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Therapy Approaches in HR+ Breast Cancer

Panelists: Joyce A. O'Shaughnessy, 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: Thursday, Jul 12, 2018



Transcript: 

Joyce A. O’Shaughnessy, MD: Hello, and thank you for joining this OncLive® Peer Exchange® entitled “Expanding Therapeutic Options for Breast Cancer.” It’s a very exciting time in breast cancer. More than ever, researchers are learning about what drives the behavior of aggressive tumors and how to personalize treatment approaches for patients with both early and advanced disease. Today, in this OncLive® Peer Exchange®, I’m joined by a group of expert colleagues who really are at the top of the field. We’ll discuss the data from the 2018 ASCO Annual Meeting and consider how this new information will add to our knowledge regarding how to improve outcomes for patients. We’re going to spend the bulk of our time talking about hormone receptor–positive breast cancer. Then, we’ll also discuss some exciting new approaches for metastatic triple-negative breast cancers.

I am Dr. Joyce O’Shaughnessy. I’m the Celebrating Women’s Chair in breast cancer research at Baylor University Medical Center, Texas Oncology, and US Oncology. Participating today on our distinguished panel is Dr. Sara Hurvitz, director of Breast Oncology at UCLA Jonsson Comprehensive Cancer Center. Hi, Sara.

Sara A. Hurvitz, MD: Hi.

Joyce A. O’Shaughnessy, MD: We also have Dr. Komal Jhaveri, a medical oncologist in the Breast Medicine and Early Drug Development Service at Memorial Sloan Kettering Cancer Center.

Komal Jhaveri, MD, FACP: Hi, Joyce.

Joyce A. O’Shaughnessy, MD: Dr. Hope Rugo, a professor of medicine and director of the Breast Oncology Clinical Trials Program at the UCSF Comprehensive Cancer Center in San Francisco, and Dr. Debu Tripathy, professor and chair of the Department of Breast Medical Oncology at MD Anderson Cancer Center.

It’s really great to be here with you today. I’m sure we’re going to have a really good discussion about 3 major segments. The first one is hormone receptor–positive metastatic breast cancer. We’ll start with that first, and I guess we’ll start with a burning question: Komal, does every woman with ER–positive metastatic breast cancer need to have a CDK4/6 inhibitor? And if so, when, in the natural history?

Komal Jhaveri, MD, FACP: That’s a very important question. Given the data that we now have for 3 approved CDK4/6 inhibitors—palbociclib, abemaciclib, and ribociclib—all 3 have now shown that in combination with an aromatase inhibitor in the first-line setting and with fulvestrant in the second-line setting—there are also some data with fulvestrant in the first-line setting—there is a consistent benefit with a consistent hazard ratio across all of the trials in post- and premenopausal women. So, I would say that the answer to that would be yes.

Joyce A. O’Shaughnessy, MD: Thank you. How about premenopausal, perimenopausal, and postmenopausal women, Sara? What kind of data do we have around those subsets?

Sara A. Hurvitz, MD: To echo what Komal has just said, these progression-free survival data that we are seeing now have never been published for hormone receptor–positive breast cancer. We’ve never gotten to 2 years progression-free survival in the frontline setting. An obvious question becomes, if all of these data are in postmenopausal women, can we apply them to our premenopausal, younger women? Indeed, we can. We have a couple of studies in the second-line setting. We have the abemaciclib data, as well as the palbociclib data, in the MONARCH 2 and PALOMA-3 studies. A subset of women enrolled; somewhere around 20% were pre- or perimenopausal. They were given an LHRH agonist. The progression-free survival differences, or the hazard ratio, was strikingly similar to the overall population. In other words, younger women do benefit from the addition of a CDK4/6 inhibitor to fulvestrant therapy as long as they’re getting an LHRH agonist.

