Year in Review: Clinical Investigator Perspectives on the Most Relevant New Datasets and Advances in the Management of Breast Cancer (Webinar Video Proceedings)
Year in Review: Clinical Investigator Perspectives on the Most Relevant New Datasets and Advances in the Management of Breast Cancer (Webinar Video Proceedings)
![]() Ian E Krop, MD, PhD ![]() Sara M Tolaney, MD, MPH Featuring perspectives from Dr Ian E Krop and Dr Sara M Tolaney. Published May 2025.
Introduction: Adjuvant CDK4/6 Inhibition DR LOVE: Good afternoon, everyone. I’m Neil Love from Research To Practice and welcome back to Year in Review, as today we talk about the management of breast cancer. We have a great faculty today: Dr Ian Krop from the Yale Cancer Center in New Haven, Connecticut, and Dr Sara Tolaney from the Dana-Farber Cancer Institute in Boston. As in all of our programs, we will be discussing the use of unapproved agents and regimens. Check out the package inserts for more specific information. So this is actually sort of part 2 of our Year in Review breast cancer series. Part 1, we didn’t know we were doing 2 parts, but part 1 was in the end of March with Drs Dent and Lin and we just had so much stuff to talk about, we were like, we’ve got to come back and spend another hour on this stuff. So we asked Sara and Ian to join us and also give you a little bit of preview about what’s coming up at ASCO and maybe a little bit about what to look for. Here's where we’re heading today. I want to start out actually talking about an email I just got yesterday and then we’ll dive into some of the papers the original faculty went through and try to get into a little bit more depth and talk to you about what’s going to be coming up at ASCO. So here’s the email I got yesterday. I don’t know how this person got my — I always get sort of interesting emails, I’m sure you do too. This one kind of surprised me so here it is. Question: Dr Ian Tannock wrote an editorial that was published in the JCO on April the 14th and titled “Why We Do Not Recommend That Women With Breast Cancer Receive Adjuvant Treatment With a CDK4/6 Inhibitor.” “I am a 50-year-old family physician with hormone receptor-positive metastatic breast cancer. My older sister has HR-positive breast cancer, which is only in lymph nodes. After 6 cycles of TC chemo she still had 2 out of 4 nodes positive. She had surgery and just finished radiation therapy. She’s on anastrozole and was planning to start ribociclib. However, her oncologist told her” — I don’t know how he got this paper, it’s not even published yet but it’s online if you want to check it out — “told her that he no longer was recommending that she take the ribo because of this editorial. Could you ask some of the researchers who are guests at your events regarding this editorial? Is there a controversy over using CDK4/6 inhibitors in the adjuvant setting?” So Sara, I know Dr Tannock has been an important voice for us, particularly as it relates to trial design, for many, many years. He often brings up things and issues, including this one that he’s brought up before, that garner a lot of attention. I recommend — I was kind of looking for a companion editorial that gives the other point of view, but I guess we’re going to have to do that. I wasn’t able to find that right now, but I can come up with some of my own thoughts. Incidentally, I don’t know if you ever saw this. This is a book — remember we had books? — called Adjuvant Therapy of Cancer. They used to have these meetings on adjuvant therapy every year, not just breast cancer but all kinds of cancer and this goes back like 40 years. Dr Syd Salmon did it. I’m just bringing that up because there’s so much complexity to adjuvant trials in general and the methodology, how to explain it to patients, et cetera. So Sara, would you like to sort of summarize what you get — incidentally, that article that he wrote, the editorial is pretty dense. There’s a lot of discussion about trial design, et cetera. What’s the bottom line of what Dr Tannock, who is from the University of Toronto, is saying here, and what are your thoughts about it, Sara? DR TOLANEY: Well, I think it was a really thoughtful commentary that was written, I think as you note, really highlighting the complexities of adjuvant trial design. While we have approval for 2 CDK4/6 inhibitors, abemaciclib and ribociclib, I think interpretation of the data is complex and so what was brought up in this commentary was, that these drugs are taken for a long time. That has associated financial costs but also significant toxicities that patients are facing where he brings up the fact that there were discontinuations in the trials due to toxicities, about 20% with each of the drugs. And if you look at ribociclib, only a little over 60% of people get through 3 years of treatment and a little over 70% get through the 2 years of abema. So clearly these are drugs that do have associated side effects. And then I think the other challenge that the commentary brings up is, are the benefits that we’re seeing from these trials in terms of preventing recurrences really as robust as they are citing? With the comments being made is that, when they looked at these benefits that are seen, when you do statistical analysis, you do censor patients if you don’t have follow-up for that patient. And so their comments were that that censoring that occurs is informative censoring and can bias your outcomes because you’re more likely to have people stay on the experimental arm than the nonexperimental arm and you’re more likely to have more robust performance status patients staying in your trials. And so they feel that the benefit is probably smaller than what we’re seeing and then they’re weighing that against the toxicity and financial cost of these agents, saying that they think it’s probably not worth it. I guess I would say that I’m not in that camp. I think that the benefits that we’re seeing from these agents are substantial. If you look at the 5-year data with abema, it’s a little under an 8% absolute benefit, about a 30% risk reduction in events in a very high-risk patient population. And with ribo you’re seeing about a 5% absolute benefit in a broader population of patients. And I think the discontinuation rates that we saw early on, for example, in monarchE are no longer what we’re seeing in practice. We know how to dose modify, we know how to deal with side effects and discontinuation rates are substantially lower than what was cited so I am utilizing these agents in my high-risk patients. DR LOVE: Ian, any thoughts? I wouldn’t be surprised if there are going to be more patients who are going to be hearing about this paper, either they find it themselves or their doctor finds it. What are your thoughts, Ian? DR KROP: Yeah. No. I completely agree with Sara. Apparently we are in the same camp on this one. Dr Tannock brings up obviously the point that, when choosing