Development of brain metastases in patients with HER2-positive and HER2-negative breast cancer

DR LOVE: Welcome to “Oncology Today: Optimal Management of Brain Metastases in Patients with HER2-Positive Breast Cancer.” This is medical oncologist Dr Neil Love. For this program, I met with Dr Sarah Sammons from the Dana-Farber Cancer Institute in Boston.

Conflict of interest statements for the faculty can be found in the program notes. And the use of agents and treatments that are not approved may be discussed in this program, so please check out the package inserts for more information.

To begin, I asked for her thoughts on why HER2-positive breast cancer appears to have a propensity for the development of CNS metastases.

DR SAMMONS: I do think that there's something about the biology of truly HER2-driven tumors that leads to the development of brain metastases. I think some of the hints that I have that that's the case — it is true that none of the therapies that we have approved in early-stage breast cancer reduce the risk of isolated CNS events, so trastuzumab, pertuzumab, T-DM1. And the incidence is just higher across the board. Even in first line, it's higher. And so there's certainly still some propensity there that's related to the biology of HER2, I think, that leads to more brain mets.

DR LOVE: It's amazing how this has evolved in HER2-positive disease. But what do we know about ER-positive and triple-negative disease in terms of response to the brain, both to hormonal therapy, to chemotherapy, particularly ADCs? Now we have Dato in breast cancer, triple-negative obviously. We have IOs are involved in some patients so, plus ADCs, of course. So what do we know about CNS activity and management of brain mets in triple-negative and ER-positive, HER2-negative?

DR SAMMONS: Yeah. So we by far have the most data in HER2-positive disease. I'll start with hormone receptor positive, HER2-negative. In terms of the endocrine sensitive patients, so the patients that you would normally put on an AI and a CDK4/6 inhibitor. The best data that we have is from the ComplEEment study, which was the Phase IIIb ribociclib AI study. And they actually made an effort to include 50 patients who had stable brain mets at baseline and they had been radiated. But they had an excellent PFS, pretty much the same as the population of patients that did not have brain mets. And so it's a pretty rare scenario to have a endocrine sensitive, new hormone receptor positive patient with brain mets. But if you do, I think radiating them and then putting them on aromatase inhibitor, ribociclib or aromatase inhibitor, abemaciclib is fine.

Sara Tolaney and colleagues did, I believe it was called the JPBO study, which looked at abemaciclib with or without endocrine therapy in active CNS disease. And the intracranial response rate was not great. It was less than 10%. However, shrinkage to some degree of the brain mets was somewhere around 30%. So, I mean, I think that's the only active data that we have, prospectively, for CDK4/6 inhibitors in endocrine therapy. So, I mean, we know that abemaciclib has some activity. We know that in stable brain mets patients, the ribociclib AI patients can do fine. And so, if it's an ET-sensitive patient who's had their disease radiated, I'll either put them on endocrine therapy with a CDK4/6 inhibitor. We know from older studies that capecitabine has an intracranial response rate somewhere around 20%. So capecitabine is still an option. In terms of ADCs, I think we're learning more about the HER2-low population and T-DXd in HER2-low disease. They did a retrospective analysis of DESTINY-Breast 04 where they looked at the intracranial response rate. And I believe off the top of my head it was around 40% versus, or 30, no, it was 25% versus 0% with chemo alone. And so, the ADCs definitely work better in the brain than just run-of-the-mill chemo, especially if the patient is HER2-low. So for a HER2-low brain met patient, I think T-DXd is a reasonable option.

DR LOVE: So and also kind of I had jotted down blood-brain barrier to ask you about, sort of classic idea whether or not it actually exists. Or can you just look at a systemic therapy and see what the systemic response rate is? And is there any reason to say, hey, that should apply to the brain? Like, there really isn't — is there a blood-brain barrier in effect when you look at data? Do you see higher response rates systemically than in the brain?

