Introduction: Long-Term Outcomes with Antibody-Drug Conjugates

DR LOVE: Good afternoon, everyone. I'm Neil Love from Research To Practice, and welcome to Year in Review, as today we talk about the use of antibody-drug conjugates in breast cancer. We have a great faculty today, Dr Hope Rugo from the City of Hope Comprehensive Cancer Center in Duarte, California, and Dr Sara Tolaney from the Dana-Farber Cancer Institute in Boston.

Today we're going to talk about what happened over the past year, including even a lot in the last few months, as always with ESMO and San Antonio, in terms of ADCs. And with all of our Year in Review programs, I meet with the faculty separately. I met with both of our faculty here in the last week, who recorded presentations reviewing the data that we're going to refer to tonight. Also, just to keep in mind, we will be talking about non-FDA-approved agents and regimens tonight. So check out the package information for more.

So here are the 2 talks. They're in the chat room. If you want to click after this and watch them. Of course, we'll send this out, this program out also with these 2 programs. We envision this really as a 3-part endeavor, so hopefully to review the data. And today we're going to talk about clinical application and where things are heading in the future.

Here's just a list of the papers that both our faculty reviewed very carefully and thoughtfully. We're, again, not going to go through every single paper, but just these are the papers for your interest. And again, we hope you'll go back and check out the presentation for more detail.

But we're going to spend most of tonight picking the faculty's brain with hopefully your help in terms of clinical application of these data and also trying to get a view of where things are heading. Hope covered HER2-positive disease in terms of ADCs. We're going to start out with that. And then we'll move over to HER2-negative disease, triple-negative and ER-positive metastatic disease. Again, all in terms of ADCs and particularly related to recent papers.

But just before we get started, I just want to take a deep breath and just chat a little bit about some more global issues related to breast cancer in general I'm just kind of curious about. And that is, I'm curious what you say to patients when you see them who have just been diagnosed with metastatic disease, whether or not it's de novo metastatic disease, and I'm curious whether you're seeing more de novo metastatic disease with subtypes or recurrent disease. I know a very common question that people have is, is there a chance that I can be cured?

And we're seeing, I mentioned the GU ASCO meeting, there, you know, you talk about saci/IO or dato/IO papers that we're going to talk about today. There they have the same concept. Enfortumab vedotin, an ADC plus pembrolizumab. The word they use all the time is gamechanger. And also you may find interesting that next week at ASCO GU, after having seen neoadjuvant EV pembro in one subset, very positive, it started out in metastatic disease, next week we're going to see it in the other subset. EV pembro, just like in HER2-positive disease, is now really standard therapy, either in the neoadjuvant/adjuvant setting. It's moved up for metastatic disease. We're going to talk today how T-DXd is doing the same thing and maybe also some of the TROP2 ADCs.

But I'm curious what you say right now, Hope, with everything changing, all these new papers, lots of exciting, encouraging data. Again, thinking about the 3 major subsets, ER-positive, triple-negative, HER2-positive, de novo versus non-de novo. In the past, survival without disease progression of 5 years was more anecdotal than you could come up with a number for. What do you say to your patients nowadays, Hope?

DR RUGO: This is a great question and I think I do use the sentence, the proof is in the pudding, a lot, which is that I think that we, as you pointed out, we used to say, okay, the median survival is this, when people really wanted to know that, although I think mostly we sort of couch it in softer terms, because I think having those specific times never really made sense. But now I think we know that survival is based on a number of different factors.

Obviously, the subtype of breast cancer you have, we know that, and the treatment options for you. But it's also based on how well you respond to your first-line treatment to some degree. With some exceptions, most people will live longer if they have a longer response to their first-line treatment. We also find that biomarkers can help us with that. So if we're doing next-generation sequencing, we know that overall survival has been shorter associated with some clonal mutations. For breast cancer, PIK3CA has been associated with shorter survival. But I do tell patients that even if they know they have these adverse factors, that we now have targeted agents that may change that.

One of the interesting things that I never discuss, and I'm interested if others do, if Sara does, is I don't talk about MYC amplification, p53 loss. We know these are poor prognostic factors, but we can't target them. So I don't actually discuss them with the patients because it seems as though it's too hard to know what to do with that data.

DR LOVE: So I'm curious, Sara, again, whether particularly HER2-positive disease now with its exciting data on T-DXd, but also, again, in the other 2 subsets, do you think we are or maybe will see a significant tail on the curve, even if it's only 15 or 20%, or maybe we really don't have enough data to think that that's maybe going to happen?

DR TOLANEY: Well, I think we've already definitely seen that in HER2-positive disease to date. Even if you look at the CLEOPATRA data you can see that tail on the curve and you can see that there are people out, with their 8-year follow-up that were free of progression. And so we do wonder if there is that small subset, 10-ish percent of patients who may be cured of their cancer. And I think it's something we're still trying to understand. I think that rate is probably, I hope, going to improve as we see longer follow-up from use of T-DXd in the metastatic HER2-positive setting.

But I think, as Hope said, we're not good yet at predicting this. There's been a lot of work that's been done. Actually, there was work presented even at San Antonio trying to understand who are these people who seem to be what we consider exceptional responders, so have very prolonged disease control out many, many years, 8, 10, 12 years. And we have some information, being HER2/3+, being de novo, not having a PI3K mutation. All of those things are good predictors. And so I think there are those small number of patients where we are seeing really good outcomes.

