Introduction: Endocrinology and Pharmacology of Hormonal Therapy for Breast Cancer

DR LOVE: Good afternoon, everyone. I’m Neil Love from Research To Practice and welcome to Year in Review, as today we launch our annual series focusing on key papers and presentations from the past year. We’re going to start out with one of the most exciting areas in oncology, not only breast cancer but hormone receptor-positive breast cancer.

We have a great faculty today, Dr Stephanie Graff, the Director of Breast Oncology at the Lifespan Cancer Institute and the Warren Alpert Medical School of Brown University, also the Medical Advisor to the Dr Susan Love Foundation for Breast Cancer Research. So sorry to see Susan leave us this past year. And Dr Erica Mayer from the Dana-Farber Cancer Institute in Boston.

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We’re getting ready to head out to San Francisco. This year, ASCO GI and GU are back-to-back weeks. We’re going to start out next week. And all of these, if you’re in San Francisco, come on over and join us. If not, all of this will be put out live online. We’re going to start out on Thursday with gastroesophageal cancers, colorectal cancer. And Saturday morning, we’ll get into hepatobiliary. The next week, we’ll come back again to San Francisco with our GU programs, prostate cancer and bladder cancer on January 26^th. And then, we’ll continue our Year in Review series with Drs Krop and Sharma, and we’ll talk about HER2-positive, triple-negative breast cancer. We can’t do all of breast cancer anymore in an hour and even close to it. And then in March, we’re reawakening our annual, well we had to stop during the pandemic but we’re bringing it back, our annual General Medical Oncology Summit from Friday to Sunday in our hometown of Miami. Actually, we’re launching it with a cool keynote session on breast cancer. We have 31 investigators who are coming to Miami. If you want to come on over and join us, that’d be great. If not, the whole weekend will be online live, so you can get comfortable on your couch and just join us virtually.

So today, we're going to talk about this. And as we do in all of our Year in Review series, this is really a 3-part program. The first, I met with Stephanie and Erica in the last week or so and recorded a presentation that goes through a bunch of papers. I highly recommend these 2 presentations. We talk a lot about these. There’s so much to talk about. We cover a lot of data. Stephanie covered the early trials. We’re going to talk about some of these, but not all of these. This is just such a huge amount of data. Erica talked about metastatic disease. Again, a whole bunch of papers. We’ll pull a few of those slides. But here tonight, we’re just going to brainstorm a little bit about what it all means and not worry so much about the slides.

So before we get started, Erica, I’ve got to offer my condolences to you for losing your head coach there, Bill Belichick. I know you all — actually, the last webinar we did in the end of December was with Rich Stone, so I’ve got to call him up and see what he thinks about that. But any comments on getting a new head coach?

DR MAYER: Oh gosh, we are definitely in mourning in New England about this. But as coach says, we will do our jobs. And hopefully, we’ll bring back, I don’t know, Mike Vravel. He used to play for the Pats. That’s my prediction.

DR LOVE: Yeah, that’s a cool idea. And I know, Stephanie, you’re a Chiefs fan. And I’ve got to say Saturday — Sunday? Yeah, Saturday night, we’re playing you guys. So good luck, but we’ll see what happens.

All right. I want to start out just before we kind of get into the papers and pick your brain a little bit about the endocrinology and pharmacology of hormonal therapy of breast cancer. We’ve come so far. And I want to just bring up a paper too in the regard. But just so many things going on. Erica, it used to be there was really not that much exciting to talk about. Now, we can barely get through this in an hour. Any just general thoughts? From your viewpoint, what were some of the highlights of this past year for you?

DR MAYER: Well it’s been an incredible year and it really feels like the pace of evolution in breast cancer has picked up substantially. We have new data coming to us with every meeting cycle. Even looking at older trials being reevaluated. We learn something every time. We’ve had new agents being approved including capivasertib most recently. And we have new results that continue to modify our treatment paradigms. Something that I find really interesting is that with all of the new drugs, as we bring them into the clinic, we’re learning more about toxicity and tolerability. And ultimately, that may be the key differentiator for us, particularly when we have so many choices available. But ultimately, I think what’s been fantastic is with all of these new tools and strategies, this is just going to benefit our patients. And I think we’re seeing people do better than ever before.

DR LOVE: So, Stephanie, this is kind of a typical graphic that you see about mechanism of action. I don’t know whether it’s just me or other people, I have a hard time kind of wading through these things. And I want to show both of you a comment actually that one of our faculty made at the San Antonio meeting. But first, I want to start out with this question. I want the audience to think about it because one of the things that we got into in San Antonio is what kind of biomarkers do you need to treat a patient second-line therapy for metastatic disease, so a patient who has disease progression on CDK4/6. We’ve got PIK3CA, ESR1, AKT/PTEN. Stephanie, do we need all or just some of this to treat patients?

DR GRAFF: I think right now, we need all of these. I think we need PIK3CA, ESR1 and AKT/PTEN. Of course, capivasertib is approved for not just PIK3CA, but also AKT and PTEN. So important to get all 3 of those to select capivasertib and alpelisib. And then ESR1 opens up options for elacestrant. Right now, I think we’ll continue to see that category of approvals expand. And what we want is the most number of tricks in our bag that we can pull from. So when we identify patients that have numerous options here, it just means that we have more drugs we can choose from.

DR LOVE: So I guess it’s going to be a race for how many biomarkers we need. I mentioned we’re doing this program on GE cancer at ASCO GI. There, they’ve got claudin and FGFR. And there, triplet, moving in that direction. So, Erica, I want to ask you specifically about a comment I heard at this meeting we did with this great faculty which I hadn’t heard before. And I didn’t initially, and I still don’t, completely understand. I’m going to ask you to explain it. This is Dr Erika Hamilton.

DR HAMILTON: There’s a lot of preclinical activity that not all the SERDs are equal, and that should make sense to us because we see different side effect profiles. Some have bradycardia, some seem to have a little bit more GI toxicity. Elacestrant is a little bit more of a SERM than a SERD compared to some of the other SERDs, and so I think as we get smarter with these we’ll realize that there are certain patient populations where one may be a little bit better for a patient than another.

DR LOVE: So, Erica, it’s kind of easier to understand how taking somebody’s ovaries out or using an AI works. But when you get into tamoxifen, a SERM, or the SERDs, to me, and she’s saying it’s kind of a continuum, et cetera. What’s your vision for this, Erica?