any therapy we need to make sure that the benefits outweigh the risk. I don’t think anybody would argue with that. But he’s bringing up predominantly methodologic aspects of a trial that could diminish the actual benefit that we’re seeing. But that applies to virtually all of our trials and I don’t think they have any specific data or reason to believe that for these 2 trials, monarchE and NATALEE, that there’re more substantial kinds of problems with the trial. So to me, given the data we see, shows a really clinically meaningful, as Sara said, 30% reduction in IDFS events roughly for both trials and that there’s a lot of patients out there for whom this therapy is appropriate. I still am going to strongly recommend the use of CDK4/6 inhibitors in the adjuvant setting for our high-risk patients. And it is true that there were patients who came off the trial because of toxicity, both of the trials, but despite that, we’re still seeing this substantial benefit. If we can manage to modulate the toxicities, learn how to manage the toxicities better, that will only increase the benefit that we’re seeing. So again, I think it’s important to think about the trial design issues and try to optimize them whenever possible. But here, I think we see clear benefit, the risks are manageable, and I think these drugs are real wins for our higher risk ER-positive patients. DR LOVE: And Sara, it also gets back to the age-old issue of PFS versus OS, but I think from a human point of view, to be able to avoid recurrence in a patient has great meaning. And also getting back to your point about how now that the trials are out there, the drugs are approved, people are learning how to use these agents more effectively and safely. You mentioned to me that your colleague, Erica Mayer, is going to be presenting some data on I guess what’s sort of a neratinib-like approach, dose escalation of abema? DR TOLANEY: Yeah. That’s right. I think the idea about this trial is, it’s called the TRADE trial, and this trial took patients getting adjuvant abemaciclib and started them at 50 mg twice daily, did it for 2 weeks, then went up to 100 twice daily for 2 weeks and then went to the full dose at 150, with the idea being that you kind of allow patients to accommodate to the drug so that you’re more likely, potentially, to get to full dose and have less treatment discontinuations. We saw that that was actually very successful with neratinib, that we do see a lot less toxicity with the dose escalation strategy and so she’ll be presenting results from a single-arm study that looked at this dose escalation strategy with abemaciclib. DR LOVE: So Ian, a quick case from the chat room, Shoba says, what about CDK4/6 inhibition, T1cN0, Oncotype of 57? DR KROP: That’s a great question. Certainly that Oncotype would indicate that that’s a tumor that will benefit from chemotherapy. Whether it also will benefit additionally from the use of CDK4/6 inhibitors, I don’t think we have strong data to say either way, whether it will or whether it will increase the benefit or decrease the benefit of CDK4/6 inhibitors. Personally, I think for that particular patient, knowing that they’re going to get chemotherapy and that there’ll be substantial benefit from that chemotherapy, I would just do the CDK first — I’m sorry, I would just use chemotherapy and then endocrine therapy alone after that, given that anatomically T1cN0 is a favorable factor. DR LOVE: Alright. Let’s get into some of the papers from the past year as well as what’s coming up and we’re starting out here with HER2-positive disease. Incidentally, here’s the paper. Again, it hasn’t been published. I don’t know how this doc found it but, the whole issue hasn’t been published, but this paper’s online right now. HER2-Positive Disease DR LOVE: So let’s talk a little bit about HER2-positive disease and Sara, I was reflecting back on a webinar we did in 2021, on our Meet The Professor series. We had this planned for a while and then right before that you presented some pretty interesting data. First there was a press release that came out. This is what Ian was referring to before, the DB03 trial, second-line therapy versus T-DM1. So I took advantage of the fact that we had you on the webinar, you had just presented the data. I showed this picture, because that was my initial impression when I saw the results from this study, again, comparing it in terms of the disease-free survival for PFS and even OS, that now we’re hoping we’re going to see these kinds of outcomes in the future. But kind of interesting thinking back to 2021, we were heavy into the pandemic, this paper came out and one of the things — and then we were talking about, at that point, this DB09 trial, which has 3 arms, THP, T-DXd and then T-DXd and pertuzumab. And as is always the case in oncology, you see a press release. So we just saw this April the 21st saying that the arm with T-DXd and pertuzumab was now positive in an interim analysis. The other arm with just T-DXd is not, I guess, mature enough at this point to talk about. And Sara, you’re going to be presenting this one again. I know you’re not going to be able to talk about specifics about it, but I did want to sort of get the audience ready for this presentation and some of the things that we’re going to think about. I just want to start out with Ian, and obviously we all want to see what the curves look like, what the hazard rates look like, what the toxicity is. But there’re a lot of other issues that I think people are going to bring up, Ian. What are some of the things you think that are going to be brought up? I guess one of the things too in this trial was that the T-DXd was used indefinitely, which will be interesting to consider. Any thoughts as we’re going into this, Ian, about what you’re going to be looking for, and assuming this has a very positive result, what it’s going to lead to? DR KROP: Yeah. So I think the question is going to be how we incorporate these data into the clinic, and as you said, obviously we need to look at what the magnitude of the benefit is, what’s the toxicity, quality of life measures for these patients who presumably are going to be on, who were on T-DXd and pertuzumab for what I’m sure will be quite a long time based on this study. So I think the issue is, the competition is chemotherapy with antibodies that we give together first, after maximizing benefit of the triplet, chemo HP, we typically then switch to a maintenance phase of just giving antibodies with or without endocrine therapy depending on the hormone receptor status. And now, after San Antonio, we also have data saying that what typically can be a very effective and low toxicity regimen of HP endocrine therapy for the ER-positive HER2-positive patients, we can now, we’ve seen data that adding palbociclib to that substantially improves the time on maintenance phase before progression. So we have an alternative to