And even as you pointed out in triple-negative disease, I think since we've seen immunotherapy move into this setting, there are a few patients we all have who seem to have had extraordinary outcomes. I think, unfortunately, that is not the norm. It is a really rare situation. But it is nice to see that there are still some. And I think to your other question about the proportion of de novo patients, I think we are doing better at curing more early-stage patients. And so when you look at the proportion of patients in the first-line setting who present with de novo disease, that is rising since we are seeing fewer recurrences, particularly in the HER2-positive setting, where we are seeing in the US at least a proportion of de novo patients really has skyrocketed, because, again, so many patients, thankfully, are cured of early-stage disease.

HER2-Positive Breast Cancer

DR LOVE: Yeah, actually, one of the reasons I thought about bringing up this topic to you is what we're about to talk about now, which is HER2-positive disease, and Hope reviewed the data on first-line therapy, particularly DB09. But just to follow-up on what we were just talking about, I think more than half, 52%, of the patients in DB09 were de novo and you were saying you actually had to cap it. It could have been higher. So it's great that we're, I guess, seeing that, because everybody else or a lot of the other patients with localized disease have a better prognosis.

But let's talk about one of the biggest stories in all of oncology this year, Hope, was DB09 and all the questions that it sparked after it was first presented, particularly in terms of the major question, I think, which is are you going to use it indefinitely or go into maintenance therapy? Can you talk a little bit, you go through all the data and I think people have seen it presented a lot and you summarize it very well here. But can you just summarize a little bit about how you're thinking through what would be the optimal approach to therapy now, not only including ADC of T-DXd but also tucatinib with the San Antonio presentation there in the maintenance setting? So, Hope, can you summarize your thoughts about where we are today in first-line therapy based on these data?

DR RUGO: I think if you start with the premise that T-DXd has been better than all of the treatments it's been tested against in the metastatic, first, second, third-line neoadjuvant and postneoadjuvant settings so far, every single trial has shown better efficacy. So we do think, you know we like to put our best foot forward. So it is a nice idea to think about, particularly in patients who have more aggressive disease when they present with metastatic disease, to start with T-DXd. And then there's the added benefit of potentially, which we don't know yet, preventing brain metastases, which is a really devastating occurrence in a patient with a great response. So that's great.

Does everybody need T-DXd in the first-line setting with pertuzumab? You do have the risk of interstitial lung disease and more nausea. So we don't know that. And I think, you know we have approval, but I think we have to individualize just like all treatments. But I will say you don't have cumulative neuropathy, which is really difficult for patients, and you have less hair loss, less issues with liver enzymes and platelets. So there is that.

But you think about treating our patients. I mean, I have patients who've been on trastuzumab and pertuzumab for 10 years, and certainly for 5 or 6 years is the norm. Even if patients are going to have progressive disease eventually, they stay on for a while. It's a huge quality of life issue. To be tied to T-DXd and pertuzumab until you have progressive disease, or for some patients, many, many more years than you know 5 years or more, that seems really difficult. Because a lot of, 80%, 75% of people will have nausea with each infusion.

So it's really appealing to think about using the same approach that we do with THP, the CLEOPATRA regimen, where you stop after best response. We just don't know how many cycles it is. And then you give palbociclib to patients who have hormone receptor-positive disease with hormone therapy and HP, or tucatinib to patients with ER-negative disease, because it did look as though tucatinib was most effective in those ER-negative patients, although it crossed both.

So that's the paradigm we've come up with. I think there are obviously going to be variations. A patient who had brain mets when they start, maybe you would still use tucatinib with endocrine therapy rather than palbo, although some data with the PATINA trial, where they didn't do regular MRIs for the brain, suggested you did have less progression in brain. It's flawed data but quite interesting. So I think right now that's what we can do in the US but they can't do it in the rest of the world. So we absolutely need a trial that will look at this maintenance approach in the current treatment paradigm, T-DXd P, and then these better maintenance strategies in all patients so we can really see the best outcome.

DR LOVE: Yeah, and I guess we should say we are still waiting for the T-DXd without the pertuzumab data. Hopefully we'll see that at some point. Sara, who are the people you're giving T-DXd to or you would like to give T-DXd to or maybe I should say who do you not want to give it to? And also, any thoughts about this algorithm Hope put up? It's interesting to me. I don't know if I've seen it before. Palbo hormonal therapy for triple-positive, tucatinib if it's ER-negative. And Hope also expressed to me concern that maybe endocrine therapy in general is underutilized. We saw the PATINA data a little over a year ago. I thought that would get everybody using it. Any thoughts about whether endocrine therapy is being utilized optimally, Sara? And again, who do you give T-DXd to right now or T-DXd pertuzumab?

DR TOLANEY: Yeah, so maybe starting off with who do we give T-DXd to up-front? I think I'm a little bit biased, but I think if you look at the DB09 data and you even look at the initial 6 months of therapy, you see that twice as many people progress on THP within the first 6 months as they do on T-DXd P. So it does suggest that even as an induction strategy, that you're going to have less progressors if you used T-DXd up-front. And so I do think it is a better regimen than using a taxane up-front. And so I tend to prefer using T-DXd and pertuzumab in the majority of patients who are presenting with metastatic HER2-positive disease.

I think the challenge that Hope brought up is the really important one, though, is that we've seen median PFS be over 40 months. And to be honest, that may not be the real median. It was presented from an interim analysis. And so we don't even know what the true median is, but in general, it's probably going to be 4 years or so. And that's just a long time to leave someone on chemo. And so while I may start off with T-DXd P, I think in truth, if we get someone to maximal response, at some point I think switching over to a maintenance strategy would make sense.

And then I very much like Hope's algorithm of thinking through how to think about maintenance strategies. So for those ER-positive patients, I like using endocrine therapy, HP/palbo. And for the ER-negatives, using tucatinib/HP for maintenance, I think would be really reasonable. Obviously, this would be totally data free to be doing this post T-DXd. We don't have good data for doing that, but I think not unreasonable to do.