DR MAYER: Well it’s a really interesting comment from Dr Hamilton. And when we think about the endocrine therapies in development, there’s sort of a spectrum of ones that behave more like SERMs, so selective estrogen receptor modulators, to ones that perform more like SERDs, selective estrogen receptor degraders. Drugs that are more SERM-like, and we think of tamoxifen as a kind of key example of that, honestly do have a little bit of a better side effect profile. And that can include elacestrant which verges a little bit more in that category. We have lasofoxifene which is a drug in development. Bazedoxifene which is actually approved for osteoporosis. Some of these drugs treat osteoporosis. They help patients feel better. So I’m really interested in further development of the SERMs because I think that they will be effective and hopefully really well tolerated.

On the more SERD side, we do see a really interesting spectrum of side effects including, for some of the drugs, some GI toxicity like some mild nausea or some diarrhea. And then we have seen this interesting signal of cardiac toxicity with asymptomatic relatively mild bradycardia that’s been shared by a few of these drugs. And how a drug that’s degrading the estrogen receptor causes bradycardia is something that I think we’re still trying to figure out the estrogen/cardiac connection. We also do see some vision changes on some of these drugs, something called photopsia which is kind of seeing halos around lights or seeing tracking around lights. Not something that creates a vision problem. You can still see fine. Your vision quality and acuity is the same, but it is something that patients taking these drugs will notice. So I think that there’s a whole spectrum of these agents. They’re not all one agent. And as they are further developed, we’re going to learn more, not only about efficacy but also what the tolerability is and the spectrum of side effects.

DR LOVE: So to kind of demonstrate how much things are changing, I wanted to talk about another thing that happened before we sort of jump into these papers and all. Because when we got to this first meeting and Virginia Kaklamani who is the head of the San Antonio meeting was there. I always meet with the faculty ahead of time of the meeting. And the faculty were in there telling me this wild story about how a press release had come out, I think it was that day actually or no, the day before, on a trial, this trial, the INAVO120 trial, triplet therapy. We were actually in the Marriott Rivercenter. We were in the same room that the ATAC trial was presented in 2003 where they showed that anastrozole is a little better than tamoxifen. But most importantly, that tamoxifen plus anastrozole was no better. And now here we are 20 years later talking about triplets. And somehow, they pulled off getting this thing presented in 3 days. Any thoughts, Stephanie, in terms of where things are moving? We talk about quadruplet therapy in myeloma nowadays. Any comments on this trend and the challenge of multiple agents? And also very interestingly, they chose to use palbo. So this is, I guess, sort of an AKT/PI3K type agent. PIK3 mutant was required to go in there. But then, they combined it not only with fulvestrant, but with palbo which I thought was very interesting. I guess because it’s better tolerated. Any thoughts, Stephanie, about whether maybe there’s going to be a future for palbo, but in combination?

DR GRAFF: Yeah. I tell patients regularly right now in my clinical practice that I feel like we’re in the messy middle of estrogen receptor-positive metastatic breast cancer because the SERDs, elacestrant and so many others, capivasertib, imlunestrant, are emerging. We still don’t know how to combine different agents. Alpelisib and capivasertib still need to start building data around combinations with other agents beyond fulvestrant. Who can still get fulvestrant as a single agent? Whether or not patients should have extended CDK4/6 inhibitor. There’s just so many unanswered questions for patients that have both PIK3CA and ESR1 mutations. How do we sequence those agents? Should we combine those agents? There’s just lots of unanswered questions right now. And so I think that we will see more triplet therapies. We will see these agents move to first-line. And I think where we are right now is not where we end up 5 or 10 years from now. And this is a very high-risk, highly selected patient population that all had PIK3CA mutated breast cancer. We still need to learn more about their ESR1 status. I know Dr Mayer is going to review that more in subsequent conversation today.

DR LOVE: So yeah, then I’ll add in there 4 days on, 3 days off for capivasertib. There’s another kind of twist on maybe trying to improve tolerability. So what about this study, Erica? It was positive. Pretty good hazard rate for PFS, 0.43 in the first-line setting.

DR MAYER: So this was really, in some ways, the splash and surprise of San Antonio because I think we weren’t expecting to see this data presented. And I’m just grateful that the powers that be allowed this to be presented for us. By the way, I think that room in the Marriott Rivercenter has probably seen more breast cancer research than almost any place on earth.

DR LOVE: Absolutely. Actually, that’s the only hotel I’ve ever stayed at in San Antonio. I think I’ve been there since the third one, and that’s the only hotel I’ve stayed at. Anyhow.

DR MAYER: So what I think is interesting about the INAVO study is that this really enrolled a very high-risks group of patients. First of all, these were patients who recurred either during their adjuvant aromatase inhibitor or not long after and all the patients had a PIK3CA mutation. So of our first-line hormone receptor-positive, HER2-negative metastatic patients, these are really much more high-risk than the, I’ll call it, usual person. And what we see here is the triplet which is building off of what, in many situations, is standard of care to receive fulvestrant and CDK4/6 inhibitor. We see a really substantial difference here. This is more than a doubling in progression free survival, 7 months to 15 months. And we see that that’s preserved at the landmarks up to 18 months of observation with a hazard ratio of 0.3. So I think if we think back to the first-line CDK4/6 studies and the PFS seen there, usually what we’re looking at is something like 12 months to 24 months. This is less and I think putting the control arm at 7 months is really telling us that this is a very high-risk population and that we are helping people do much better.

A couple other points. If you look at the separation in these curves, this happens pretty early on. And so the drop-off in the control arm is happening just by the second month. So immediately, we’re having an affect here improving outcomes. And also, for these patients, this is a group where perhaps we might be moving closer to chemotherapy with what we’re seeing in terms of resistance. And by using the triplet, we are most likely pushing out that moment in time when a patient would have to flip over to get chemotherapy. So I felt really encouraged seeing this.

And it’s a really interesting comment about palbociclib because I think in the past couple years, many of us have moved away a little bit from use of palbociclib. But it’s so important to remember that this is an extremely well tolerated CDK4/6 inhibitor. Of the 3, I think it is the best tolerated. And for that reason, I think it does combine well with, here, a PI3 kinase inhibitor. We’ve seen in the PACE study that it combines well with immunotherapy. And there may be a future for palbociclib as part of these combinations.

