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The Role of Fulvestrant in HR+ Breast Cancer

Panelists:Adam M. Brufsky, MD, PhD, FACP, University of Pittsburgh School of Medicine; Francisco Esteva, MD, PhD, Langone Medical Center; Komal Jhaveri, MD, FACP, Memorial Sloan Kettering Cancer Center; Hope S. Rugo, MD, UCSF Helen Diller Family Comprehensive Cancer Center; Lee Schwartzberg, MD, FACP, The University of Texas Health Science Center
Published: Friday, Mar 02, 2018



Transcript: 

Lee Schwartzberg, MD, FACP: I want to take this back to the real world for a second. Now we have CDK4/6 and endocrine therapy in the first line. We have no data on the second line, so now we’ve changed from 3 lines of endocrine therapy, when we had less drugs, to 1 definite line of therapy.

Hope S. Rugo, MD: We’re going to see a lot of PI3 kinase inhibitor data this year. I think we’re going to see 2 different phase III trials.

Adam M. Brufsky, MD, PhD, FACP: You think it will be better than what we’ve seen so far?

Hope S. Rugo, MD: Yes. I think these are great drugs.

Lee Schwartzberg, MD, FACP: The alpha inhibitors?

Adam M. Brufsky, MD, PhD, FACP: The alphas, yes.

Hope S. Rugo, MD: They’re beta sparing, but I think that these drugs are good and I’ve seen really prolonged responses even in patients who previously received everolimus—so I’m a big fan. The other thing is when we look at all of this, what’s going to happen in patients over time? I think when we were looking at bevacizumab, the idea was that maybe you responded for longer but then you didn’t respond to anything else afterwards. Something happened. Why is survival not better? There’s a lot of crossover here, so survival is hard in hormone receptor–positive disease trials. But we looked at our long-term follow-up of PALOMA-2 and presented that at San Antonio, and now the PFS in the population with longer-term follow-up in patients who received palbociclib is 27-plus months. That’s the longest we’ve seen. I expect it will be similar in the other trials with no subset differences. Everybody benefited, even people with long treatment-free intervals.

Adam M. Brufsky, MD, PhD, FACP: That’s different than what Matt Goetz presented on the MONARCH study. We’re getting to the point, and that brings us back to the questions we want to know. People want to know this in the real world. Are there subsets of patients who don’t need these drugs up front, CDK4/6 inhibitors, and can just live on hormone therapy alone?

Francisco Esteva, MD, PhD: They’re very hard to find.

Adam M. Brufsky, MD, PhD, FACP: But you can look at the subset analysis of MONARCH-2 and MONARCH-3.

Francisco Esteva, MD, PhD: If you look at the subset of the forest plots with palbociclib and ribociclib, it’s hard to find those patients.

Adam M. Brufsky, MD, PhD, FACP: But what about in the MONARCH trial? I’m trying to think of which one it was.

Komal Jhaveri, MD, FACP: This was a combination of 2 and 3.

Adam M. Brufsky, MD, PhD, FACP: It was combination of 2 and 3, but the patients who had a disease-free interval of greater than 3 years did not benefit.

Hope S. Rugo, MD: One of the problems is that most of the confidence intervals were not reached. Some of them were not reached on both ends, but most of them were not reached on the farther end because there’s just not long enough follow-up yet. In PALOMA-2, even the patients who had a disease-free interval of 5 years, which it was measured a little bit differently, still benefitted and had similar hazard ratios. Now, is that going to be economically feasible around the world? Probably not, but we are clearly benefitting all of these patients, and it may be the people who have very endocrine-sensitive disease who could stay on therapy for 8 years.

Adam M. Brufsky, MD, PhD, FACP: There have been analyses that were presented this year. They presented the data from FALCON, FIRST, and CONFIRM with single-agent fulvestrant. Is there still a role for that now in an era where you have CDK4/6 inhibition?

Lee Schwartzberg, MD, FACP: I think this is a specific patient population, the older patient population, patients over 80 years old who we still see in a community practice who have a 10-year disease-free interval or present with de novo disease. You don’t necessarily want to put them on a drug that’s going to be expensive and cause fatigue. With those patients, from FALCON, we see that if you have bone-only disease, you do reasonably well with a single-agent fulvestrant. I think it’s really a very small subset, because the CDK inhibitors are so well tolerated in most people. So, it’s maybe 10% of patients or even less.

Hope S. Rugo, MD: I think that’s what Matt Goetz also showed. Those bone-only patients have a really long treatment-free interval. I have one patient who’s on fulvestrant alone. She relapsed at 35 years.

Adam M. Brufsky, MD, PhD, FACP: Yes, that’s the point. It’s great that it’s an 8-years-from-diagnosis kind of deal.

Hope S. Rugo, MD: At 35 years, really?

Adam M. Brufsky, MD, PhD, FACP: You live with it. It’s like hypertension.

