP: A very small proportion, unlike the ER-positive population, in which about 40% of PIK3CA mutations are seen, have alterations of the PI3K/AKT/mTOR pathway. Yet, this is significant enough for us to think about targeting this pathway for this particular subtype. The very first AKT-targeted trial was the phase II LOTUS trial, which has now been published. This trial looked at a specific AKT inhibitor, ipatasertib. In the first-line triple-negative metastatic setting, they combined it with paclitaxel. Patients either got paclitaxel with placebo or paclitaxel with ipatasertib. The primary endpoint looked at progression-free survival in the entire population, but they had a stratification factor specifically for patients who had a PTEN-low status.

In terms of the primary endpoint, there was a new medical increase and a statistically significant increase in the progression-free survival, but that was rather modest—the same way we see it in our ER-positive patients with PIK3CA mutations and PI3K inhibitors.

When they looked at the PTEN-low status, this benefit was slightly larger and better. Furthermore, they looked into a smaller population where they had any alteration in PI3K/AKT, or PTEN loss. There, they saw that the benefit was even slightly better.

That’s why I think the next step for this agent is to look at it in the phase III study, which is looking at this combination in the first-line setting in patients who have an alteration in PI3K/AKT/mTOR, or have a PTEN alteration. I think that result will really help us define space for this molecule in the triple-negative subtype.

Hope S. Rugo, MD: There are other AKT inhibitors that are quite interesting, that are coming down the pike. I was surprised at the LOTUS data, and I’m even more interested in the suggestion of a survival benefit that Rebecca Dent presented. And Peter Schmidt’s data on AZD5363 is intriguing as well. A new area is kind of opening up in triple-negative disease.

Joyce A. O’Shaughnessy, MD: Yes. Well, thank you very much. I think we covered the waterfront, in terms of the ASCO Annual Meeting. What last comments would you like to make? Is there anything that you’d like to emphasize from ASCO?

Komal Jhaveri, MD, FACP: I think our themes of where to escalate and where to de-escalate are very obvious, based on these meetings where we’re trying to add more targeted therapies to a backbone in patients. An example is our CDK4/6 inhibitors, and our everolimus. We have newer targeted agents. And then, we’re also thinking about de-escalation and are trying to figure out where we want to de-escalate so that we can avoid the financial and physical toxicities of combination therapies. We are making a lot of progress, and I think we’re looking forward to more and more of this data so we can further refine how we treat our patients and connect to give them what they need, whether it’s more or less.

Joyce A. O’Shaughnessy, MD: Thank you.

Sara A. Hurvitz, MD: I agree. I couldn’t agree more. I would just add that I think the biomarker era and the era of personalized medicine is coming now. We are actually seeing data, like the data from LOTUS, that is helping us to define patient populations where our therapies will work. Things like cell-free DNA and circulating tumor DNA are going to have a huge impact in the future, in the way that we design studies to evaluate how to best treat patients using real-time data regarding what’s happening with the tumor.

Joyce A. O’Shaughnessy, MD: We saw the SOFT and TEXT update, and a simultaneous publication in the New England Journal of Medicine with this huge benefit—a 10% to 15% absolute benefit in disease-free survival with a LHRH agonist and an AI, even over a LHRH agonist and tamoxifen, never mind tamoxifen alone. It’s practice-changing. As I look back at women who did not get that, there’d be my own practice, you know? And because of this differential between tamoxifen and the AI, and we’ve seen that in the postmenopausal setting too… It’s that early split in the curve that makes the difference in AI versus tamoxifen. The same is true there. That’s definitely practice-changing. That’s a big benefit for the younger women, going forward.

Debu Tripathy, MD: We’re continuing to make incremental changes in personalized therapy. Maybe these are not huge steps, but you can talk about things that are a bit lower tech, like ovarian suppression and the impact that has, and balancing it against side effects using PRO data that have been generated so that you can actually help decide who’s going to go through those therapies and how to monitor them, all the way up to real-time molecular monitoring, which I hope starts to get built in to some of our studies. Then we can get a very early look as to whether someone’s destined to progress or not. It may even offer our patients opportunities for some of these novel phase II trials, to get one of several therapies in sequence and then stick with the one that dropped molecular counts the most. We’re not quite there yet, but these are the kinds of things that that we’re moving toward.

Joyce A. O’Shaughnessy, MD: Hope, how about you?

Hope S. Rugo, MD: I, of course, agree with what everybody has said. One of the encouraging things about this year’s ASCO Annual Meeting, in particular, and maybe this year, 2018, is that we’re not seeing all of these big non-focused trials. Hopefully what we’re doing is changing the whole thinking into treating patients better, in a smarter way, by understanding the genomics and changes of their cancer and the benefits from various different therapies. I think TAILORx is practice-changing. I think the updated data from TEXT and SOFT is incredibly important for our patients. I also feel like the studies looking at different pathways that are being targeted are really exciting. To me, this is the most exciting area right now.

Joyce A. O’Shaughnessy, MD: Well, thank you very much. This was a really great conversation. These were great contributions. Thanks so much. And on behalf of our panel, we thank you for joining us. We hope you found this Peer Exchange® discussion to be very useful and informative.

Transcript Edited for Clarity 

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Transcript: 

Joyce A. O’Shaughnessy, MD: Our last target of great interest in triple-negative breast cancer is AKT, which is so important since so many triple-negatives have lost PTEN and INPP4B, and have activated AKT. Can you update us on what’s going on there, Komal?