DR LOVE: So I want to get into some other papers. But just to point out, and I think I see more of this coming in the future too, look at the control arm. At a year, almost 70% have relapsed. And then by 18 months, almost 80%. And so there are a lot of patients who do not do well on the second-line endocrine therapy. It would be great to know who they were in advanced. Maybe even skip second-line therapy or hopefully get something better. And, of course, the whole issue of tolerability with these agents, see how that develops.

Current and Emerging Strategies for Localized Hormone Receptor (HR)-Positive Breast Cancer — Dr Graff

DR LOVE: In any event, let’s talk about some of the other papers and particularly the issue of earlier-stage disease, Stephanie, that you reviewed and certainly, 2 of the papers that got the most attention this year. When I heard they were going to be presented, I was like, yay, this sounds really — because we’ve been hearing about this in lung cancer. Lung cancer is about a year ahead, maybe 2 years ahead of you, I think. In any event, yay. IO in breast cancer to start with. And now, neoadjuvant setting. But what is the bottom line here, Stephanie? I don’t want to go through all the slides. You just tell me, what was your take on what they saw? What do you think it means?

DR GRAFF: So I think both in the CheckMate 7FL study and in the KEYNOTE-756 study what we saw was that combination of immunotherapy in hormone receptor-positive, early-stage breast cancer is a future direction that we can all expect to come to a clinic near us for patients. I don’t think it’s going to be approved in the next 3 months. I think we’re probably waiting for those trials to show event-free survival given the toxicity profile. But I think the most important takeaway is these are high-risk patients. Both trials selected patients who had Grade 3 tumors, lymph node-positive disease, or who were what we call hormone receptor-low, ER expression of 1 to 10%. And, again, just like Dr Mayer was pointing out earlier with the INAVO trial, that’s not your usual estrogen receptor-positive breast cancer patients. That’s not your 70-year-old with an Oncotype of 16, right? That’s your 35-year-old with a Ki-67 of 70% on their estrogen receptor-positive breast cancer. And so I think that there are this small group of very biologically aggressive estrogen receptor-positive breast cancers that adding immunotherapy is going to be worth the associated toxicity that comes with adding that therapy.

DR LOVE: So, Erica, I’m curious. Of course, at this point, what we’re seeing is an increase in path CR rate. Pretty low to start. Even when it increases, it’s still only around 25%, so nothing like HER2-positive disease or triple-negative disease. It looks not too much to separate these 2 out. What’s it going to take for you to want to do this in your practice or the FDA to approve it? In lung cancer when it came out, there was a PFS advantage and it got approved. Do you think that’s what’s going to happen here?

DR MAYER: Well I found these presentations really interesting looking at the subsets of trying to parse out among the patients accrued to the study who was having the biggest benefit. And when looking at the clinical pathologic features and biomarkers, it looked like the patients who were PD-L1-positive with the highest level, the CPS score of 10 or 20 or more, were getting a lot of benefit from the IO with path CR rates that honestly approach what we’ve seen with chemotherapy in the other subsets of breast cancer, also patients who were ER-low. We all have these people in clinic who have these ER scores in the single digit range and they’re technically positive, they’re not technically triple-negative but you kind of feel like biologically, they more resemble triple-negative than they do our traditional luminal breast cancers. And those patients also received the greatest benefit in terms of high pCR rate. Interestingly, Ki-67 didn’t correlate which I find a little puzzling, but that was not a strong signal.

We aren’t going to see the EFS from the nivo study unfortunately just due to the changes in trial design, but we do look forward to seeing this from 756. And I think when we see EFS, if it does correlate with pCR or if there’s other ways that we can use biomarkers to create kind of a clinical signature of who are good candidates, I hope that will be attractive enough to get approval for ER-positive disease.

And I think my takeaways from this really have to do with that low ER group. And I am very tempted now to expand my use of preoperative pembrolizumab to include those patients who honestly I think they are much more triple-negative-like in practice, and try to extend the benefits of pembrolizumab to that group.

DR LOVE: So before I go to the next slide, let me ask you, Erica, do you see a role in trying to sort these things out of genomic assays like Oncotype?

DR MAYER: I don’t recall that Oncotype itself was necessarily predictive of this. These are all patients for whom we want to give chemotherapy, so we’re sort of beyond Oncotype at that moment.

DR GRAFF: I don’t think either study has reported Oncotype and I don’t think either study required that for eligibility. Presumably, both would be able to calculate an inferred Oncotype score. I do agree with Erica that I think that either TILs or PD-L1 is going to help us best select who should get these. I pray that KEYNOTE-756 gives us that data. It has not yet been reported and broken down in that manner.

DR LOVE: Yeah, I was thinking about genomic assays, not so much about the issue of whether to give chemo but more maybe there’s going to be something in there that might, you were mentioning low ER, maybe something there that may be more than just measuring individual factors. But that’s a lead-in to a couple other papers that Stephanie covers, and one was the role of neoadjuvant genomic assays, Oncotype. We did a survey of investigators right before the pandemic, I think 2019, where about one-third of them were using genomic assays, mainly Oncotype, in the neoadjuvant setting. Stephanie, anything you want to say about there have been data before this suggesting that it could be helpful? I don’t know how often you do this. But any thoughts about the role of Oncotype in the neoadjuvant setting, Stephanie?

DR GRAFF: Yeah. So this paper was published this last year in Breast Cancer Research and Treatment, and I think it just really highlights that using Oncotype DX on the biopsy specimen in hormone receptor-positive early-stage breast cancer is a valuable tool that can select patients that are good candidates for neoadjuvant chemotherapy versus neoadjuvant endocrine therapy or who maybe you’re going to give neoadjuvant chemotherapy to or take straight to the operating room for surgery. Obviously, this was something that I was doing regularly during the pandemic because there was a little bit more complication in managing our OR and our volume and getting patients managed safely at a time when hospital social distancing was at a peak. And now that that’s opened up again, although maybe not for long as we see COVID numbers surge, we’re back to using Oncotype largely again in the postoperative setting. But I think that this data is really reassuring that TAILORx and RxPONDER endpoints are equally valid when done on a biopsy specimen in that sort of neoadjuvant space. And you can use the same endpoints to inform your practice.