Francisco Esteva, MD, PhD: We’re still waiting for the MONALEESA-3 trial of fulvestrant with or without ribociclib. Based on the FIRST and FALCON studies with fulvestrant, which show really excellent results with fulvestrant alone, if you see an improvement by adding ribociclib on top of an excellent result, that’s quite significant. We’ve seen that with abemaciclib and, to some degree, in the second line in PALOMA-3 with palbociclib as well. But in the front line, I’m looking forward to the MONALEESA-3 results because with FALCON and FIRST, we’ve seen such good responses with fulvestrant alone. If that is a positive trial, it’s something to consider.

Adam M. Brufsky, MD, PhD, FACP: The thing that struck me about FALCON, FIRST, and CONFIRM was that in visceral metastatic disease, there was not much of a benefit, right? Is that true?

Lee Schwartzberg, MD, FACP: Right.

Hope S. Rugo, MD: It’s true. There was actually no benefit in FALCON. There is a trial going on that I think is going to help us a lot, which is a trial done in Europe that has fully accrued and is looking at fulvestrant versus an AI with CDK4/6 inhibition. I think that’s going to answer the question you’re talking about, that trial.

Adam M. Brufsky, MD, PhD, FACP: Do you have women at Memorial Sloan Kettering who come in and don’t get CDK4/6 inhibitors in that setting?

Komal Jhaveri, MD, FACP: No.

Adam M. Brufsky, MD, PhD, FACP: Everybody will get fulvestrant.

Komal Jhaveri, MD, FACP: Predominantly. In my practice right now, I have one woman who came in with de novo metastatic disease. She actually ended up having surgery, had a plan in place to start adjuvant chemotherapy, and then ended up having a PET scan at an outside hospital showing 2 lesions in the bone. Then she came to me. She was started on letrozole when she came to me, and I continued the letrozole. While we have data from the FALCON trial for fulvestrant, I feel like there are a couple of things I think about with fulvestrant, and let me know if you guys agree with me. If you think the treatment interval is far along and one would benefit with endocrine therapy alone, I see all of AIs as equally effective. I know there are survival data with fulvestrant, but we also have survival data in the second-line setting with fulvestrant. So, I can use fulvestrant based on the PALOMA-3 data, based on the MONALEESA data that we will see, and based on the abemaciclib data. I feel like with most of the drugs that we’re developing right now for metastatic disease for ER-positive breast cancer, we use fulvestrant as the endocrine partner based on preclinical data that have shown superiority. So, if I use a fulvestrant alone up front, I don’t know if I really have data.

Adam M. Brufsky, MD, PhD, FACP: You’re missing all those patients who have ESR1 mutations; they’re 30%.

Komal Jhaveri, MD, FACP: I’m missing patients with AKT mutations, ESR1 mutations, or PI3K inhibitors once we have the SANDPIPER and the SOLAR data. With all of these trials, we really don’t have data for letrozole with palbociclib after fulvestrant. We have data for fulvestrant at the second-line and beyond. So, I struggle with that decision. I love the FALCON data, but I think this is how I analyze in my head.

Transcript Edited for Clarity 

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Transcript: 

Lee Schwartzberg, MD, FACP: I want to take this back to the real world for a second. Now we have CDK4/6 and endocrine therapy in the first line. We have no data on the second line, so now we’ve changed from 3 lines of endocrine therapy, when we had less drugs, to 1 definite line of therapy.

Hope S. Rugo, MD: We’re going to see a lot of PI3 kinase inhibitor data this year. I think we’re going to see 2 different phase III trials.

Adam M. Brufsky, MD, PhD, FACP: You think it will be better than what we’ve seen so far?

Hope S. Rugo, MD: Yes. I think these are great drugs.

Lee Schwartzberg, MD, FACP: The alpha inhibitors?

Adam M. Brufsky, MD, PhD, FACP: The alphas, yes.

Hope S. Rugo, MD: They’re beta sparing, but I think that these drugs are good and I’ve seen really prolonged responses even in patients who previously received everolimus—so I’m a big fan. The other thing is when we look at all of this, what’s going to happen in patients over time? I think when we were looking at bevacizumab, the idea was that maybe you responded for longer but then you didn’t respond to anything else afterwards. Something happened. Why is survival not better? There’s a lot of crossover here, so survival is hard in hormone receptor–positive disease trials. But we looked at our long-term follow-up of PALOMA-2 and presented that at San Antonio, and now the PFS in the population with longer-term follow-up in patients who received palbociclib is 27-plus months. That’s the longest we’ve seen. I expect it will be similar in the other trials with no subset differences. Everybody benefited, even people with long treatment-free intervals.

Adam M. Brufsky, MD, PhD, FACP: That’s different than what Matt Goetz presented on the MONARCH study. We’re getting to the point, and that brings us back to the questions we want to know. People want to know this in the real world. Are there subsets of patients who don’t need these drugs up front, CDK4/6 inhibitors, and can just live on hormone therapy alone?

Francisco Esteva, MD, PhD: They’re very hard to find.

Adam M. Brufsky, MD, PhD, FACP: But you can look at the subset analysis of MONARCH-2 and MONARCH-3.

Francisco Esteva, MD, PhD: If you look at the subset of the forest plots with palbociclib and ribociclib, it’s hard to find those patients.

Adam M. Brufsky, MD, PhD, FACP: But what about in the MONARCH trial? I’m trying to think of which one it was.