T-DXd plus pertuzumab for a prolonged duration of time with no maintenance phase versus a chemotherapy HP followed by a maintenance phase potentially with palbociclib for the ER-positive patients as an alternative for that. And I think people were going to try to figure out, knowing we have this new regimen, what makes more sense to give in the long-term in terms of maximizing both disease control and quality of life for these patients who overall tend to do very well. DR LOVE: Sara, anything you want to say? Again, I know obviously it’s embargoed, the specific data, but anything you want to say about this, and also Ian’s point about triple-positive patients? On the previous program with Rebecca and Nancy, of course there was a lot of excitement, we talked about the PATINA trial. I’m curious too, Sara, whether you have actually given palbo in this situation outside of a protocol setting. I assume you can’t give T-DXd and palbo together. So any thoughts about how this is going to play out, Sara? DR TOLANEY: Yeah. I will say, I’ll just echo Ian’s comments. I think the PATINA data were really exciting. It really was the longest PFS we had ever seen for metastatic HER2-positive disease, to really hit over 40 months for PFS I think is extraordinary with a very well-tolerated regimen. I do think, however, we have to be cautious because that is a treatment approach that really was taken for patients who got through induction therapy without disease progression and had ER-positive, HER2-positive disease. So it is not the all-comer metastatic HER2-positive patient, and so I think we do have to put that into perspective. And when DESTINY-Breast09 was developed, it was actually designed — actually right after Ian presented the data for T-DXd monotherapy in DESTINY-Breast01, when we saw that there was this tremendous benefit, it was already in line in a very pretreated population with CLEOPATRA, so it seemed like if you moved that up it would probably beat CLEOPATRA. So it was designed before we even knew you could hit a 29-month PFS with DB03. And so it was just designed to keep giving the drug because we really wanted to make sure that we were having good long-term outcomes. I think we’ve learned, however, that there are strategies to think about induction and maintenance. And so I think we’ll have to see the data from DESTINY-Breast09, and I think we’re expecting it should be better than DESTINY-Breast03, right? That was a pretreated population where we were hitting about 30 months. And so if you’re really getting prolonged benefit, I think the questions are going to come out, well who needs continued therapy? Who can get away with induction strategies, and what’s the appropriate maintenance after induction T-DXd? And so there is an ongoing study actually now, led by the MEDSIR group and Javier Cortés, which is looking at T-DXd induction in the first-line setting followed by HP therapy with endocrine treatment. So I think we’re going to learn more and more about how to tailor and optimize strategies. But again, always nice to have more treatment approaches and options that hopefully can really change long-term outcomes for patients. DR LOVE: I’m hoping that other arm’s going to report soon because it’s going to be kind of interesting to contemplate, are we really going to go ahead and use pertuzumab if that’s the only data we have? I guess there’s not going to be too much choice there. I’m curious, Ian, what your experience is in the metastatic setting with patients who are on T-DXd for prolonged periods of time. Do you see them developing progressive fatigue, cytopenias, et cetera, or do they more sort of settle in and do okay? DR KROP: You know, that’s an interesting question. I think, obviously patient’s experience varies from person to person, but for T-DXd we don’t see many of the classic cumulative toxicities. We don’t see neuropathy building up over time. We don’t see progressive myelosuppression typically. And fortunately, the ILD rates tend to be concentrated in the first year and don’t seem to be cumulative very much after that first year. So patients can stay on the drug for a long time, obviously they do, and that’s what’s translated to such nice results from DB03. It’s just I think it’s more of a, some patients just kind of get worn down with kind of modest, moderate asthenia, fatigue and modest GI toxicity just over time. It’s not usually something that forces people to stop. I think it’s just some patients just get worn down a little bit. But again, a lot of patients can stay on this for a very long time. DR LOVE: So another topic we talked about in the prior conference was the use of neratinib in patients with brain mets. We talked about this study looking at T-DM1 plus neratinib. Of course, Nancy Lin has a great interest in brain mets. She also talked about the SUMMIT trial looking at neratinib with trastuzumab in HER2-mutant triple-negative breast cancer, interesting situation. Sara, I’m kind of curious in general how often do you see HER2-mutant disease? We’re doing this program next week on non-small cell lung cancer. HER2-mutant disease is more common than HER2 — and they even use it in sometimes first line it’s so impressive. What do we know about T-DXd in HER2-mutant disease, and what are your thoughts about neratinib or, for that matter, tucatinib with HER2-mutant disease? DR TOLANEY: Yeah. So we do see HER2 mutations, more commonly in the ER-positive, HER2-negative setting, where generally initially it was reported to be somewhere between 2 to 5% and a little bit more common in the lobular patients. We have, however, seen some data that has looked at those more pretreated patients post-CDK where rates have been as high as 10% in the pretreated post-CDK population. So we do see this and we’re getting a lot of NGS panels now post-CDK, so we do periodically pick this up. I think the data from SUMMIT suggests that you can use a TKI and see robust benefit. There’s also some data with tucatinib in the HER2-mutant setting also showing benefit. And then there’s even data with T-DXd in an all-comer solid tumor trial for HER2-mutant disease, which also shows very robust response rates and, even in the subset of breast cancer patients in that trial, response rates were also very robust. So I think we have lots of choices here. I think the truth is that usually we’re running patients through endocrine-based therapy and then when they do, if they’re HER2-low or HER2-ultra-low, we’re going to move to T-DXd. So I’ll be honest, I think the interest in using a TKI here has waned a little bit as we tend to shift people a little bit more to the ADC, which also has activity in the HER2-mutant setting. DR LOVE: Yeah. I think Nancy was pointing out though, a lot of patients go through multiple therapies with brain mets nowadays, so this at least is another option to consider. So this is a paper from the last year but wasn’t in our Year in Review