Komal Jhaveri, MD, FACP: A very small proportion, unlike the ER-positive population, in which about 40% of PIK3CA mutations are seen, have alterations of the PI3K/AKT/mTOR pathway. Yet, this is significant enough for us to think about targeting this pathway for this particular subtype. The very first AKT-targeted trial was the phase II LOTUS trial, which has now been published. This trial looked at a specific AKT inhibitor, ipatasertib. In the first-line triple-negative metastatic setting, they combined it with paclitaxel. Patients either got paclitaxel with placebo or paclitaxel with ipatasertib. The primary endpoint looked at progression-free survival in the entire population, but they had a stratification factor specifically for patients who had a PTEN-low status.

In terms of the primary endpoint, there was a new medical increase and a statistically significant increase in the progression-free survival, but that was rather modest—the same way we see it in our ER-positive patients with PIK3CA mutations and PI3K inhibitors.

When they looked at the PTEN-low status, this benefit was slightly larger and better. Furthermore, they looked into a smaller population where they had any alteration in PI3K/AKT, or PTEN loss. There, they saw that the benefit was even slightly better.

That’s why I think the next step for this agent is to look at it in the phase III study, which is looking at this combination in the first-line setting in patients who have an alteration in PI3K/AKT/mTOR, or have a PTEN alteration. I think that result will really help us define space for this molecule in the triple-negative subtype.

Hope S. Rugo, MD: There are other AKT inhibitors that are quite interesting, that are coming down the pike. I was surprised at the LOTUS data, and I’m even more interested in the suggestion of a survival benefit that Rebecca Dent presented. And Peter Schmidt’s data on AZD5363 is intriguing as well. A new area is kind of opening up in triple-negative disease.

Joyce A. O’Shaughnessy, MD: Yes. Well, thank you very much. I think we covered the waterfront, in terms of the ASCO Annual Meeting. What last comments would you like to make? Is there anything that you’d like to emphasize from ASCO?

Komal Jhaveri, MD, FACP: I think our themes of where to escalate and where to de-escalate are very obvious, based on these meetings where we’re trying to add more targeted therapies to a backbone in patients. An example is our CDK4/6 inhibitors, and our everolimus. We have newer targeted agents. And then, we’re also thinking about de-escalation and are trying to figure out where we want to de-escalate so that we can avoid the financial and physical toxicities of combination therapies. We are making a lot of progress, and I think we’re looking forward to more and more of this data so we can further refine how we treat our patients and connect to give them what they need, whether it’s more or less.

Joyce A. O’Shaughnessy, MD: Thank you.

Sara A. Hurvitz, MD: I agree. I couldn’t agree more. I would just add that I think the biomarker era and the era of personalized medicine is coming now. We are actually seeing data, like the data from LOTUS, that is helping us to define patient populations where our therapies will work. Things like cell-free DNA and circulating tumor DNA are going to have a huge impact in the future, in the way that we design studies to evaluate how to best treat patients using real-time data regarding what’s happening with the tumor.

Joyce A. O’Shaughnessy, MD: We saw the SOFT and TEXT update, and a simultaneous publication in the New England Journal of Medicine with this huge benefit—a 10% to 15% absolute benefit in disease-free survival with a LHRH agonist and an AI, even over a LHRH agonist and tamoxifen, never mind tamoxifen alone. It’s practice-changing. As I look back at women who did not get that, there’d be my own practice, you know? And because of this differential between tamoxifen and the AI, and we’ve seen that in the postmenopausal setting too… It’s that early split in the curve that makes the difference in AI versus tamoxifen. The same is true there. That’s definitely practice-changing. That’s a big benefit for the younger women, going forward.

Debu Tripathy, MD: We’re continuing to make incremental changes in personalized therapy. Maybe these are not huge steps, but you can talk about things that are a bit lower tech, like ovarian suppression and the impact that has, and balancing it against side effects using PRO data that have been generated so that you can actually help decide who’s going to go through those therapies and how to monitor them, all the way up to real-time molecular monitoring, which I hope starts to get built in to some of our studies. Then we can get a very early look as to whether someone’s destined to progress or not. It may even offer our patients opportunities for some of these novel phase II trials, to get one of several therapies in sequence and then stick with the one that dropped molecular counts the most. We’re not quite there yet, but these are the kinds of things that that we’re moving toward.

Joyce A. O’Shaughnessy, MD: Hope, how about you?

Hope S. Rugo, MD: I, of course, agree with what everybody has said. One of the encouraging things about this year’s ASCO Annual Meeting, in particular, and maybe this year, 2018, is that we’re not seeing all of these big non-focused trials. Hopefully what we’re doing is changing the whole thinking into treating patients better, in a smarter way, by understanding the genomics and changes of their cancer and the benefits from various different therapies. I think TAILORx is practice-changing. I think the updated data from TEXT and SOFT is incredibly important for our patients. I also feel like the studies looking at different pathways that are being targeted are really exciting. To me, this is the most exciting area right now.

Joyce A. O’Shaughnessy, MD: Well, thank you very much. This was a really great conversation. These were great contributions. Thanks so much. And on behalf of our panel, we thank you for joining us. We hope you found this Peer Exchange® discussion to be very useful and informative.

Transcript Edited for Clarity 
View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Miami Breast Cancer Conference®: Attendee Tumor Board OnlineNov 30, 20181.5
Community Practice Connections™: 1st Annual Paris Breast Cancer Conference™Dec 31, 20181.5
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