Debu presented and published, or is publishing, the very important MONALEESA-7 data, which was an entire study dedicated to younger women who were pre- or perimenopausal. This study looked at endocrine therapy plus an LHRH agonist with or without ribociclib. The hazard ratio, 0.553, is exactly what we’re seeing in postmenopausal women, with objective responses in excess of 50% for all of these studies. We’re getting data that we see with chemotherapy. This really is pretty impressive data for both younger and older women.

Joyce A. O’Shaughnessy, MD: I think that’s really an important point, too, about where the CDK4/6 inhibitors are taking us. It certainly takes us away from endocrine monotherapy, although we’re going to ask Debu about that in a little bit. It also may be taking us away from chemotherapy, a little bit, in the first-line setting. Is that happening in your practice, Sara?

Sara A. Hurvitz, MD: It is. Our NCCN and ASCO guidelines tell us that we should be using endocrine or hormonally directed therapies for hormone receptor–positive breast cancer in all but the most rare situations of visceral crisis or fulminant; for example, liver failure. The results we’re seeing are impressive. They’re impressive because the therapeutic index is well preserved. We’re seeing great outcomes, and we’re having less toxicity than we see with traditional chemotherapy.

Joyce A. O’Shaughnessy, MD: Yes. Even in the premenopausal patients, where we get very worried—somebody with de novo metastatic, very, very aggressive disease—the median progression-free survival, even in those young women, in the first-line setting, is in excess of 2 years. This is better than we would get with chemotherapy. That’s really a sea change, isn’t it? I think we’re all kind of getting more and more comfortable with CDK4/6 inhibitors in the first-line setting.

Hope S. Rugo, MD: I do think that there probably is a group of patients who will do very well with endocrine therapy alone. I think we now treat so heavily in the adjuvant setting that most of the patients we see are always going to get CDK4/6 inhibitors. But occasionally, you’ll find an older patient with a single soft tissue lesion who’s never had endocrine therapy. It may make more sense for them, in terms of the complexity and cost of therapy, to start with endocrine therapy alone and use the CDK4/6 inhibitor as second-line treatment. I rarely see a patient like that—maybe 1 every few years—but I do think it’s something to keep in mind. It’s not an obligatory addition, but most patients will benefit. In patients who come in with de novo metastatic disease, who have a liver lesion or something like that, we actually have a treatment where we could now avoid chemotherapy upfront. Ovarian suppression is a really important part of that combined therapy with patients. Your study, Debu, showed that some of those patients could get tamoxifen?

Debu Tripathy, MD: That’s right. In the MONALEESA-7 trial, we actually looked at the option of tamoxifen or a nonsteroidal aromatase inhibitor. About 25% of the patients were, in fact, on tamoxifen. Although the study wasn’t powered to look at the benefit individually, the hazard ratios were very similar with tamoxifen, and so that is an option. It may not be what I start with, but when patients are having a lot of trouble with aromatase inhibitors, it is certainly an option.

Then, to speak to the issues in older women, it’s been shown across all of the studies, including in an FDA analysis that was done, that the adverse event rate is a little higher, but the outcomes are just as good, or maybe even better. We have a poster that looks at patients over the age of 65 and over the age of 70. They also do well. I think it is really hard to decide who not to treat, keeping in mind that we haven’t yet shown a survival benefit. The trials weren’t designed to show that. What has now emerged in the studies that are looking at quality of life is the time to deterioration in quality of life or, in some cases, improvement in quality of life, which is definitely more favorable in the CDK4/6-treated group.

Hope S. Rugo, MD: In terms of the adverse events from the FDA’s pooled analysis and just from my own clinical practice, I have found that older patients have more profound fatigue. They do fine otherwise, but the profound fatigue is a big issue. So, I tend to dose-reduce patients in that setting, which is an interesting thing. The FDA analysis also showed that there were more dose reductions in those patients. It’s just something to keep in mind when we’re treating patients who are older.