Komal Jhaveri, MD, FACP: This was a combination of 2 and 3.

Adam M. Brufsky, MD, PhD, FACP: It was combination of 2 and 3, but the patients who had a disease-free interval of greater than 3 years did not benefit.

Hope S. Rugo, MD: One of the problems is that most of the confidence intervals were not reached. Some of them were not reached on both ends, but most of them were not reached on the farther end because there’s just not long enough follow-up yet. In PALOMA-2, even the patients who had a disease-free interval of 5 years, which it was measured a little bit differently, still benefitted and had similar hazard ratios. Now, is that going to be economically feasible around the world? Probably not, but we are clearly benefitting all of these patients, and it may be the people who have very endocrine-sensitive disease who could stay on therapy for 8 years.

Adam M. Brufsky, MD, PhD, FACP: There have been analyses that were presented this year. They presented the data from FALCON, FIRST, and CONFIRM with single-agent fulvestrant. Is there still a role for that now in an era where you have CDK4/6 inhibition?

Lee Schwartzberg, MD, FACP: I think this is a specific patient population, the older patient population, patients over 80 years old who we still see in a community practice who have a 10-year disease-free interval or present with de novo disease. You don’t necessarily want to put them on a drug that’s going to be expensive and cause fatigue. With those patients, from FALCON, we see that if you have bone-only disease, you do reasonably well with a single-agent fulvestrant. I think it’s really a very small subset, because the CDK inhibitors are so well tolerated in most people. So, it’s maybe 10% of patients or even less.

Hope S. Rugo, MD: I think that’s what Matt Goetz also showed. Those bone-only patients have a really long treatment-free interval. I have one patient who’s on fulvestrant alone. She relapsed at 35 years.

Adam M. Brufsky, MD, PhD, FACP: Yes, that’s the point. It’s great that it’s an 8-years-from-diagnosis kind of deal.

Hope S. Rugo, MD: At 35 years, really?

Adam M. Brufsky, MD, PhD, FACP: You live with it. It’s like hypertension.

Francisco Esteva, MD, PhD: We’re still waiting for the MONALEESA-3 trial of fulvestrant with or without ribociclib. Based on the FIRST and FALCON studies with fulvestrant, which show really excellent results with fulvestrant alone, if you see an improvement by adding ribociclib on top of an excellent result, that’s quite significant. We’ve seen that with abemaciclib and, to some degree, in the second line in PALOMA-3 with palbociclib as well. But in the front line, I’m looking forward to the MONALEESA-3 results because with FALCON and FIRST, we’ve seen such good responses with fulvestrant alone. If that is a positive trial, it’s something to consider.

Adam M. Brufsky, MD, PhD, FACP: The thing that struck me about FALCON, FIRST, and CONFIRM was that in visceral metastatic disease, there was not much of a benefit, right? Is that true?

Lee Schwartzberg, MD, FACP: Right.

Hope S. Rugo, MD: It’s true. There was actually no benefit in FALCON. There is a trial going on that I think is going to help us a lot, which is a trial done in Europe that has fully accrued and is looking at fulvestrant versus an AI with CDK4/6 inhibition. I think that’s going to answer the question you’re talking about, that trial.

Adam M. Brufsky, MD, PhD, FACP: Do you have women at Memorial Sloan Kettering who come in and don’t get CDK4/6 inhibitors in that setting?

Komal Jhaveri, MD, FACP: No.

Adam M. Brufsky, MD, PhD, FACP: Everybody will get fulvestrant.

Komal Jhaveri, MD, FACP: Predominantly. In my practice right now, I have one woman who came in with de novo metastatic disease. She actually ended up having surgery, had a plan in place to start adjuvant chemotherapy, and then ended up having a PET scan at an outside hospital showing 2 lesions in the bone. Then she came to me. She was started on letrozole when she came to me, and I continued the letrozole. While we have data from the FALCON trial for fulvestrant, I feel like there are a couple of things I think about with fulvestrant, and let me know if you guys agree with me. If you think the treatment interval is far along and one would benefit with endocrine therapy alone, I see all of AIs as equally effective. I know there are survival data with fulvestrant, but we also have survival data in the second-line setting with fulvestrant. So, I can use fulvestrant based on the PALOMA-3 data, based on the MONALEESA data that we will see, and based on the abemaciclib data. I feel like with most of the drugs that we’re developing right now for metastatic disease for ER-positive breast cancer, we use fulvestrant as the endocrine partner based on preclinical data that have shown superiority. So, if I use a fulvestrant alone up front, I don’t know if I really have data.

Adam M. Brufsky, MD, PhD, FACP: You’re missing all those patients who have ESR1 mutations; they’re 30%.

Komal Jhaveri, MD, FACP: I’m missing patients with AKT mutations, ESR1 mutations, or PI3K inhibitors once we have the SANDPIPER and the SOLAR data. With all of these trials, we really don’t have data for letrozole with palbociclib after fulvestrant. We have data for fulvestrant at the second-line and beyond. So, I struggle with that decision. I love the FALCON data, but I think this is how I analyze in my head.

Transcript Edited for Clarity 
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