And then to your point about endocrine therapy utilization, I very much agree that, unfortunately, I do think it is being underutilized. We saw even in the HER2CLIMB-05 study that of the ER-positive patients, only 45% got endocrine treatment, so less than half. And that's a problem because we do know that it adds significant benefit. So I think we all need to remember for our ER-positive patients to use endocrine treatment.

DR LOVE: Yeah, in that box over there to the right where you see the PATINA data, 44 months PFS is really impressive. So I want to, of course, Hope in her talk, goes through some of the trials, the DEMETHER study, looking at that strategy of short-term T-DXd followed by pertuzumab/trastuzumab and then hormonal therapy and whatever. But also, the study on the right, looking at giredestrant and inavolisib, that says a lot. So hopefully there will be a lot more data coming out, a lot more sensitivity about this important issue.

I also wanted to mention another thing that Hope talked about that I had not heard before, and I thought was pretty practical and important. So we've seen the DESTINY-Breast12 study looking at T-DXd in brain mets. I always use that when we talk outside of breast cancer, when they get into does T-DXd work in the brain? But one of the things that Hope brought up, of course, you can comment on the efficacy there, Hope, and also a question I hear from oncologists, which is, can you hold off on radiation therapy and try T-DXd? What about if they're eligible for SRS versus whole brain?

But the other thing that you brought up, and so if you could comment a little bit on that, would you ever start medical therapy and hold off on radiation, Hope? But the other thing you brought up that I thought was really interesting was that there was a pretty significant, and correct me if I'm wrong, pretty significant incidence of ILD, yeah, 15%. But I was surprised by your thoughts about why this was, and your take was this was related to the steroids being given for the brain mets. So can you talk — and PCP. Can you get into that?

DR RUGO: Yeah, absolutely. So first is it's an interesting question. Do you wait to do the radiation? I think that based on the data we have from both DESTINY-Breast12 and the original HER2CLIMB study, it does appear that you could wait in patients who have asymptomatic, sort of low-volume disease. But I find generally my patients would prefer to treat, actually, and do the treatment too. They find it very anxiety-provoking to study these, wait and follow these lesions. And I just dealt with that with one patient.

But there's just — sometimes when you get a response, the tumors get a little bigger, or they have a little edema or necrosis, and it's just there's a lot of anxiety, and you have to have everybody look at the scans. So I think individually, certain patients, you could avoid that. And the other place where I thought it was really helpful maybe to avoid additional SRS even, and I certainly would avoid whole brain. I mean, that's one situation where I think patients would be on board with.

But these patients who've had a lot of prior radiation, I don't think we're going to be seeing them so much anymore as we move these drugs earlier. But there you actually do get cumulative CNS effects when you keep radiating. You get more radiation necrosis, et cetera. And so I think that — and potentially even cognitive effects. There I think treating first and holding off on further radiation might be a reasonable approach. So I think you just have to individualize for these patients. And I for sure, if you could do, if you had multiple tiny lesions and you could treat and push off the whole brain, I would do that.

For the risk of infection, I mean, having had a transplant background for 9 years before I moved into breast cancer, I'm big on prophylaxis against PJP. And so I give — and now it's so fortunate that we don't have to give dapsone and create all sorts of problems. We can give atovaquone. So I either use sulfa drugs if they're not sulfa allergic or atovaquone if they are. And 20 mg — and because our patients are also somewhat immunosuppressed from their treatment, I use 20 mg for 2 weeks, so a slightly tighter restriction for giving prophylaxis. In DESTINY-Breast12, they saw a rate of almost 16% and the highest mortality reported over 2%. But a lot of those patients had opportunistic infections.

So I think it is really the situation where they were getting steroids for whatever reason and they didn't have prophylaxis. This has been suggested. I haven't seen a detailed analysis, but it's just a lesson to all of us to remember to give these drugs, which are very well tolerated and completely prevent the infections.

DR LOVE: Sara, any thoughts about this? I mean, do you think that we're calling some people ILD from T-DXd that actually is infectious?

DR TOLANEY: I think it definitely is occurring. I mean, I think it's hard to tell the difference to be honest. Even people in the winter come in with a cold, the flu, COVID, right? All sorts of things happen. And we see ground glass on your CT. And how do you know what it's from, right? So we try to discern by symptoms and figure out, well, does it seem like it's viral? Was it not? We try to test viral serologies. But it's tough with colds that we can't all test for. And so I think we definitely have to make a judgment call about whether it's truly drug-induced ILD versus infection. With the PJP issue, obviously that's a much more serious situation. And, again, there have been deaths due to PJP. And so really, I think, as Hope noted, important that people are prophylaxed when they are on prolonged steroid use.

DR LOVE: So we're going to get into localized disease, and particularly the 2 big presentations on neoadjuvant T-DXd alone and also with THP. The alone arm was closed. And, again, Hope reviewed this as well as the post-neoadjuvant trial. So I won't go through the data, but more interested in how you're translating this into practice. So, again, I'm going to start out with you, Hope. Can you talk a little bit about how right now, again, putting regulatory issues aside and potential entry into trials like I-SPY, et cetera, how you're thinking through neoadjuvant therapy? Are you? Would you like to be able to use T-DXd neoadjuvantly? Would you like to be able to use it postop after neoadjuvant therapy with residual disease or even path CR? If you have the rare situation of a patient who goes to surgery first, would you use it there? When you go through these 2 studies, Hope, what do you come up with in terms of the way you want to take care of your patients?