Komal Jhaveri, MD, FACP: To Debu’s point about tamoxifen being a good endocrine partner, I think it’s more and more important now that we have that data. The only data that I think we have with a CDK4/6 inhibitor is based on MONALEESA-7. I think it’s helpful. Now that we are using more and more ovarian suppression and aromatase inhibitors earlier on for our patients, if those patients were to progress, that would be a good option to consider, at least in those women who have already seen or have progressed on an ovarian suppression/letrozole combination. Using tamoxifen, ovarian suppression, CDK4/6 in the metastatic setting, for those unfortunate women, would be a great option.

Sara A. Hurvitz, MD: There was an issue with QTc prolongation in tamoxifen-treated patients in that study, so I don’t know that I’d be completely comfortable. Tamoxifen does increase it. And with ribociclib having that rare but important event, that would be a consideration. If you also look at the actual progression-free survival for tamoxifen versus an aromatase inhibitor in that study, it was lower. I still would lean toward the aromatase inhibitor in my own clinical practice.

Hope S. Rugo, MD: I think that’s what we all would do. In a tolerance issue, you could always switch. Maybe you would choose fulvestrant, not tamoxifen—it’s hard to know.

Sara A. Hurvitz, MD: Right.

Joyce A. O’Shaughnessy, MD: The MONALEESA-2 data were interesting. That trial changed my practice. Historically, we’d give these patients an aromatase inhibitor for 5 years, etc. But when you look at the Kaplan-Meier curves in that de novo metastatic setting with the addition of ribociclib, the curves are miles apart. For the patients who were on ribociclib, they just kind of flattened out. That was very striking. It really changed my practice. I thought, “Hmm, how could I not offer them a CDK4/6 inhibitor?” So, that was interesting.

But on the flip side of that coin, in MONALEESA-2, patients were in pain. Patients who had elevated pain scores rapidly improved, getting to the point where we could maybe avoid the chemotherapy. So, on both ends of that biologic spectrum, there was actually substantial benefit.

Hope S. Rugo, MD: That first data that came out, about de novo metastatics, came from PALOMA-1. An unexpectedly large number of de novo metastatic patients did incredibly well. It’s interesting that it’s played out through all of the phase III studies.

Transcript Edited for Clarity 

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Transcript: 

Joyce A. O’Shaughnessy, MD: Hello, and thank you for joining this OncLive® Peer Exchange® entitled “Expanding Therapeutic Options for Breast Cancer.” It’s a very exciting time in breast cancer. More than ever, researchers are learning about what drives the behavior of aggressive tumors and how to personalize treatment approaches for patients with both early and advanced disease. Today, in this OncLive® Peer Exchange®, I’m joined by a group of expert colleagues who really are at the top of the field. We’ll discuss the data from the 2018 ASCO Annual Meeting and consider how this new information will add to our knowledge regarding how to improve outcomes for patients. We’re going to spend the bulk of our time talking about hormone receptor–positive breast cancer. Then, we’ll also discuss some exciting new approaches for metastatic triple-negative breast cancers.

I am Dr. Joyce O’Shaughnessy. I’m the Celebrating Women’s Chair in breast cancer research at Baylor University Medical Center, Texas Oncology, and US Oncology. Participating today on our distinguished panel is Dr. Sara Hurvitz, director of Breast Oncology at UCLA Jonsson Comprehensive Cancer Center. Hi, Sara.

Sara A. Hurvitz, MD: Hi.

Joyce A. O’Shaughnessy, MD: We also have Dr. Komal Jhaveri, a medical oncologist in the Breast Medicine and Early Drug Development Service at Memorial Sloan Kettering Cancer Center.

Komal Jhaveri, MD, FACP: Hi, Joyce.

Joyce A. O’Shaughnessy, MD: Dr. Hope Rugo, a professor of medicine and director of the Breast Oncology Clinical Trials Program at the UCSF Comprehensive Cancer Center in San Francisco, and Dr. Debu Tripathy, professor and chair of the Department of Breast Medical Oncology at MD Anderson Cancer Center.