DR LOVE: So another paper that Stephanie talked about, Erica, actually came out of your place. It’s kind of a quality improvement type of thing that was really cool. Hal Berstein was on one of our San Antonio things and was talking about this. I guess the story was that you all had these established sort of guidelines for when Oncotype should be used which is what you all use. And then you went back and saw what people are actually doing and you found that I guess your initial guidelines was not to send it less than 1 cm and not to send it over age 65 which is kind of interesting. And then you saw a whole bunch of your people were ordering it and getting high values in some cases for small tumors. And, of course, there are women over 65 who might want to think about chemotherapy. Any thoughts about this? I love the way you approached it.

DR MAYER: Yeah, this is a very nice study that was led by one of our advanced fellows, Dario Trapani, who is very interested in quality work. And so he was looking at our internal guidelines for reflex testing. We, as a group, came up with internal guidance that we wanted to use with our pathologists to help streamline the process. We have delays in clinic where if you have to wait to see med onc after surgery and then decide about Oncotype and then it’s a further delay. So here at our institution, if it meets certain criteria, the pathologists will just auto send Oncotype, so that helps get that result back faster. And we had to draw some guidance in terms of situations when we thought it was appropriate and situations where it was more provider discretion. So, for example, small cancers generally don’t need an Oncotype so that was more provider discretion.

I think what came out of this that was interesting is that in the older patients, we definitely do send Oncotype in older patients but the reasons for sending it tend to be quite specific. And we really, in those situations, are trying to get people out of chemotherapy and trying to not have to give chemotherapy. And so what was seen was that in the patients who were older for whom it was sent, there was a little bit more higher scores that were observed. And I think that kind of reflects some of the patient selection for who was picked in this sort of provider preference. But, in general, I’d say using the reflex Oncotype has been wonderful in our practice just because it just helps reduce all of the back-and-forth communication to get things done.

We also at Dana-Farber were very early adopters of Oncotype back in 2015 when it first came out — sorry, 2005. It’s been 15 years. And really have embraced the use of Oncotype, particularly in our older population. And there’s very nice work from one of my colleagues, Mike Hassett, that came out not long after Oncotype showing definitively that we use less chemotherapy in older patients with the use of Oncotype. So I think that using reflex testing is a really nice way to make sure the test gets done and that it can be used appropriately.

DR LOVE: You just pushed a memory. I actually interviewed Soon Paik from the NSABP the night before he presented the first thing. All right. Well here’s the big one, folks. We just do this all the time. We just sort of take the temperature and see where we are. Choice of CDK in the first-line setting. We saw some more data over the last few months at ESMO and SABCS. Bottom line, how do you think through choice of CDK, Stephanie?

DR GRAFF: So the snapshot you’ve got up right now is looking at it in the adjuvant setting. Of course, right now, our only drug approved is abemaciclib so the choice is easy. We did get updates this year on NATALEE which is looking at ribociclib that shows early separation of the curves. A little bit lower-risk population. Some patients with lymph node-negative disease were included in NATALEE as well, so the separation of the curves is a little less wide than it in with monarchE at the same timepoint with abemaciclib. And I think that that reflects the slightly lower-risk population. Of course, we’re waiting for approval or further follow-up with ribociclib in that early-stage breast cancer space. I’m hopeful that we’ll soon have a second approval which will give us some more options to personalize care and engage in shared decision making with our patients. For the most part, I’m probably going to be stick with abemaciclib for my high-risk patients, given just the weight of the evidence and having ribociclib when it’s approved for patients that are intolerant or patients with that lower-risk disease, again, based on the evidence.

DR LOVE: Yeah. Sorry, got my brain fog there. I thought we were on metastatic. But yeah, we are. And the question there I’m really curious about, Erica, is the bar to use CDK in general. And it’s kind of interesting that we keep looking for high-risk patients. I can understand they’re going to get greater benefit. But I’ve been kind of surprised it doesn’t seem to filter down. With the earlier adjuvant therapies, tamoxifen, AI, et cetera, maybe the hazard rate gets established with higher-risk patients. But if you want to calculate what the absolute benefit is, you take the hazard rate, apply it. If it looks like the risk/benefit is positive which it often is with minimal benefit with endocrine therapy, consider it. Any thoughts about, is that where — now we’re seeing with ribo the same effects in the node-negative. Any thoughts where this is going to land, Erica, in terms of the bar to consider treatment or financial considerations as well?

DR MAYER: Yeah. You’ve just brought up so many important points that we have to think about when we’re considering an adjuvant CDK4/6 inhibitor. My impression is that our use of this category of drugs in the adjuvant setting has been increasing as we get further data and further confirmation. When the monarchE data first came out, we did not have long-term follow-up yet. We know abemaciclib definitely has side effects including diarrhea and fatigue and neutropenia with all these agents. And there were concerns also about, is this restricted to just a high Ki-67 population or is it more broadly applicable? I think as we’ve seen greater maturity of monarchE, it’s so interesting. And we can see when we follow the Kaplan-Meier plot that the overall benefit from the drug continues to increase in the years further that the trial is being followed. I find this fascinating because the drug stopped at 2 years and yet, the benefit continues to grow in this carryover effect. What’s happening while people are taking abemaciclib that’s changing the milieu of the cancer such that when the drug is done, the benefit enlarges? Is there some sort of immunologic effect? I’m not sure we know, but I find that data really compelling. And I think as we’ve seen that, that has provided greater confidence and interest in using abemaciclib as broadly as we can within the indication.

I agree with Dr Graff. I really welcome the NATALEE data looking at a second CDK4/6 inhibitor with a positive signal. And I think what’s so important about NATALEE is that it’s this broader population of people that’s including everyone except the most kind of benign Stage I patients. But almost everyone else is included under the NATALEE umbrella. And in particular, we all have these high-risk node-negative patients, maybe a T3N0 or high-grade T2N0, where you just want to give them more, but they don’t fit monarchE. And so I really think that that’s the population of patients that I’m particularly interested in expanding my use of adjuvant CDK4/6 and including ribociclib as part of that. And, of course, what I liked about the ribociclib presentation for San Antonio is the first time we saw the data, 80% of the patients were still taking drug. So it’s really hard to say is it helping because they’re still on it. The next presentation we’ve seen now, I think there’s only 20% of people still taking drug. So we are gradually with more maturity seeing the longer-term impact. And I think that’s going to be a key thing to pay attention to as we continue to see updated data from the NATALEE study.