DR RUGO: Well, I would say, we have this great data, and it will be incorporated into the clinical setting eventually for most people in most places depending on access to drug. And it's already being used in early-stage disease in the US. But it is a further really strong argument not to take patients who have tumors that are of reasonable size to surgery first because there is no data on adjuvant T-DXd in patients who go to surgery first. So we really don't want to do that. We want to be very careful to know that patients have HER2-positive disease. With that said, both DB11 and DB05 enrolled patients who had very high-risk disease, inoperable at diagnosis or node-positive at surgery for DB05, and then high-risk including inflammatory disease in DB11. So I think that we like T-DXd to give it if you can manage the ILD. And the ILD rate with DB11 was the lowest that's ever been reported, less than 5%.

So how do you put all this together? Because then we know that 8 cycles of T-DXd wasn't better. I think that what I have thought about, and Sara and I have talked about this a lot too, is it would have been nice if we could have started with THP and then said, do you really need T-DXd out back? But the downside of that is then you still get neuropathy and hair loss. So do you really want to do that? If you give docetaxel, you can have epiphora also and permanent hair loss. So I think that what we might do is use the DB11 approach for patients who have a lot of cancer.

And then for residual disease, the question is do you give DB05 or do you give T-DM1? And I guess I would probably lean towards giving T-DXd postop because if they were already responding, I think you're going to have to know if patients had response or not to T-DXd because some patients are not going to respond. And if they never responded to T-DXd, we're not going to give it postop. So I think that's really where we're going to have to individualize and use a more nuanced approach to treatment. And if somebody could, like maybe they fit into CompassHER2. They could just get THP for 12 weeks and then go to surgery, then that would be a situation where we'd use DB05 for rescue.

DR LOVE: So, Sara, anything you want to add to that? And, of course, you can imagine our chat room is already asking about cell-free DNA in this situation.

DR TOLANEY: Yeah. So I very much agree with Hope. I will say that I think in someone who has very high-risk disease, so large tumor, node positive, I think we would prefer using preop T-DXd. So using a DB11 strategy. Because, again, we can get away with just 4 doses of T-DXd in the preop setting whereas if you're holding out on it for the adjuvant setting and the residual disease setting, that's 14 cycles associated with much higher risk of ILD, much more toxicity. So I like the preop approach. I think the challenge that we're facing is that it's not just anatomic risk that drives treatment benefit, right? It is biology.

And so if we knew who was so HER2-driven they would just get away with 12 weeks of THP alone, that would be pretty cool because then we could spare them more prolonged treatment in T-DXd. And so I think to your cell-free DNA question, I think it — could it be incorporated into this preoperative setting to help us tailor duration of treatment? And we're not there yet. I think this is where we need trials to help us, but maybe that could help us figure out who could get away with THP up-front and who may need to progress on to get T-DXd.

DR LOVE: Yeah, we were actually talking about the I-SPY data in a program we just put out on cell-free DNA in terms of using it there. But let's not get into that because, Hope, I've got what we call an elevator case here. So you get in the elevator on the 11th floor, it's going down, and Venu is standing next to you and said, oh, Dr Rugo, I've got a 60-year-old woman, metastatic hormone receptor-positive, HER2-positive breast cancer, progressed on THP followed by HP for a year. Has now been on T-DXd for 3 and a half years, complete response, currently on 1 dose reduction because of fatigue, ctDNA negative. I'm curious what your thoughts are about that. And she wants to know, can I escalate to HP and palbo and endocrine therapy?

DR RUGO: It's a great question, and I think it's fabulous that she's had such a nice response to T-DXd first. The ctDNA is a complicated question because we know that if you have rising ctDNA, it correlates with a shorter PFS, and these people will progress. But we have no idea if changing treatment earlier based on rising ctDNA makes a difference in outcome. So that's a big issue. Being ctDNA negative is good. This is a good thing. But when you stop the T-DXD is it suddenly going to become positive? So you're good now, but what does that mean for the future? We just don't know what it means about the question that he or she is bringing up, right? So what I would do in this patient, 3 years NED, ctDNA negative, I would consider this. The patient, as far as I can tell, didn't have endocrine therapy. I don't know. Was the HP in the maintenance after the THP? But maybe they —

DR LOVE: I don't see it.

DR RUGO: They might have had an AI and not fulvestrant. And I had a patient who was on all of those therapies before we had CDK4/6 inhibitors and before T-DXd or HER2CLIMB and she stayed on abemaciclib and fulvestrant, even after receiving fulvestrant before, along with H, for 4 years. So, I think longer than T-DM1. I think the endocrine therapy can really help a lot. So I would go with the approach of the endocrine therapy, which she hasn't gotten, and palbo and H. I don't know if you need P, but if you could get HP, that's fine. And see how she does. Because it will give her a chemotherapy holiday, which I think will be helpful.

DR LOVE: Alright, a couple more things that Hope got into and I'm curious, Sara, what your thoughts are. First, this study, the ERICA trial, looking at olanzapine with T-DXd. And you know it's amazing, when I talk to breast cancer investigators about acute GI side effects, they always bring up olanzapine, like in the first sentence. But once I get out to the lung cancer people, the GI people, GYN, they never bring it up. They're still figuring things out. And I think the general — I'm not sure about the general oncologists as well. But, Sara, can you comment a little bit about this trial, what they saw, but even more, what you've observed in terms of acute GI toxicity and the role of olanzapine?

DR TOLANEY: I think one of the challenges we face with T-DXd is that there can be acute nausea that can happen within those first 3 to 5 days but there can also be delayed nausea. And so up-front for our patients with T-DXd, we generally do recommend 3-drug prophylaxis. So patients are getting a steroid as well as a 5-HT3 and a K1 to prevent nausea. But if they do get nausea on top of that in those first 3 to 5 days, I have found that olanzapine is particularly helpful. Or in the delayed nausea setting, I also find that olanzapine works really well.