It’s really great to be here with you today. I’m sure we’re going to have a really good discussion about 3 major segments. The first one is hormone receptor–positive metastatic breast cancer. We’ll start with that first, and I guess we’ll start with a burning question: Komal, does every woman with ER–positive metastatic breast cancer need to have a CDK4/6 inhibitor? And if so, when, in the natural history?

Komal Jhaveri, MD, FACP: That’s a very important question. Given the data that we now have for 3 approved CDK4/6 inhibitors—palbociclib, abemaciclib, and ribociclib—all 3 have now shown that in combination with an aromatase inhibitor in the first-line setting and with fulvestrant in the second-line setting—there are also some data with fulvestrant in the first-line setting—there is a consistent benefit with a consistent hazard ratio across all of the trials in post- and premenopausal women. So, I would say that the answer to that would be yes.

Joyce A. O’Shaughnessy, MD: Thank you. How about premenopausal, perimenopausal, and postmenopausal women, Sara? What kind of data do we have around those subsets?

Sara A. Hurvitz, MD: To echo what Komal has just said, these progression-free survival data that we are seeing now have never been published for hormone receptor–positive breast cancer. We’ve never gotten to 2 years progression-free survival in the frontline setting. An obvious question becomes, if all of these data are in postmenopausal women, can we apply them to our premenopausal, younger women? Indeed, we can. We have a couple of studies in the second-line setting. We have the abemaciclib data, as well as the palbociclib data, in the MONARCH 2 and PALOMA-3 studies. A subset of women enrolled; somewhere around 20% were pre- or perimenopausal. They were given an LHRH agonist. The progression-free survival differences, or the hazard ratio, was strikingly similar to the overall population. In other words, younger women do benefit from the addition of a CDK4/6 inhibitor to fulvestrant therapy as long as they’re getting an LHRH agonist.

Debu presented and published, or is publishing, the very important MONALEESA-7 data, which was an entire study dedicated to younger women who were pre- or perimenopausal. This study looked at endocrine therapy plus an LHRH agonist with or without ribociclib. The hazard ratio, 0.553, is exactly what we’re seeing in postmenopausal women, with objective responses in excess of 50% for all of these studies. We’re getting data that we see with chemotherapy. This really is pretty impressive data for both younger and older women.

Joyce A. O’Shaughnessy, MD: I think that’s really an important point, too, about where the CDK4/6 inhibitors are taking us. It certainly takes us away from endocrine monotherapy, although we’re going to ask Debu about that in a little bit. It also may be taking us away from chemotherapy, a little bit, in the first-line setting. Is that happening in your practice, Sara?

Sara A. Hurvitz, MD: It is. Our NCCN and ASCO guidelines tell us that we should be using endocrine or hormonally directed therapies for hormone receptor–positive breast cancer in all but the most rare situations of visceral crisis or fulminant; for example, liver failure. The results we’re seeing are impressive. They’re impressive because the therapeutic index is well preserved. We’re seeing great outcomes, and we’re having less toxicity than we see with traditional chemotherapy.

Joyce A. O’Shaughnessy, MD: Yes. Even in the premenopausal patients, where we get very worried—somebody with de novo metastatic, very, very aggressive disease—the median progression-free survival, even in those young women, in the first-line setting, is in excess of 2 years. This is better than we would get with chemotherapy. That’s really a sea change, isn’t it? I think we’re all kind of getting more and more comfortable with CDK4/6 inhibitors in the first-line setting.

Hope S. Rugo, MD: I do think that there probably is a group of patients who will do very well with endocrine therapy alone. I think we now treat so heavily in the adjuvant setting that most of the patients we see are always going to get CDK4/6 inhibitors. But occasionally, you’ll find an older patient with a single soft tissue lesion who’s never had endocrine therapy. It may make more sense for them, in terms of the complexity and cost of therapy, to start with endocrine therapy alone and use the CDK4/6 inhibitor as second-line treatment. I rarely see a patient like that—maybe 1 every few years—but I do think it’s something to keep in mind. It’s not an obligatory addition, but most patients will benefit. In patients who come in with de novo metastatic disease, who have a liver lesion or something like that, we actually have a treatment where we could now avoid chemotherapy upfront. Ovarian suppression is a really important part of that combined therapy with patients. Your study, Debu, showed that some of those patients could get tamoxifen?