DR LOVE: And that carryover effect was seen with adjuvant tamoxifen. It was amazing when we saw it. And that was a big part of why it had the benefit and was usually lower-risk. Stephanie, you had a thought?

DR GRAFF: Yeah, I just wanted to add. You had asked what it’s going to take to see us start utilizing this more widely. And for me in clinical practice, I feel like my patients with hormone receptor-positive are told by the radiologist that does their biopsy and their primary care doctor or gynecologist that calls them with their result and the surgeon that they meet first over and over and over again that they have good cancer. Because they’ve been sort of conditioned to hear that hormone receptor-positive breast cancer is good. And we know that’s not true, right? We have seen that pan New England Journal of Medicine article where the risk of recurrence at 20 years with lymph node-negative breast cancer or N1 disease is still kind of astronomical. And so I think that it’s going to take kind of a societal shift led by us, the medical oncology community, talking about what the risk of this disease really is.

And then that has to be countered weight by a point that you brought up, Neil, of the financial toxicity. And, of course, we’ve seen shifts where maybe now Medicare is going to start negotiating some cost. I’d love to see some CDK4/6 inhibitors go into that. Palbo is going to go generic. And so maybe we’re going to start to see some ability of us to grapple with the cost of these drugs as a society as well.

DR LOVE: Yeah, I hear that same kind of story from the lung people. They walk in and say, oh guess what, you have EGFR mutation, you won the lottery. Except it’s still metastatic disease. Anyhow.

DR GRAFF: Yeah.

DR LOVE: One other point about this, Erica, is kind of getting the patient through therapy. And I’m curious what your experiences are. We saw some data that were very encouraging that dose reduction doesn’t look like it impacts the benefit from adjuvant abema. How do you deal with diarrhea? Do you treat people preventatively? What are the issues in getting people through therapy?

DR MAYER: Yeah. So that’s a really important question and something we really are working on daily in clinic. It’s important to know with abemaciclib that the diarrhea side effect, which is the one that was most common to lead to dose holds, dose reductions, dose discontinuations in monarchE, tends to happen early. And so usually, within the first 6 to 8 weeks or so is when the diarrhea will peak and then it burns out a bit. And it can still be episodic over the rest of the 2 years, but the worst of it is in the beginning. It’s very important to educate your patient so that they’re prepared that this can happen, but you’re going to get over it and also to tell people to be aggressive about their use of loperamide. If somebody with max medical support is still having trouble, then we can feel very comfortable with a dose reduction that we’re going to hopefully maintain efficacy but be able to keep the patient on drug.

We recently launched a trial at Dana-Farber and throughout the Dana-Farber network, this is called the TRADE study, that’s looking at a short dose escalation of abemaciclib for patients who are onboarding to adjuvant abemaciclib. Just within the first couple months, gradually increasing the dose to try to overcome that early diarrhea period and get people kind of safely and securely into the rhythm of things. And so that trial is currently open and accruing. And we hope that might provide a new paradigm for how we can dose the drug. Until that’s ready, I’m not recommending to do it. But it is something that I hope will improve the experience for patients.

DR LOVE: So one more early-stage paper. And I’m sorry, chat room, we’ll get to you soon. We’re getting chat room, everything, we’re getting behind, et cetera. But I love this paper, SERENA-3. A window of opportunity study looking at this oral SERD, Stephanie. And all about the translational data which is spectacular, I think. But anyhow, what’s the bottom line what they saw?

DR GRAFF: Yeah. So this trial is looking at camizestrant in a window of opportunity trial. We talked way at the beginning of this recording about the SERDs and SERMs that are up and coming. Camizestrant is one of those. And this trial took patients who knew they had breast cancer and had a surgery scheduled and say, hey you know what, while you’re waiting for surgery, here take this pill. It gave it at 3 doses 75 mg, 150 and 300, and compared their diagnostic biopsy with their surgical specimen. And said look, did your estrogen receptor degrade? Did the drug do what we said it did? Did your Ki-67 reduce? Does the drug stop proliferation of cancer? And low and behold, camizestrant does what we think it does. Regardless of the dose, 75, 150, 300, we saw reduction in estrogen receptor alpha and regardless of the duration of therapy, 5 to 7 days or 12 to 15 days, we saw both degradation of estrogen and reduction in Ki-67. I think that this is exciting sort of proof of principle. It gives us confidence in dose reduction for SERDs in development. It gives us confidence that we’re going to be able to see reduction in tumor volumes in the metastatic setting with these drugs. And it gives us optimistic data that these drugs might be effective in a neoadjuvant setting or even in the adjuvant space because they’re so effective at targeting their target.

DR LOVE: So maybe we can do an extra hour here today. Are you 2 free? Just kidding. But I’ll just say 2 words about this study, love it. It is great. I’d love to see more studies. I’m sure there’s more coming.

Advances in the Care of Patients with HR-Positive Metastatic Breast Cancer — Dr Mayer

DR LOVE: And now, let’s talk about metastatic disease. I brought this up earlier, but let’s jump into it. Again, Erica, big discussion point for a number of years. Things going back and forth. Where are you? And where are we today about choice of CDK in the first-line setting?

DR MAYER: Yeah, this has been a hot topic for quite a while. We have 7 large Phase III randomized trials in the first-line and pretreated setting for metastatic hormone receptor-positive disease looking at the 3 CDK4/6 inhibitors. These are all positive studies. They all improve progression-free survival with a hazard ratio of about 0.5. So for many years, we’ve said they’re all basically very similar drugs and they’re interchangeable. It’s when we look at overall survival where we’ve seen this differentiation and a thought of maybe they’re not all the same drug.

As we can see in the images, the studies using ribociclib, the MONALEESA series of studies, all had positive outcomes in terms of overall survival. And I think that has led to some shifts in our treatment patterns. Many of us are now selecting ribociclib as the partner of choice when we are beginning patients on aromatase inhibitor and CDK4/6 inhibitor. In contrast, the trials that use palbociclib, the PALOMA trials, were not positive studies. And those ones led to some of our changes away from palbociclib for what it’s worth.