series, but I just want to get your take on it, because this is actually a poster that our group did of 2 surveys we did, one in 2018, one in 2024 of investigators including the 2 of you. Our thing is people do practice guidelines based on evidence, we just like to ask what people do. And we had a very prestigious group of investigators responding to this. And just kind of reflecting back also on the history, because this was right before KATHERINE was presented in 2018. So you can see at that point, we presented a case of a patient who had minimal residual disease. And again, this was before KATHERINE, so people were using either trastuzumab alone or with pertuzumab. By 2024 everybody had switched over to T-DM1. But another question we were interested in is whether or not people were using post-T-DM1 neratinib. And you can see, this is a case, was ER-positive, so triple-positive. When we said ER-negative, nobody was using neratinib. But even particularly again in 2024, just 6 months ago, we saw a fair number of people, but not everybody, using neratinib. When we flipped the case and said there was more disease residual, there again, 2018, you see a little bit more trastuzumab/pertuzumab but also some neratinib. You see a lot more neratinib now. Again, this is ER-positive, we didn’t see it in ER-negative. So I just want to ask the two of you what your thoughts are nowadays. It seems like something we haven’t talked about that much, but it’s still out there, Sara, which is neratinib. One of the other things we found that was very interesting was that we actually asked people, what numbers do you give to a patient? It wasn’t just how you treat them. We wanted to know, if a patient said, I want to know what my risk of relapse is without any treatment at this point, if you give me T-DM1, and if you give me T-DM1 and neratinib. How does that change the actual number? And the thing that was interesting was that there were a number of investigators who actually said there was an advantage in a number of situations of giving neratinib, but yet they didn’t use it. I don’t know whether they presented to the patient as an option or not. We should have asked them that. And also I assume the reason was concerns about toxicity, Sara, which has been out there for a while. I don’t know whether now people are more comfortable, as you were talking about, in terms of dose escalation. But any thoughts about sort of this snapshot we took of 2018, 2024, particularly as it relates to the use of post-adjuvant neratinib, Sara? DR TOLANEY: Well, I mean, I think we’ve been very fortunate to have the data from KATHERINE showing us that T-DM1 in essence reduces risk of recurrence by half. So it has really, as you can see, in 2024 everyone’s really using T-DM1 for those patients with residual disease. I think the question about whether or not you should follow completion of T-DM1 with neratinib is certainly a controversial one, because when ExteNET was conducted, which looked at a year of neratinib, it was so long ago that it was at a time when we were not utilizing pertuzumab and we were not utilizing T-DM1. So the data that we saw in that trial showed that there was about a 2.5% absolute IDFS benefit from neratinib. But then they did all these very cool exploratory analyses, and the patients who had residual ER-positive disease had a little over 7% absolute benefit from using neratinib in this setting. So it looked very robust but the problem is, is none of them had seen prior T-DM1 or pertuzumab. So I think if we were to try to quote a patient what additional benefit will they get from neratinib after receiving T-DM1, the honest truth is I don’t know the answer to the question, because we actually don’t have any data to know what that benefit is. And so I guess my take is, if someone has residual node-positive disease after preop therapy and is also ER-positive, we know those people do have high risk of recurrence, even after T-DM1. The node-positive patients have about a 30% rate of recurrence even after T-DM1 in KATHERINE, now with like 8 plus years of follow-up. And so I worry about those people. So if they have residual node-positive, ER-positive disease I do have a discussion about neratinib. But I’m very honest that I don’t actually know what the absolute benefit is from treating them. DR LOVE: So just a couple of papers to look for at ASCO related to this. Along the lines of PATINA, there’s going to be some data looking at ribo with trastuzumab and endocrine therapy. This is a Korean study that’s going to be presented. Also Hope Rugo’s going to be presenting a paper on treatment rechallenge after T-DXd interstitial lung disease, so we’ll look out for that. PARP Inhibition DR LOVE: Let’s talk a little bit about PARP inhibitors. Of course in our original conference we had 6 weeks ago, we talked about the updated data from the OlympiA study looking at olaparib in BRCA germline patients and the benefit that was seen there in those patients, including with survival. And I’m curious about how you’re approaching the use now, now that the data out there are a little bit mature, in terms of when you use — we have the FDA bar. I don’t know whether you go under that bar or not. We presented a couple of scenarios. So Ian, for example, if you have a patient who’s ER-positive but has 3 nodes positive, the FDA says 4, do you consider, for example in a BRCA germline patient, using it in a patient like that? How far below the bar, if any, are you willing to go? DR KROP: Yeah. I would strongly consider it in a patient like this given the strength of the data from the trial, and the fact that a year of olaparib is fairly well tolerated for most patients. Where do you draw the line? I think 3 positive nodes, we know there’s nothing biologically dramatically different between 3 positive and 4 positive nodes. So I mean, I think the absolute difference, the absolute benefit’s going to be a little less in this patient than a patient with 4, 5, or 6 positive nodes. But I think if you do the math, knowing the hazard ratio, it’s still going to be an absolute benefit that I think is probably worthwhile for this patient. DR LOVE: So a similar question. This is a triple-negative case, again, a little bit underneath the 2 cm bar for node-negative. Again, curious how you think through using PARP inhibitor. You have a BRCA germline patient, for example, Sara. Also, I’m curious about your experience now that it’s been out there for a while, patients in the adjuvant setting, how they tolerate olaparib. DR TOLANEY: Yeah, so this looks like a Stage I patient, so a T1c triple-negative breast cancer patient. So in this case, I would give them adjuvant chemotherapy, probably dose-dense AC-T in this scenario. I would not give a PARP inhibitor here just because the risk of recurrence in someone with a Stage I triple-negative disease who gets treated, risk of recurrence is pretty low, and so it’s