And so I think one really important lesson is this trial certainly looked at giving 5 mg during those first 5-day period. I will say personally I tend to use 2.5 mg. I just find it's a lot better tolerated. People do get kind of sedated with olanzapine. I do have them just do it at bedtime. But I find that that's usually sufficient. And so that's generally what we recommend is give up-front 3-drug prophylaxis, add on olanzapine at 2.5 at bedtime if needed in those first few days and then use it as well for delayed nausea if needed.

DR LOVE: So the other paper that Hope talked about, and actually I see in the chat room Rosanna is asking about, again, a patient with urothelial bladder cancer who got ground glass opacities after 21 days of T-DXd. And we actually have had cases — I had a case the other day, Grade 2 ILD with bladder cancer. Again, outside of breast, I don't know if people are sensitized to the Grade 1 is okay to rechallenge, Grade 2 not. But Hope, can you talk about these data looking at rechallenge with T-DXd showing that with Grade 1 it's feasible and maybe not with Grade 2?

DR RUGO: Yeah, I think it's really important. We actually published a pooled analysis of T-DXd trials earlier this year, end of last year. And I think that data showed very similar to this real-world data, which I think is important when you're treating patients in the community and you're not using all of the fancy trial approaches and the CTs and adjudicated ILD. And we saw almost the same results. So patients who had asymptomatic ground glass opacities were retreated and they stayed on, some of them, for almost a year with additional benefit in terms of their disease. We had some people who had both, in both studies recurrent Grade 1 ILD and were retreated and dose reduced and did fine. And then we had a rare Grade 2, which patients stopped. For the retreatment with Grade 2, that's not in our guidelines and we don't recommend it. I think the situation — because mortality is such an elusive issue with T-DXd-related ILD, we don't understand who the patients are who get very bad ILD. And one patient who was on DB04 had Grade 3 ILD and eventually died in the second year. So she was an added on mortality.

So we know that if you have higher grade, your risks are significantly higher. So you have to be careful. If you had, as Sara mentioned earlier, Grade 2 ILD on your scan, but you just had COVID or you just had flu, you have asthma, you have to be able to say, this is not related. When we're going to be giving radiation with T-DXd and DB05 type treatment, this is radiation pneumonitis because it's really localized and then you can retreat. But in a situation where somebody has ILD from T-DXd, we should not retreat if they have symptoms.

HER2-Negative Breast Cancer

DR LOVE: So we're going to move on now and talk about triple-negative and ER-positive metastatic disease. And I think it's going to take the rest of the conference just to get the clinical bottom line. And I don't even want to go through all the data. I want to just get to what it means because I think it's going to take that long to just even begin to sort it out. This is like ADC fall or autumn or something. We had like just a huge, incredible amount of new data to check out, particularly — so starting out with triple-negative disease. So, Sara, can you just trace basically what's happened now in the last 6 or 8 months since ASCO in terms of first-line therapy, both in the patients eligible for IO and not?

DR TOLANEY: Yeah, so you're right. I think a lot has happened over this last year with the idea being that there's been a lot of interest in trying to move ADCs out from the pre-treated metastatic triple-negative setting into the first-line setting. And so what we've now seen is that for patients who have PD-L1 positive metastatic triple-negative disease and are candidates for immunotherapy, that the combination of sacituzumab and pembrolizumab did better than chemotherapy and pembrolizumab with improved progression-free survival with a hazard ratio of about 0.65 in the ASCENT-04 study. So that, in essence, is shifting the sacituzumab/pembrolizumab combination to be, I think, hopefully we'll see FDA approval soon, but nowadays, at least in the NCCN guidelines, and so can be a choice for up-front treatment.

For the PD-L1 negative patients or those patients who are not candidates for immunotherapy, we now have 2 different trials that have been presented. One looking at sacituzumab/govitecan compared to chemo of physician's choice in ASCENT-03 showing that it was superior in terms of progression-free survival. And then another study, TROPION-Breast02, looking at datopotamab deruxtecan, or Dato-DXd, and comparing it to treatment of physician's choice chemotherapy, also showing improvement in progression-free survival. That study also met overall survival benefit.

And so there are some nuances that I'm sure we'll get into in terms of differences between those trial designs and outcomes, but generally, I think, support using either TROP2 ADC for patients who are not candidates for immunotherapy up-front.

DR LOVE: So to try to move a little bit deeper in terms of how you think this through clinically, where we have to make decisions, Hope, I'll show you a couple slides that Sara discussed in more detail comparing the data with sacituzumab and dato. And again, not patients who do not have PD-1, not candidates for IO therapy. She has this pretty cool summary of how to think about both options, particularly in terms of tolerability. There's the issue about survival benefit, but again, the crossover. And the entire talmudic discussion is on Sara's presentation.

But the bottom line, first of all, I guess 1 question I asked her, but I'll ask you too, Hope. Do you think there's a difference in this scenario in terms of efficacy that you prefer 1 versus the other because you think it's more effective? Or is it more related to side effects? And also, this is a very cool thing that she put together too in terms of what might move you one way or the other in terms of prior comorbidities? People who have prior diarrhea, ophthalmic issues, et cetera. So, Hope, how do you view this issue in terms of selecting between the 2 first line triple-negative?

DR RUGO: Yeah, I mean, I like this table. I will say that there aren't patients who present with metastatic disease who have significant mucositis at baseline because they haven't gotten any treatment. But I think that some patients do get aphthous ulcers and have more stomatitis in their life. So they might not have it right then, but that might be one of your reasons. I think for your overarching question, which is do we really think that there are differences? We've been diving into this data in detail as clinicians, you know clinicians with experience giving these drugs, with experience in these patients. How do we really understand the differences?