What we saw in San Antonio was updated overall survival for the MONARCH 3 study, which is the first-line abemaciclib study, which has been presented before in an immature form and now, this is reaching maturity. And this was presented by Matt Goetz. What we saw in this study was that although the patients who received abemaciclib as part of their first-line therapy had what I think was a pretty dramatic improvement in overall survival, over a year prolongation in overall survival, this did not technically meet the criteria for statistical significance as designed by the trial. Now I’ll point out the MONARCH 3 trial was the smallest of the first-line studies. It was a 2:1 randomization and had the lowest statistical power to show overall survival benefit. So it really wasn’t set up to show this finding. That being said, we do see this 13-month improvement in overall survival. This was seen also in patients with visceral disease, which is a group of patients that we sometimes think abemaciclib might be a little more appropriate for.

And Dr Goetz also presented updated progression-free survival data continuing to show this really dramatic improvement in progression-free survival. And I think what’s very interesting, and this is 8-year follow-up of the study, is that at this moment, 8 years in, 1 in 5 patients has not progressed. We all have these people in our clinics, people who started abema when the drug became approved, and they are carrying on with disease stability. So this is a very active drug. And I think, you know, I’m getting asked, am I changing anything? Am I not giving abema? And I would say I still feel like this is a very active drug for us. If I have to go by the data, I will pick ribociclib as my CDK4/6 of choice in the first-line setting. But if the patient can’t take ribociclib for some reason, a cardiac issue, liver issue as that drug had caused QT prolongation or LFT abnormality, I will select abemaciclib as my treatment of choice. Because I really do feel that these are quite strong data.

And getting back to palbociclib, there was a very interesting kind of rapid update that was presented from a trial called PARSIFAL-LONG. PARSIFAL is an older study that was randomization between aromatase inhibitor and palbociclib or fulvestrant and palbociclib. And the results of PARSIFAL showed that both arms performed very well. There was no difference in the endocrine partner. What the leaders of that trial did is they created a follow-on study where they just followed the patients combining the arms to see how they did. And what they reported at San Antonio was that the overall survival in PARSIFAL-LONG for these patients treated with palbociclib was 65 months. That is essentially identical to what we see in MONARCH 3 and MONALEESA-2. And I think it raises the question of whether palbociclib also has this overall survival prolongation that just didn’t come out in PALOMA-2 for whatever statistical or study-specific reason. I don’t think that means we revive palbociclib into the first-line setting the way we did before necessarily. But, again, I think many of us are feeling more interested in returning to palbociclib, particularly in patients for whom that might be a good choice.

DR LOVE: Stephanie, do you want to add your sort of art of oncology approach to this decision? Erica said if there’s some factors that push her away from ribo, she’ll go with abema. Some constipation? Is that enough for you to do it?

DR GRAFF: Yeah, the MONARCH 3 data really didn’t change anything for me in my utilization of abemaciclib. Ribo has been my sort of go-to first-line choice for metastatic hormone receptor-positive CDK4/6 inhibitor just because of the weight of the data and the early overall survival data. But MONARCH 3, I think the p-value is a statistical fluke. It is the smallest sample size. It was a 2:1 randomization scheme. And for those of you that attended San Antonio and have access to the online library, Bill Barlow did a lovely commentary on that trenches review. Bill is the SWOG biostatistician on how to think about biostats. So if you want to take a second and watch that, it’s helpful. And so I think just sometimes, stats don’t do what we need them to do. One of my favorite quotes is Mark Twain. There’s 3 kinds of lies, lies, damn lies and statistics. And you know what, sometimes we get statisticed. I shy away from palbo, again, based on where the data sort of fell. But I still use palbo too because you know what, it’s a little bit better tolerated. And sometimes, I have patients that have drug-drug interactions that make me unable to prescribe one of the other drugs. And when I mention diarrhea, their face lights up in fear and they say there’s just no way, and I do palbo. And sometimes, that’s the right choice for my patient. And that’s what the art of oncology looks like.

DR LOVE: So a quick consult to you, Erica, from the chat room. Swati has a 37-year-old woman with ER-positive breast cancer, intramedullary mets, CSF cytology is negative. Wants to know, do CDK, is there a preferred CDK if there’s CNS involvement? Does the CDK penetrate the CNS?

DR MAYER: Yeah, that’s a tough case. Early on in the development of the CDK4/6 inhibitors, there were a series of studies done with abemaciclib monotherapy that looked at CSF concentration of abemaciclib with exposure, and demonstrated penetration of the agent into the CNS. So among the CDK4/6 inhibitors, if I had to select which drug gets into the CNS the best or at least which drug do we have data for, it would be abemaciclib. I would hope that patient might need some radiation with the CNS involvement. And then if they’re first-line, trying the endocrine would make sense. I would also add there was a pooled analysis of T-DXd studies at ESMO demonstrating an amazing amount of response seen with T-DXd with either pretreated or untreated CNS disease. And so my interest in T-DXd for that patient is also higher than it would be otherwise.

DR LOVE: Yeah, we had a wild case of HER2-positive esophageal cancer with an incredible response to T-DXd. Okay, yeah. And she actually follows up and says no brain mets. This is first-line. And the patient was sent for radiation therapy.

Okay, capivasertib. I already alluded to the interesting schedule of this, Stephanie. Adam Brufsky at San Antonio says he tells his patients to take the weekend off. I’m wondering how compliance is going to be, incidentally, with this kind of schedule which I don’t remember hearing too much about schedules like this before. But anyhow, just got approved. Stephanie, any initial thoughts about the agent? Have you actually used it?

DR GRAFF: I have not had a chance to prescribe capivasertib yet. I know from investigator meetings that the 4 days on, 3 days off emerged based on some really strong data that they saw in their Phase I where when they were doing 3 days on, 5 days off versus 5 days on, 2 days off, they saw shifts in their tolerability. So I think that as you’re considering this for your patients and thinking about their side effects, I would try to stay true to that 4 days on, 3 days off. I don’t remember, I don’t want to misquote, whether it was more diarrhea one way and more cytopenias the other way. But I do think that that was evidence-driven. And so probably Monday through Thursday, on. Friday, Saturday, Sunday, off in a traditional 3-day weekend kind of strategy is going to be successful for our patients. And then just remembering that patients that have AKT — sorry, patients with PTEN or AKT mutations are going to be eligible in addition to patients with PIK3CA mutations which means we’re all going to have to go back through all of those genomic profiles we’ve ordered over the last several years and made notes in our records. If the patient does not have a PIK3CA mutation, now we have to go back and say wait, did they have PTEN? Did they have AKT? Because potentially, again, this expands that bag of tricks we can choose from for our patients.