hard to justify, I think, giving additional year of therapy. There’s a lot of interest, though, in trying to think about whether we could substitute chemotherapy in these Stage I patients with PARP, and there’re some trial designs that are being put out there to think about how to study this, because I think that is actually an interesting question. So here again, I wouldn’t be adding it to this patient. But generally I do think, as Ian mentioned, I think the PARP inhibitor is generally pretty well tolerated. I think the issue we tend to see is a little bit of cytopenias. So the anemia, in particular, can happen with a year of olaparib. So that does have to get monitored. And then there is this kind of low-grade nausea that happens when you start someone on olaparib. So I usually do give them some ondansetron to take at home. But I do find that that kind of goes away after the first several weeks of being on treatment, and people maybe take an antiemetic very periodically thereafter. DR LOVE: So what about, just as long as we’re talking about PARP inhibitors, Ian, curious about your approach to patients with metastatic disease. And here we present a patient with de novo hormone receptor-positive metastatic disease in a patient who has a BRCA mutation. Would you integrate a PARP inhibitor into the first-line therapy of this patient? If not, where would the PARP inhibitor come in? DR KROP: Yeah, I mean I certainly would integrate a PARP inhibitor into her treatment, but I wouldn’t do it now. We know that a, particularly de novo patient, is likely to do very well for an extended period of time with endocrine therapy plus a CDK4/6 inhibitor. And, while I think PARP inhibitors in general are better tolerated than most of our chemotherapy regimens, I don’t think they’re as well tolerated as a CDK4/6 inhibitor. I typically maximize my endocrine therapy before I would switch to a PARP inhibitor for an ER-positive patient. So I kind of think of it as between endocrine therapy and chemotherapy but not before that. DR LOVE: So Sara, what about the triple-negative patient who is PD-L1 positive, again, BRCA germline mutation? Would you include a PARP inhibitor, olaparib, as part of up front treatment or farther down the line? DR TOLANEY: I would usually use it further down the line because we do know that there is overall survival benefit with the use of checkpoint inhibition in that first-line triple-negative PD-L1-positive setting, whereas we don’t have overall survival benefit in, for example, OlympiA, so I do usually reserve it for second line. DR LOVE: So again, ASCO preview in terms of PARP inhibitors. Interestingly here, I was going to ask you about neoadjuvant PARP. We saw a paper, it seems like a couple of years ago, I think it was talazoparib where they had a high path-CR rate. I don’t see too much since then. Anyhow, there’s going to be a paper looking at — this is an interesting combination of olaparib and carbo as neoadjuvant therapy that’s going to be presented. Also interesting, just related to BRCA, a paper looking at hormonal therapy in patients with breast cancer who have BRCA mutations. And then finally, genetic counseling video-based, I’ve been wondering why there isn’t more of this. I think there is a fair amount now, but it seems like it makes so much sense to use telemedicine in the genetic counseling. Sara, do you have that at Dana-Farber or do all these people still get live, in-person genetic counseling? DR TOLANEY: We actually have a trial also, that Huma Rana at our site has been running, where they also were giving people video consultation and patients actually really loved it. So I think it is a great alternative, particularly in resource-poor settings where we just don’t have enough genetic counselors around, and so it does seem to work well. DR LOVE: I guess I’m waiting for an AI genetic counselor, but we’ll see about that. Antibody-Drug Conjugates DR LOVE: Alright, antibody-drug conjugates, we talk about that a lot in almost every solid tumor nowadays. And the faculty from the original program reviewed the information on Dato-DXd, which of course is now approved, in hormone receptor-positive breast cancer. Impressive results. And here’s actually Nancy’s summary of the data with Dato in hormone receptor-positive disease. You can check out her presentation that goes through this. Also in triple-negative breast cancer, although not approved, a lot of data looking at that. And what I wanted to find out from the two of you is, how are you thinking through sequencing of antibody-drug conjugates in various situations? Where is Dato fitting in? So Ian, for example, we say you’ve got a patient who is hormone receptor-positive, HER2-negative, gets ribo and anastrozole first-line, gets second-line elacestrant, now has progressive disease but is soft tissue and bone, and the patient is asymptomatic, no PIK3 or AKT/PTEN mutations and the IHC is 0, so T-DXd is not an issue. You have the possibility of Dato. You have the possibility of sacituzumab, capecitabine, et cetera. How would you think through this situation, Ian? And how are you thinking through, in general, where to place Dato? DR KROP: Yeah. So for the patient who is, for this probably pretty small subset of patients that is truly IHC 0 and not ultra-low, where T-DXd, at least right now is not, we don’t have data to say it’s effective. The question of where to put Dato, where to put sacituzumab, I think is interesting. In truth, a patient like this who is asymptomatic, has relatively low burden of disease, I find that capecitabine is a good stepping stone from endocrine therapy to intravenous chemotherapy. It’s pretty well tolerated for many patients. It doesn’t cause you to lose your hair, you don’t have to come in for infusion. So for a patient like this, I typically would do capecitabine first, and then would consider using Dato after that. In the past, I would’ve thought about using sacituzumab. But now that we have Dato available, I think the fact that it’s every 3-week infusions is an advantage over sacituzumab. So that’s how, for this particular patient, I probably would use it after capecitabine. DR LOVE: What about, Ian, side effects, tolerability, quality of life, saci versus Dato? DR KROP: Well so yeah, it’s kind of what I was — interestingly, even though they’re both topoisomerase inhibitor payload ADCs, they both target the same target, TROP2, they have quite different toxicity profiles. Sacituzumab causes substantial myelosuppression and some GI toxicity, whereas datopotamab has very little myelosuppression but does cause stomatitis in a substantial fraction of patients. So in terms of how to use those, again, I think for datopotamab I think we’re learning how to manage the stomatitis, prophylactic steroid mouthwashes, either dexamethasone, or if you can’t get access to dexamethasone because it’s hard to find these days, I think there’s some prednisolone