And because of the crossover, I think survival is off the table. We just don't understand. I think one thing that we have all learned is that, and we knew this already, was that the way trials are done is they setup these restrictions for enrollment that sometimes are just created out of the air. Like, why does it have to be 6 months? Why isn't it right when people recurred? And I think we learned from this study that you should be able to allow patients to go on these better drugs who are relapsing while getting their adjuvant therapy. And I think we've all given SG in that setting and seen very nice results. And in TROPION-02, we saw great results with Dato-DXd in the 15% who relapsed in the first 6 months.

So I think that we have good data that we should be treating these patients who have early relapse similarly and that we should not use this as a differentiating factor in clinical trial enrollment. And it's something I think as investigators and as clinicians we all need to be really careful about in talking to our colleagues in pharma when they design these trials because it really comes back to bite us and I think it's unfair to patients. But I think we have to use the individualization. We have to talk to the patients. It's a day 1, day 8 versus day 1 every 3 weeks. It's the differential toxicity profile.

But one of the things that came up in our discussions was does it make a difference that there was a better overall response in the dato group? But if you put the responses together, and I don't know if that's in one of those comparative slides, you can see that they're just really different in the control arm. And so you can't do this cross-trial comparison because the duration of responses were identical in the 2 trials. I mean as close as you can be as identical. But the actual response rates are different. But there were 10% of patients in TB0, TB2 who had PD-L1 disease in less than 1% that may have contributed because those patients have a better response to therapy. And if your therapy is better, you have a better response. So we don't really know. I wouldn't use that as a reason. I would really use these issues here. But instead of significant mucositis at baseline, I would just say history of aphthous ulcers or difficulty with steroid mouthwash issues.

DR LOVE: So, I mean, there's also the consideration of the experience of mucositis, which hopefully can be prevented. But that leads into me asking you, Sara, if you could also, I mean, at this point people I think have had for sure lots of experience with sacituzumab, but increasing experience with dato. But still it hasn't really been out there that long. Can you just review in your own mind what you're thinking about in terms of potential toxicity, inconvenience, quality of life for each one of them? And if you're in a situation as really occurs a lot, I think, with triple-negative and ER-positive disease where you could go with either one, how you make that decision?

DR TOLANEY: Yeah. So I think one of the most basic differences is that these drugs do have a different schedule. So I think one advantage for Dato-DXd is you only have to come in once every 3 weeks for an IV infusion as opposed to sacituzumab where you come in 2 weeks in a row, so day 1, day 8, and then you get a week off. So I think that certainly can influence people. I think in terms of the side effect profiles, sacituzumab does have a high rate of neutropenia and about half of our patients end up needing growth factor support. And so that certainly can come up as an issue. The other thing is it can cause diarrhea. And most people can just use periodic loperamide and that works quite well.

With Dato-DXd, though, I think there are a couple unusual toxicities that we're not quite as accustomed to. And one is ocular toxicity. So we can see dry eyes and potential risk of keratitis. And so the drug does require getting a baseline eye exam and does require using rewetting drops 4 times a day to prevent the ocular surface toxicity. It also has this risk of mucositis. And so it does require using a steroid mouthwash 4 times a day to prevent the mouth sores from arising. It works really well to use, but certainly is something people have to be aware of. Both of these drugs can cause some nausea.

With Dato-DXd, I tend to use 3-drug prophylaxis, which I think works really well. With sacituzumab, I usually can get away with 2-drug prophylaxis and that works well, but something for both of them. So, I think, again, with Dato-DXd, it's just the eye issue and the mucositis that are a little bit different. But it doesn't cause the neutropenia like sacituzumab does, so people don't really end up needing growth factor support or anything like that. So different profiles.

DR RUGO: I will say that in I-SPY, even with 4 doses of dato and durva, we still saw some Grade 3 stomatitis, even with the steroid mouthwash 4 times a day. So, it is something — I think the other thing, just we didn't talk about, Neil, was that you could switch. If you had a toxicity from one you didn't like, you could switch to the other, which I think is, in some ways, a nice option for patients because we run into this all the time.

DR LOVE: Yeah, that's a really great point. A couple other things. So let's get into the issue of IO plus ADC. I was talking about this really phenomenal combination of enfortumab plus pembro, but here we also see this same strategy being used. Sara, can you just comment a little bit about the theory here about why there's synergy? And I was surprised of the fact that there's some thought maybe it would work with PD-1 negative patients or tumors. But what's the theory behind it, Sara?

DR TOLANEY: I think there are a few theories. One is there's some thought that you get more immunogenic cell death, that you can enhance antibody-dependent cellular cytotoxicity, and that, you know we are doing a better job killing cancer cells, right? And so, you're probably going to get better antigen expression and that may allow for better synergy with the checkpoint inhibitors, so more T-cell infiltration that could occur. And so, I think we were excited about trying to combine ADCs with immunotherapy, not just in the traditional sense where immunotherapy works in the PD-L1 positive patients, but as you pointed out, also curious to see if it could even allow for immunotherapy to work in PD-L1 negative patients since we do think there may be this better synergistic activity.

DR LOVE: And Hope, again, Sara presented this, but can you just comment a little bit about what we know, again, about these 2 TROP2 agents with IO? We have mature data with sacituzumab, or reported data.