DR LOVE: So, Erica, Karen Green, hey Karen, I always love seeing Karen in the chat room, wants to know if a patient has a PIK3 mutation, no diabetes, would you do capi or alpelisib?

DR MAYER: So I think that’s a great question. And both of these agents have now shown positive data in pretreated patients. The CAPItello-291 study is quite modern. This is a study of patients with advanced disease. At least half of them had had prior CDK4/6 inhibitor therapy. A number of them had visceral involvement. So I think it really reflects a modern practice. Also an important difference between CAPItello-291 and SOLAR-1 which is the study that led to alpelisib approval is that the CAPItello study did allow patients who had diabetes, not on insulin or hemoglobin A1C less than 8. So that’s much broader than what was allowed in SOLAR-1. What we saw is that in the patients with the pathway alteration, there was a significant improvement in progression free survival with a hazard ratio of 0.5. Now this was positive in the overall population, hazard ratio of 0.6. But the improvement from 3.1 months to 7.3 months was really seen mostly in the pathway altered. And this is what’s led to the very recent approval of this agent.

I think the very important differentiator is the toxicity profile. We do know with capivasertib that we can see diarrhea. And that occurs in almost the majority of patients although only about 10% with Grade 3 diarrhea. The official safety data that’s presented I think underestimates rash. And both Dr Graff and myself have seen some of the data that’s looked at kind of combining all the different ways that people describe rash and showing that the rate of all-grade and Grade 3 rash is higher than what I think we’ve initially seen. But importantly, the rates of hyperglycemia are much lower. And remember, some of these patients had diabetes. And the rate of Grade 3 hyperglycemia was only 2%. It’s like 50% in SOLAR-1 if the patient had something getting close to diabetes. And for me in practice, I think the hyperglycemia has really been one of the most challenging side effects to try to manage and one that has had such a detrimental effect on quality-of-life in patients. With diarrhea and rash, we know how to manage this. And when I give capivasertib, I’m probably going to give people prophylactic antihistamine to prevent rash. I’m going to do a lot of education about diarrhea. I’m going to have my ONN talk to that patient every week and make sure that they are on-target with toxicity management. But I think that I am interested to use this drug in practice now. And I’m going to probably be prioritizing this for my patients.

DR LOVE: Stephanie?

DR GRAFF: I’m cautiously optimistic about the hyperglycemia. Again, I think Erica outlined nicely that the CAPItello-291 population is just maybe a little bit healthier than the SOLAR-1 population was which may account for the hyperglycemia differential. We have an oral therapies clinic that has some lovely algorithms about what happens when a patient starts an oral chemotherapeutic, what labs they have at what interval, phone checks versus APP visits versus MD visits. And it’s just lickity split which is great for my clinical practice. But we are going to be managing our capivasertib patients the same as our patients with alpelisib in terms of frequency of blood glucose checks initially just because I think that as we treat patients with capivasertib who are obese, insulin resistant, prediabetic, more in line with my patient population than perhaps the trial population, I’m worried that I’ll see a slightly higher rate of hyperglycemia.

DR MAYER: I think we see that with so many of our targeted agents that once we use them in the real-world and in our real patients, the toxicity profile may end up being a little different than what we saw in the trials.

DR LOVE: Absolutely. So we’ve already talked a bit about oral SERDs and you reviewed this, Erica. And, of course, the players right now that seem to be most prominent in the ones that you reviewed, elacestrant which of course is approved, camizestrant, we were just showing that laboratory study, the translational study, and imlunestrant which is not only being studied in monotherapy, but also in combination. This is a paper with abema, but I think it’s been looked at with other agents. So, Erica, can you just sort of give us the bottom line about what you see in terms of efficacy and tolerability? And what differences, if any, seem to exist between these agents?

DR MAYER: Well our approved agent is elacestrant which is an oral SERD. And this approval came from the EMERALD study. This was a study of pretreated patients. All of them had had prior CDK4/6 inhibitor. All of them had had prior endocrine therapy including about 30% with prior fulvestrant. So it really reflects what we see in practice. Patients were randomized to receive elacestrant monotherapy versus investigator choice endocrine monotherapy. So there’s no targeted partner here. It’s just the single agent. The overall results of the study showed what many of us had considered a somewhat modest improvement in progression free survival with the use of elacestrant.

But a subsequent follow-up analysis has, I think, really highlighted who benefits. This was a subset analysis done looking at outcome based on duration of prior CDK4/6 inhibitor. And what we see is that the patients who were on their prior CDK4/6 inhibitor for longer, for example, for a year or more beforehand, had a much bigger benefit from elacestrant with an improvement in their PFS from about 2 months with standard of care or for the provider choice to almost 9 months with elacestrant. I don’t think this is telling us something magical about CDK4/6 inhibitor. I think the duration part really refers to maintenance and retaining endocrine sensitivity. That if your patient has an ESR1 mutation and they have retained endocrine sensitivity, they may benefit from the use of elacestrant.

We saw a subset analysis at San Antonio that I thought was really interesting looking at outcomes in the EMERALD study based on different clinical pathologic features or different mutational status. The one that really jumped out to me was patients who have both ESR1 and PIK3CA because those are the 2 actionable mutations in breast cancer for which we have targeted therapies. And if you see both of those, which should you pick? Should you pick the oral SERD or should you pick the PI3 kinase inhibitor? And what was seen in this analysis was that all the subgroups they identified benefited from using elacestrant instead of the provider choice endocrine. The benefit seen in the PIK3CA mutant population was a little more modest. It went from about 2 months to about 5 months, so it’s a little less than the other groups. And we know that if there’s a PIK3CA mutation, that means a little bit more resistance. But that group benefited. And if I have my patient with both mutations and if they have, let’s say, relatively low-volume disease or relatively slow growing disease, I’m going to pick the elacestrant before I move them to the honestly more toxic PI3 kinase inhibitor. If that patient has a little bit more going on, then I really might want a doublet.