Debu Tripathy, MD: That’s right. In the MONALEESA-7 trial, we actually looked at the option of tamoxifen or a nonsteroidal aromatase inhibitor. About 25% of the patients were, in fact, on tamoxifen. Although the study wasn’t powered to look at the benefit individually, the hazard ratios were very similar with tamoxifen, and so that is an option. It may not be what I start with, but when patients are having a lot of trouble with aromatase inhibitors, it is certainly an option.

Then, to speak to the issues in older women, it’s been shown across all of the studies, including in an FDA analysis that was done, that the adverse event rate is a little higher, but the outcomes are just as good, or maybe even better. We have a poster that looks at patients over the age of 65 and over the age of 70. They also do well. I think it is really hard to decide who not to treat, keeping in mind that we haven’t yet shown a survival benefit. The trials weren’t designed to show that. What has now emerged in the studies that are looking at quality of life is the time to deterioration in quality of life or, in some cases, improvement in quality of life, which is definitely more favorable in the CDK4/6-treated group.

Hope S. Rugo, MD: In terms of the adverse events from the FDA’s pooled analysis and just from my own clinical practice, I have found that older patients have more profound fatigue. They do fine otherwise, but the profound fatigue is a big issue. So, I tend to dose-reduce patients in that setting, which is an interesting thing. The FDA analysis also showed that there were more dose reductions in those patients. It’s just something to keep in mind when we’re treating patients who are older.

Komal Jhaveri, MD, FACP: To Debu’s point about tamoxifen being a good endocrine partner, I think it’s more and more important now that we have that data. The only data that I think we have with a CDK4/6 inhibitor is based on MONALEESA-7. I think it’s helpful. Now that we are using more and more ovarian suppression and aromatase inhibitors earlier on for our patients, if those patients were to progress, that would be a good option to consider, at least in those women who have already seen or have progressed on an ovarian suppression/letrozole combination. Using tamoxifen, ovarian suppression, CDK4/6 in the metastatic setting, for those unfortunate women, would be a great option.

Sara A. Hurvitz, MD: There was an issue with QTc prolongation in tamoxifen-treated patients in that study, so I don’t know that I’d be completely comfortable. Tamoxifen does increase it. And with ribociclib having that rare but important event, that would be a consideration. If you also look at the actual progression-free survival for tamoxifen versus an aromatase inhibitor in that study, it was lower. I still would lean toward the aromatase inhibitor in my own clinical practice.

Hope S. Rugo, MD: I think that’s what we all would do. In a tolerance issue, you could always switch. Maybe you would choose fulvestrant, not tamoxifen—it’s hard to know.

Sara A. Hurvitz, MD: Right.

Joyce A. O’Shaughnessy, MD: The MONALEESA-2 data were interesting. That trial changed my practice. Historically, we’d give these patients an aromatase inhibitor for 5 years, etc. But when you look at the Kaplan-Meier curves in that de novo metastatic setting with the addition of ribociclib, the curves are miles apart. For the patients who were on ribociclib, they just kind of flattened out. That was very striking. It really changed my practice. I thought, “Hmm, how could I not offer them a CDK4/6 inhibitor?” So, that was interesting.

But on the flip side of that coin, in MONALEESA-2, patients were in pain. Patients who had elevated pain scores rapidly improved, getting to the point where we could maybe avoid the chemotherapy. So, on both ends of that biologic spectrum, there was actually substantial benefit.

Hope S. Rugo, MD: That first data that came out, about de novo metastatics, came from PALOMA-1. An unexpectedly large number of de novo metastatic patients did incredibly well. It’s interesting that it’s played out through all of the phase III studies.

Transcript Edited for Clarity 
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