mouthwashes that you can use instead. That’s been shown to help a lot so I tend to use that. And other than that, I think it’s a relatively well-tolerated ADC. Some patients get some dry eyes and other ocular toxicity, but those can be managed, I think, for most patients with kind of lubricant eyedrops. DR LOVE: So Sara, again, in terms of sequencing here, we have the same case I just presented, but now we’re saying much more commonly HER2-low. Obviously, T-DXd would be a primary consideration but sort of what comes next? How are you thinking about sequencing Dato right now in patients with ER-positive disease, Sara? DR TOLANEY: I mean I think here, if someone had progressed after 2 lines of endocrine therapy and was HER2-low, not everyone has to get T-DXd, even though DESTINY-Breast06 clearly shows benefit in this population. If someone has asymptomatic mild disease, maybe that was on endocrine therapy for a long time, that may be someone I still think about capecitabine for and go to T-DXd next. So I think we make a judgment call here about the sequence about whether everyone should get T-DXd versus doing it second. But then I think the question arises, if you did give T-DXd, would you consider sequencing another TOPO I payload ADC after T-DXd? Would you give sacituzumab or would you give Dato-DXd subsequently? And the truth is we don’t have prospective data yet on this. We have some retrospective series that suggests that that second ADC doesn’t work quite as well as the first one in general. The PFS is a little bit shorter. But there are some patients who don’t respond to one and then respond to the second one. And so I think the challenge is we just don’t have the answer. So I will say, I do give the second ADC, and I make a determination about which ADC to give, whether it’s Dato or sacituzumab, depending on the patient, because as Ian pointed out, there’re different toxicity profiles. So if someone has a history of ILD, obviously to T-DXd, then Dato is contraindicated. And if someone’s got a lot of cytopenias, maybe you don’t want to give sacituzumab, you’d have to utilize growth factor support. So it’s nice to have a choice because you can individualize it for the patient. DR LOVE: So again, in terms of what’s coming up in a few weeks at ASCO in terms of ADC, Dr Tolaney again appears, because we’re going to see sacituzumab and pembro. There’s a press release out there. This is in PD-1-positive metastatic triple-negative disease, where obviously chemo and IO in these patients is currently used. And this trial has a press release saying it’s positive. Sara’s going to be presenting this ASCENT-04 trial. We’ll see how positive it is, whether it’s going to be enough to switch therapy. Any thoughts, Ian, about this strategy of adding IO to ADCs? You know, we have in first-line therapy now in bladder cancers an IO and ADC, enfortumab vedotin. Any thoughts about the synergy that we think we’re going to see there, Ian? DR KROP: Yeah. I think it’s an idea that has a lot of strong biological underpinnings. We know that ADCs act as very good chemotherapy delivery systems, and therefore they are good at generating kind of the immunogenic cell death that we see with chemotherapy, which should be synergistic with a checkpoint inhibitor. And there are additional — there are preclinical data, we’ve had actually for a number of years, even back from when T-DM1 was first developed, suggesting that you get particular increases in immunogenicity and antigen presentation when you have an ADC delivering your chemotherapy rather than chemotherapy alone. So I think there’s good reason to think that this is going to be synergistic, and my guess is we’re going to see that in this study. DR LOVE: So in terms of other ADC papers, here is a paper with saci plus pembro as neoadjuvant therapy in the NeoSTAR study. And then getting back to T-DXd, which of course is an antibody-drug conjugate, Dr Dent’s going to be presenting more data from DB06, looking at HER2-low and ultra-low. Just sort of taking the current temperature there, Sara, the DB06 ultra, it was an ER-positive disease. What are you doing about ultra-low HER2 and triple-negative disease, Sara? Are you using it? DR TOLANEY: It’s a good question. You’re right. We don’t have any data for T-DXd’s benefits in metastatic triple-negative disease that’s ultra-low. Our pathologists now are reading ultra-low expression, so I do now get that in my pathology report. And so if someone was ultra-low, I would think about using T-DXd in the triple-negative setting. I realize we don’t have great data. And in fact, even in the low setting we only had 58 patients from DESTINY-Breast04. I typically will use T-DXd after sacituzumab in the triple-negative setting, but I would consider utilizing it. DR LOVE: So we also have another AI paper, so many AI papers nowadays, trying to assist and figure out how to interpret HER2-low and ultra-low pathologically. Ian, I know you’ve been very involved with this issue. I know there are new assays out there trying to quantitate HER2, but it’s still such a vexing problem. We were talking before, there’re not too much HER2-0 anymore. Where do you see this heading, Ian? Do you think that in the near future we’ll be able to be more precise about who shouldn’t get T-DXd? DR KROP: Yeah. I think that’s going to be really the question. And maybe if the DESTINY-Breast15 study and other studies show that T-DXd works in HER2-0 then we won’t have to quantitate HER2 at all, which I think would be a lot easier for our pathologists certainly, and for us as well. But I think this kind of gets back to actually the abstract you were just showing that’s going to be presented, looking at that Rebecca Dent’s talking about biomarkers from DB06. We really could use biomarkers for prediction of benefit of all of the ADCs. We really have struggled with that, and even obvious things like HER2 itself and TROP2. It’s been ambiguous regarding how good of a predictor it is for benefit of these drugs. There is some work being done by a pathologist at our group, David Rimm, who’s trying to look at both HER2 and TROP2 in the same samples to try to help us predict or help us determine, should we be giving, should we start out with a TROP2 ADC or a HER2 ADC for the many patients who potentially would be eligible for both. But I think, until we have some biomarkers that really predict which drug’s going to work for which patient, we’re kind of shooting in the dark, and that includes the HER2 testing where, again, we really haven’t been able to come up with a really useful test so far. DR LOVE: So we’re also going to see a paper on patritumab deruxtecan, the HER3-DXd, the TUXEDO-3 study. This will be really interesting. I guess it’s obviously not approved, but I’ll be curious whether here, or obviously it’s been looked at in lung cancer as well. Another saci, this is saci/tirumotecan or Sac-TMT. They’re going to present