And I’m really looking forward to seeing data from ongoing studies including a trial called ELEVATE that’s looking at elacestrant with targeted combinations. Because I think the era of endocrine monotherapy is kind of behind us a bit and I’d really like to be using elacestrant with combinations.

DR LOVE: So I was mentioning the issue of the other SERDs. Here are some data from SERENA-2 looking at camizestrant. Any differences in terms of what you see here, for example, compared to elacestrant. Erica?

DR MAYER: Oh, for me. So this was a study randomizing pretreated patients to get fulvestrant monotherapy or different dose levels of camizestrant. And these were patients, many of whom had had prior CDK4/6 inhibitor and pretreated. The overall analysis showed that the camizestrant patients in the ITT population did better than fulvestrant monotherapy with an improvement from about 3.7 months to about 7 months. But the bigger benefit was seen in patients who had an ESR1 mutation which, again, we think is the biomarker of selection for oral SERDs. And in those patients, there was a more substantial improvement in progression free survival that really wasn’t seen in patients with ESR1 wild type.

So we await more data with camizestrant in the first-line SERENA-4 study. We also have all of these drugs moving into the adjuvant setting including another oral SERD, giredestrant. We have 2 adjuvant studies with camizestrant, a very large study with imlunestrant. And it’s really exciting to think about how this big category of endocrine therapies could completely enter our treatment paradigms. And as Dr Graff said, is an important tool in the toolbox or trick in the bag that we can have available for people.

DR LOVE: You mentioned combination. I noticed there was this paper that you went through looking at imlunestrant with abema. I think there was another one with PIK3 or AKT. What’s been seen in these? It looks like at least with the abema, reasonably well tolerated. Any thoughts about this kind of combination, Erica?

DR MAYER: Yeah. They were cohorts from the EMBER study which is a multi-cohort Phase I trial that is led by our friend, Komal Jhaveri. And she presented some really interesting data from that study. There was one cohort of patients presented who had all had prior CDK4/6 inhibitor and then went on to get imlunestrant, and showed that those patients had a median progression free survival of about 7 months. Now when we give fulvestrant in this setting, we sometimes see a PFS of, like, 2 months. And to see 7 months was really robust. She also showed combinations of imlunestrant and abemaciclib or imlunestrant, abemaciclib and AI, so like a triplet. And in both of those settings, there was a very prolonged progression free survival which we would expect with the combinations. But what I think is really interesting is imlunestrant can cause some diarrhea. We know abemaciclib can cause some diarrhea. But what she was able to show is that the combination together did not cause substantial diarrhea, that it was manageable. And I felt really encouraged to see that data that we can continue to think about combinations together.

DR LOVE: So just a couple words about antibody drug conjugates. Again, I refer you to both of these great presentations for more details. Tonight, we’re just kind of picking out a few points of interest and getting you interested to watch those presentations. So, Stephanie, we saw at ESMO more data from the DESTINY-04 trial with T-DXd, HER2-low. What’s your bottom line right now in ER-positive metastatic disease when you generally introduce T-DXd? And if the regulatory issues are aside, would you be using it earlier?

DR GRAFF: I think that for me, the takeaway for DESTINY-Breast04 is obviously, this is a landmark study. Knowing if your patient is HER2-low is critical. It’s something that should be noted early and often as you’re thinking about your treatment options for patients. But I think for me, if anything, what I would say is that in the hormone receptor-positive HER2-low space, I would continue to push those other lines of hormonal therapy. I would be using a CDK4/6 inhibitor, a PIK3CA agent, an ESR1 agent prior to introducing IV therapy. Of course, IV therapy comes with very significant toxicity, very different side effect profiles. And I think that, again, we want as many options as we can for our patients. So don’t underestimate the value of oral therapy. And I right now am using it guidelines-based after 1 prior line of systemic chemotherapy or, of course, waiting on the next trial looking at moving HER2-low therapy earlier in the lines of therapy. And we’ll continue to see how that strategy plays out, both in hormone receptor-positive and hormone receptor-negative HER2-low breast cancer.

DR LOVE: So final comment from Erica. In your practice outside of a trial setting in metastatic disease ER-positive HER2-low, what comes first, T-DXd or sacituzumab? And any thoughts in your experience with datopotamab deruxtecan? The lung people are also starting to figure this one out. I’m curious particularly what you’ve seen and experience in terms of mucositis with that agent.

DR MAYER: Yeah. So we have an embarrassment of riches here with multiple antibody drug conjugates. And they’re all kind of like interchangeable modular units. And some of them target Trop2 like sacituzumab or Dato. And then some of them have the DXd payload. And so I think the big challenge that’s coming up for us is, how do we sequence all of this? In my practice, I prioritize T-DXd over sacituzumab if I’m at a point in time where there’s the choice. I find that the survival and PFS data from DESTINY-Breast04 is so compelling. And for those of us who were at the plenary at ASCO last year, I think we all had goosebumps and tears and it was just amazing. And so I think it’s just such a transformative agent in our space.

But then the question is when the patient progresses, is the disease resistant because the HER2 has mutated and it is no longer a good target or has the cell itself become resistant to the DXd payload? And how do we know which of the agents, assuming we are going to have more and more of these agents, would be the next one to sequence? There’s going to be a whole spectrum of trials launched in the very near future that are going to be looking at some of these sequencing questions, which to give first, how to look for resistance, how to identify which would be the next best agent.

I’m really interested in the Dato. I think that the data from TROPION-Breast01 was very provocative. But mucositis is one of the key toxicities. And in that trial, patients are getting prophylactic steroid mouthwash just like we do when we give everolimus. And thank goodness we have a lot of tricks that we can use to help manage toxicities. But as Dr Graff said, all of these agents which incredibly active, do come with side effects. And we really want to maintain our patients on endocrine therapy as long as we can before we make the jump.

DR LOVE: And I want to refer you to Erica’s presentation to learn more about patritumab deruxtecan targeting HER3. That’s also being used in other cancers including lung cancer. So we’ll see where things go with that.

I want to thank you so much, Erica and Stephanie, for working with us today. Audience, thank you for attending. It feels good to be back now. We’re kind of getting warmed up here for the beginning of the year. Next week, we’ll be out at the ASCO GI meeting, but it’s all going to be online. We’re starting out on Thursday talking about colorectal cancer. Be safe, stay well, and have a great night. Thanks so much, Erica. Thanks a lot, Stephanie. Have a good one.