DR RUGO: Well, so, we have reported data with SG pembro versus TPC pembro. The one thing that the TB05 is looking at here is, we got DB, we got TB, but TB05 is that they're looking at ADC alone in this patient population, which I thought was really interesting because the ADC alone is tough given the fact that we've seen a survival benefit with chemotherapy and pembro compared to chemotherapy alone. I think the ASCENT-04 data is great. I think SG pembro compared to the standard chemo pembro was better. It will be interesting to see what the outcome looks like as we go farther. Again, I think this 6 months or — it doesn't make a whole lot of sense, 6 months or longer versus 0 to 6 months.

And I've seen some amazing responses in patients who went on SG pembro who had early relapse who were strongly, who had strongly PD-L1 positive disease. So we'll wait for TB05 here to see whether the monotherapy is just better than giving pembro in those patients. But overall, I think this has now already been adopted as a standard of care in the US and hopefully we'll hear more from this moving forward.

I think the interesting question that you just brought up was, would this combination work in patients who have PD-L1 negative disease? And I will say that regulatory, our regulatory colleagues are not sold on this yet. So, in the — for sacituzumab tirumotecan, or sac-TMT, the third TROP2 ADC that is in a bunch of Phase III trials, TroFuse-011 has 1 arm that is giving the combination of pembro with sac-TMT in PD-L1 negative disease. But the FDA made it a 2 to 1 to 2 randomization because they said, you already know it doesn't work. But actually, I don't think we know it doesn't work. I'm holding out a lot of hope there.

DR LOVE: So, Sara, again, going back to the ASCENT-04 study you presented at ASCO, I know the first question everybody started asking me was, what about people who have already had IO in the localized setting, KEYNOTE-522? I don't think there were that many patients in this study who'd had prior IO. For practical purposes, how are you making the decision about whether to bring back the IO for metastatic disease?

DR TOLANEY: That's, I think, a tough question that we don't know the answer to because, as you point out, in ASCENT-04, one, as Hope pointed out, we did require people be at least 6 months out from completion of systemic therapy. So if they did get IO, they had to be 6 months out from it or longer, and only 4% of patients in the trial had received prior immunotherapy in the early disease setting. So we just don't have sufficient data. But I think we all make up rules for what we do. So if I had a PD-L1 positive patient, I would want them at least 6 months out to think about re-exposure to immunotherapy. I just think it's really unlikely using immunotherapy in someone who just received it and recurred on it or just within a few months of it is likely adding any benefit. So I at least like a 6-month window.

DR LOVE: So I want to try to get on also to ER-positive, HER2-negative or low metastatic disease, but just to let you know that Sara does discuss in her talk these trials now looking at PD-L1 negative disease to see whether or not there could be a role for IOs in that setting. Let's talk about hormone receptor-positive disease, and, of course, we need to talk about HER2-low and T-DXd as well. Obviously, it's an option as well in triple-negative disease. We can even get back to that. But, Sara, can you summarize what we've learned in terms of both Dato-DXd and sacituzumab in the ER-positive, HER2-negative or HER2-low situation? And maybe start out with how you think through utilizing these agents in patients, first of all, who are candidates for T-DXd because they're HER2-low.

DR TOLANEY: Yeah, so we know T-DXd certainly has had tremendous benefit compared to chemo, both in HER2-low as well as ultra-low disease based on DESTINYBreast-04 and DESTINYBreast-06. And so now we have approvals for T-DXd where it can be used as your very first chemo agent in metastatic hormone receptor-positive disease if you're HER2-low or ultra-low.

But then it raises the question of where do these TROP2 ADCs fit in? Because we have data from TROPiCS-02, which looked at sacituzumab/govitecan compared to chemotherapy in patients who had had, in essence, 2 to 4 prior lines of chemotherapy in the metastatic setting. And that showed improvement in both PFS and OS. TROPION-Breast01 had a somewhat different population. These were patients who had received 1 to 2 prior lines of chemotherapy in the metastatic setting. And so a little bit less pretreated than TROPiCS-02, where they did show improvement in terms of progression-free survival but no overall survival benefit. But I think we have to be cautious because T-DXd was approved during the conduct of TB-01.

And so there were patients who crossed over to get ADCs subsequently post control arm progression. And so that wasn't the case in TROPiCS-02. And so I think not really fair to cross-trial compare. But certainly it does mean that either dato-DXD or sacituzumab would be a choice in the pretreated setting. We did see this data from ASCENT-07 that tried to move sacituzumab up from that pretreated setting into the first-line chemo setting. And Hope was involved in leading this trial, and so I'm sure will have comments on this. But it unfortunately did not show that sacituzumab was better than chemo.

In essence, the progression-free survival by blinded independent central review actually looked pretty much identical between the 2 arms. And so we couldn't say that it's better than chemotherapy. And so I think it remains a choice for patients who have pretreated disease.

So I think most of us are giving T-DXd to many patients if they're HER2-low or ultra-low as their first chemo. That being said, many of us also like to use capecitabine. And so we'll reserve T-DXd sometimes to be their second chemo agent and then think about a TROP2 ADC later line, although the benefits of sequencing ADCs is probably not as robust as someone who's ADC-naïve. But if someone's HER2 null, meaning they don't have any level of HER2 expression and are not candidates for T-DXd, then most of us are using the ADC, a TROP2 ADC as their second chemo agent.

DR LOVE: This is starting to remind me of the conversations we would have about relapsed myeloma before CAR-T and bispecifics came along. It was like so complicated. Also, just to point out, I thought pretty interesting here that the investigator assessment actually, Hope, did show a benefit, a hazard rate of 0.78. I don't know, I guess you have to go with the central if that was — you didn't see much difference there. But the people actually taking care of the patients thought it was better. Anyhow, anything you want to say about that, Hope, and why would you see a difference like that? But also, some of the clinical pearls about sequencing, which is obviously very complicated.