data, now this is in metastatic triple-negative disease, the OptiTROP study. So that’ll be interesting complement to what Sara is going to be presenting. Up-Front Treatment of HR-Positive Metastatic Disease DR LOVE: I want to talk a little bit about endocrine therapy. And actually I’m going to start out with ASCO. And we’ve been looking forward to see what this SERENA-6 trial is going to show. Apparently we’re going to find out, Sara, in the plenary session, which is there’s, again, a press release saying that this study is positive. Could you talk a little bit about — this will be presented by Dr Turner as part of the plenary session on the Sunday of ASCO. Could you talk a little bit about what this study looks at, what you’re going to be looking for in this study, Sara? And where do you think we’re going to be after ASCO? Are we going to be following patients looking for ESR1 to develop? DR TOLANEY: Yeah, I think this is a really exciting trial because it could be a paradigm shift in the way we think about approaching our metastatic breast cancer patients. This trial took patients who started off on an aromatase inhibitor and a CDK4/6 inhibitor. And after they had been on therapy for at least 6 months, they then went on to get ctDNA screening every 2 to 3 months. And if they were found to have an ESR1 mutation, they then got randomized to switch over to get camizestrant and continue their CDK4/6, or just continue on their aromatase inhibitor and CDK4/6 inhibitor. And then the study was looking at progression-free survival. We already know from the PADA-1 study that if you take patients who are on AI/CDK, and they develop ESR1 mutation, and they don’t have disease progression on radiographic imaging, and you switch them to fulvestrant/CDK they do a lot better. Their progression-free survival is a lot longer. So it kind of just makes sense. Like if you have ESR1 mutation, the aromatase inhibitor’s not going to work anymore, so you want to switch to a degrader that’s going to make you do better. So one, I think we’re expecting this to be a positive trial. Obviously, knowing it’s a plenary makes you think that the benefit’s going to be very large. But I think this is a complicated study to interpret and I think we’re going to have to really try to see more data, because this is allowing for a change in therapy before radiographic progression. This is very different than our normal approach to a metastatic breast cancer patient. The patients in the control arm, we wait until they have radiographic progression, then they can go on to a SERD/CDK. But this trial didn’t mandate crossover. So the interpretation of PFS2 is going to be a little bit complicated because it’s not like everyone on the AI/CDK arm went on to get camizestrant and go on to something else. So I think that’s why interpreting this trial is going to be hard. But if you do see a really large difference, and we see again a PFS2 difference, it does make you think that maybe switching earlier would be a good strategy. And this would be a big change in the way we practice, because it would mean we’d be monitoring ctDNA routinely in our first-line patients. So it would be a shift. DR LOVE: So yeah. I wonder whether it is going to be a large benefit. It’s going to surprise me if it is large. It’ll be a pleasant surprise. I got one of these weird flashbacks I get from like 40 years ago. I was thinking about this book again. I don’t know if you’ve ever heard of the Scottish adjuvant trial. I actually interviewed Dr Stewart from I think Scotland, who did the trial. They actually randomized between adjuvant tamoxifen and tamoxifen on relapse. And they still showed the benefit of adjuvant tamoxifen. I think it’s probably the only adjuvant trial that they did. It’s so rare to do that type of a study. Anything you want to add to Sara’s comments about what could be a practice-changing trial, Ian, and really maybe potentially going to change how we follow these patients? DR KROP: Yeah. So actually, I think part of the reason this could be a plenary or selected for plenary, is because if we start using this it’s going to change how we essentially practice oncology for these metastatic breast cancer patients, and presumably it may translate to detection of other emergent mutations over time that we’re going to start following, and then switching based on that. So I think it’s exciting. Again, I think we’re going to have to look at the details. I think PFS2 is very important here and it really would have been nice for this to have been designed kind of like PADA-1, which was, you know, PADA-1 actually did switch over patients to fulvestrant who initially did not, who were not randomized to the crossover early on, and yet still the PFS2 was longer for the patients who switched early rather than late. But I think, as Sara said, I think we’re not going to have the same equivalence here because the control arm is not going to get camizestrant or even another oral SERD probably in many parts of the world. So I think we’re just going to have to keep that in mind when we’re looking at the results. DR LOVE: So Sara, we’re also going to see more data from the EMBER-3 trial that we saw for the first time in San Antonio. And we were doing several CME programs during San Antonio, and I kept asking all the faculty, like what do you think about this trial? To me, it was over my head in many ways. I keep talking to Dr Jhaveri about it. I’m just kind of curious, I guess 5 or 6 months later, Sara, what your thoughts are about this, and are there situations where you think it makes sense to use a SERD, imlunestrant, plus an AI, even in somebody who’s had it, so the sort of postMONARCH abema in somebody who didn’t have previously abemaciclib? Any thoughts about where this is heading? Do you think it’s going to get approved, Sara? DR TOLANEY: I think the one arm of that trial that was easy to interpret was that imlunestrant is better than, in essence fulvestrant, in ESR1-mutant patients. So that should be a new option as an oral SERD. But I think what you’re alluding to is the complexity of the trial design of comparing imlunestrant/abema to imlunestrant in an all-comer population, not restricted to ESR1 mutant patients, where there was improvement in progression-free survival. But it did not have a control arm for fulvestrant/abema. So we don’t really understand what incremental benefit there is from utilizing imlunestrant in place of fulvestrant, and I think that is one of the challenges with interpreting this. That being said, they found benefits across all the subsets, whether you had a prior CDK or not, whether you had a PI3K mutation or not. And so it did seem to be very robust. I will say, from a physician perspective, it’d be wonderful to be able to give patients 2 oral drugs and not have to use fulvestrant/CDK in a post-CDK population. So this would be very nice. I guess I’ll be curious to see what the