DR RUGO: Yeah, I mean, I think, one of the things that people may not be aware of is, why do you have BICR, blinded independent central review? If you don't have a blinded study, no placebo control, you have to use BICR because everybody knows. So you want a blinded panel. But if you have a placebo-controlled trial, you can have investigator assessment as your primary endpoint.

So in this trial, because it wasn't blinded and it couldn't be, we had to use BICR. And then when we went back to see why was it that the differences were reasonably big with investigator versus BICR, it was because we had patients who had new pleural effusions and new liver lesions where the BICR thought that it was unclear. But for clinicians who are treating patients who have HR-positive disease, endocrine resistant, this was, and of course, they're a little biased about TPC versus SG, that this is something that drives them to change therapy. So I think that that was quite interesting.

The sequencing question is a big one. If you show the, even the investigator PFS for SG in that setting, it looks very much like everything we've seen with TROP2 ADCs. We did see this suggestion of a survival benefit, and we'll follow that over time because maybe we change, I mean, this is far-reaching, but maybe we change the microenvironment and respond better to even subsequent therapy. So even if your PFS isn't better, your survival is.

Now, so what are we going to do? We're going to give T-DXd because the PFS was longer in the first-line setting and the HER2-low and ultra-low. And as Sara said, I totally agree with the idea of the TROP2 ADC in the second or greater line in patients who are HER2 0. And then we do see in clinical practice some patients whose best response to T-DXd is progression, more than what we saw in the trials in the real-world setting. So that's where we have to be flexible.

But I tend not to be thinking I should be giving deruxtecan after deruxtecan since the payload resistance seems to really drive this. There is a trial going on now that is looking at that specific sequence out of, in the TBCRC consortium and out of Dana-Farber. But I think, I like to maybe change even the chemo, even if it's making the same target, if I'm going to use sequence therapy. And as you're showing, the optiTROP sac-TMT showed similar benefit in hormone receptor-positive pretreated disease as we saw with the other TROP2 ADCs. But we don't have first-line data, of course, in that setting. It is fascinating to me that the PFS is the same across all of these trials with TROP2 ADCs. So they don't seem to have the same PFS as the T-DXd, at least in DB04 and DB06.

DR LOVE: So Sara, final comments, just a couple other things. Also we talked a little bit about sac-TMT, not available in the United States right now. We saw the efficacy, hard to indirectly compare. But we can, I think, indirectly look at tolerability issues. And I'm not clear if it's more like a dato profile or a sacituzumab profile. It looks in between. But I don't know, have you actually used sac-TMT? And what's your take on tolerability, Sara?

DR TOLANEY: Yeah, I would agree. I do think it is in between in the sense that we see a little bit less neutropenia than sacituzumab govitecan. And while sacituzumab doesn't usually cause much in the way of mucositis, sac-TMT does, but not quite as much as you get with Dato-DXd but I still would recommend using dexamethasone prophylaxis with sac-TMT. And so I think again you are getting a little bit of a mixture of the side effects, but not quite to the same level as either.

DR RUGO: It's important for people to know that it's a 20% lower dose in the US trials than in the Chinese trials.

DR LOVE: And again, Sara goes through her algorithm. But I just want to finish out with another case that I see here in the chat room. It sounds like a current case somebody actually, Raj, would like some feedback to hopefully be helpful. This is a 40-year-old patient, Hope, triple-positive, Stage II disease, neoadjuvant AC-THP, residual disease, T-DM1, also ovarian suppression with AI. So Raj has the message in terms of endocrine therapy. But the patient develops a large brain met. Neurologic defects, has surgery, SRS. The tumor in the brain is HER2-positive, but now ER-negative. So the doc wants to put her on T-DXd, wants to know what about hormonal therapy. This patient's flipped. I don't know if it's real or not. What do you do in this situation? If she were clearly ER-positive, Hope, would you integrate endocrine therapy or just T-DXd?

DR RUGO: Well, so we don't have data on giving T-DXd with endocrine therapy, so I think you're treating metastatic disease now. I think the question is about the treatment of the brain metastasis that's been resected and radiated. Do you give T-DXd or would you give, I mean, we'd really like it if we had some study looking at tucatinib and trastuzumab in those patients as a sort of maintenance approach.

But I have a patient like that, and she just kept progressing in brain. So we gave T-DXd, we gave tucatinib in the HER2CLIMB regimen, and you see this. But once the patient's NED, it's hard to know what the right treatment is to prevent recurrence if they have no disease anywhere. The fact that it's ER-negative is interesting and really driven by HER2, but I think if you were still treating systemically to prevent recurrence, we don't know the answer to that.

I think because the brain met is, if it was a big brain met, like he was saying, really a big issue for the patient with neurologic deficits, it's likely that that will be her primary issue throughout the course of her disease. So I probably wouldn't give her the continued toxicity of endocrine therapy if I was going to give T-DXd. I just might think about an all-oral regimen as her next step if she has no systemic disease anywhere.

DR LOVE: Alright, well, that was very helpful. Hopefully that will be helpful for the physician. One of the feedbacks we've gotten a lot over the years is people in practice like it a lot when they see you struggling to come up with an answer. They know they're not alone in not knowing that there is an actual correct answer that's going to be on the boards or whatever. It's good to know that even people who do this all the time sometimes are not sure exactly what to do. So thank you so much, Hope and Sara, for joining us. Audience, thank you for attending.

Be safe, stay well, and have a great night. Thanks so much, Hope. Thanks, Sara.

DR RUGO: Thank you.

DR TOLANEY: Thank you.

DR LOVE: Have a good one.