regulatory agency does with this because of the lack of contribution of components that was addressed in the design. And then also they may want to wait on overall survival trends, because the trend to OS at the time they presented this, the hazard ratio was a little over 1. I think it was just pure immaturity of the data. But they may want to wait for maturity, and then we’ll have to see how they address the contribution issue. DR LOVE: So Ian, anything you want to add to that? And also, I saw actually the postMONARCH paper was actually published, whether you use that strategy. Do you use abema in patients who had a prior CDK with either palbo or ribo? DR KROP: Yeah. I think the data are very clear. And this is essentially the 3rd positive trial of a CDK4/6 inhibitor after progression on a prior CDK4/6 inhibitor, and most of those studies are positive. So I think it gives another option for those patients who have still evidence of endocrine-sensitive disease. We’re always looking to try to maximize our endocrine therapy lines of treatment for the patients who can benefit. So I think, as Sara said, the hard part in this particular trial is just understanding the role of imlunestrant in that combination. But I think having a combination of oral SERD plus a targeted therapy is something that we all were kind of hoping for, because the duration of benefit for SERD alone has been relatively short in most cases. So having the ability to combine with the targeted therapy provides, I think, a very attractive option. It’s just the way this particular study was done is just it makes it a little bit more complicated. DR LOVE: So Sara, we’re also going to see a Phase III trial of Dr Erika Hamilton on PROTAC degrader. I mean this one needs a nickname. I’ll call it vepdegestrant. But I had the pleasure of spending a couple hours with Dr Hamilton a few months ago trying to figure out what this does. Can you explain your vision of how these agents work, and what you think we’re going to see in this Phase III study? DR TOLANEY: Yeah. So, I mean, I will say that I call it vepdeg for short to make my life easier. This was ARV-471. So this is an oral PROTAC that really, in essence, chews up the estrogen receptor. And I think we’ve been excited about this agent because it, 1, is very well tolerated and has had robust activity at least in the Phase I setting. There were a couple of patients even who had progressed on an experimental oral SERD, and then went on to vepdeg and had a response. And so it just seemed like maybe there’s something different, because mechanistically this is different than a typical oral SERD. But we do know from the press release that this particular trial compared vepdeg to fulvestrant head to head. It had a hierarchical design to test benefit in the ESR1 mutations and then the ITT, but we do know it only met the endpoint in the ESR1 mutant population. So we did not see a benefit in the ITT, which I think we were all kind of hoping to have a SERD that also worked outside of just the mutation patients, but it is more consistent with what we’ve seen with all the other SERDs, where it’s only working in those patients with mutations. So at least we know it works there, but again, not having that broader activity. DR LOVE: So we’re all going to see some more data for the INAVO120 trial, with inavolisib as a part of first-line therapy, PIK3 mutated. Now we’re going to see survival data. If you check out the slide deck, there are a whole bunch of survey slides that we also presented and first showed, for example, that this triplet now, quickly, became standard of care with investigators. We’ll see some data also with inavolisib, specifically looking at the issue of hyperglycemia. Just kind of curious, Ian, what your experience has been so far with inavolisib in terms of tolerability, hyperglycemia, rash, et cetera, particularly compared to alpelisib and capivasertib. DR KROP: Yeah. So I’m actually participating in this trial, and I think it has modest — this is a kind of more traditional PI3 kinase inhibitor before we started having the allele-specific inhibitors and the AKT inhibitors. So this is, as has — when the data will be shown, I think it’s reassuring in these patients who have higher risk for developing hyperglycemia because they’re obese or pre-diabetic. But I think we’ve all learned how to manage the hyperglycemia with these drugs. DR LOVE: So Sara. I’ve got to squeeze in one quick case from one of our favorite docs, Dr Karen Green. Here it is. I’m just going to read what she says. “A 48-year-old woman with a BRCA1 mutation, Stage IIIc, triple-positive breast cancer with residual disease in lymph nodes after neoadjuvant TCHP. Now getting T-DM1 plus tucatinib versus PBO on the Compass ESCALADE trial, and ovarian suppression and an AI. Very high-risk disease. Would you also try to use a PARP inhibitor even though HER2-positive or CDK4/6?” DR TOLANEY: That’s an interesting question. So it sounds like very high-risk HER2-positive, ER-positive patient with residual disease that has a BRCA mutation. They’re on the Compass HER2 residual disease trial, which actually just completed accrual, which looked at adding tucatinib to T-DM1. So we don’t know which arm she’s getting, whether she’s getting that TKI being added to the T-DM1 or not. Here the standard would be to utilize endocrine therapy in addition to T-DM1. So you could try to maximize endocrine therapy, as was mentioned, like ovarian suppression and AI, for example, if she’s premenopausal. But we don’t have data for utilization of PARP inhibition in the HER2 positive patients. It’s a rare subset, and so we don’t have substantial data here. So I have not utilized PARP in the HER2-positive setting. If you knew, for example, that she just got T-DM1 alone, could you imagine adding on neratinib post-completion of T-DM1? That might be an additional strategy. The use of CDK4/6 inhibition is an interesting question as well. In fact, we had tried to address this question. There was a trial that had, a Phase III study called eMonarcHER, that was taking these patients who had residual HER2-positive, ER-positive disease, and after they completed their year of HER2-directed therapy, would get randomized to 2 years of abemaciclib or not. But that trial, unfortunately, was just really not feasible to do. And I think the landscape is changing, because soon we will see DESTINY-Breast05, looking at T-DXd in this residual disease population. So I think our strategies are going to evolve. But for now I would say endocrine therapy, OS/AI, is probably what I would do in addition to the trial that she’s on. DR LOVE: So Sara and Ian, thank you so much for chatting with us today. We all learned so much, so much to look forward to at the ASCO meeting. Audience, thank you for attending. Be safe, stay well, and have a great night. Thanks so much, Sara. Thanks, Ian. DR TOLANEY: Thank you. DR KROP: Thank you. |