DR SAMMONS: Yeah, I think about that a lot. The short answer is the responses are generally different. So I'll just give you examples. DESTINY-Breast 04, just in the retrospective series, the response rate in the brain was around 25% for the HER2-low population. The extracranial response rate of T-DXd is between 50 and 60%. And so definitely getting more extracranial activity in the HER2-low patients. You think about sacituzumab/govitecan, the extracranial response rate in triple-negative disease is around 30%. We have not seen good responses in the brain in our retrospective series of saci, kind of less than 10%. So I do think that there are differences. Is it a blood-brain barrier? Is it a blood-tumor barrier? Which sort of is a more new age approach because there's — the blood-brain barrier is actually thought to probably be disrupted with a brain metastasis and particularly once you've had radiation. And so, they more talk about this entity called the blood-tumor barrier. There's a lot of efflux pumps that actually actively try to pump these agents out of the brain. So, there's that. There's the ability to get in and then there's the ability to stay in. And so, it's definitely still a problem. With triple-negative disease, the elephant in the room is that we have no compound that has been shown to improve overall survival yet for triple-negative brain mets. Immunotherapy has not been shown to improve overall survival. Sacituzumab has not been shown to improve overall survival in brain mets patients, at least in the ASCENT trial. We haven't seen ASCENT-04 brain met data yet. And so that is really the most area of unmet need.

DR LOVE: I'm trying to remember whether your colleague, Sara Tolaney, when she presented DESTINY-B09, presented brain mets, T-DXd versus CLEOPATRA. Was that presented? Was there any difference?

DR SAMMONS: It was. I was just reviewing that data. So the brain mets population did really well in DB09. They actually did better than the non-brain mets population. The hazard ratio for the brain mets patients in DB09, I believe, was about 0.3 versus maybe 0.5 in the non-brain mets population. So, they did really well.

Local therapy approaches for the treatment of brain metastases

DR LOVE: Yeah, I was also, I mentioned, I kept thinking about other tumors, particularly when you put up your slide saying deferral of local therapy in HER2-positive brain mets. I thought the language was interesting because, of course, the first time I started hearing a lot about what I would call systemic treatment of brain mets was EGFR-mutant and other RET- and ALK-mutant non-small cell lung cancer. And there, they just sort of call it using systemic therapy and they don't mention deferral, but I think deferral is a really good thought. But it really gets into also this question of how much activity can you expect from a therapy? But in particular, and this is what I'm really curious about in thinking about how you present it with breast and how I've been hearing about it in lung, what are the situations where you would consider holding off on radiation therapy? And one I thought was interesting because your thing says no symptomatic mass effect. In lung, they say no CNS symptoms. And I never know exactly what that means. But realistically what kind of CNS or brain situation are you looking at, either clinically or radiologically, where you go, oh, no, they've got to get radiated?

DR SAMMONS: Well, any symptomatic disease radiation is recommended. Because —

DR LOVE: No, I mean, I've heard cases where they had a little numbness in one arm. Is that enough to do it?

DR SAMMONS: For me, it would be. Because that means there's some sort of nerve compression and you really need a response. And the reality is radiation is incredibly effective for brain mets. And you're sort of — it depends on the scenario. If I have a patient that is T-DXd naïve and I know that I can get an intracranial truly response rate of 72% and a clinical benefit rate around 90%, I feel very comfortable holding off and doing a 6-week MRI. But if that patient already has progression on T-DXd, they already have maybe progression on tucatinib, that's when it starts to get really tricky. You don't really have any agents that have a slam-dunk shot of working. And so you're going to want to pull for radiation.

DR LOVE: Another thing in your criteria, which I don't remember seeing before, was size. You have down here 2 cm. So diffuse brain mets less than 2 cm. Again, is that sort of a — would you say the same thing if you had a patient naïve to T-DXd and they had 3 cm tumor or greater?

DR SAMMONS: Yeah, I mean, you've got to have guidelines to help sort of guide the general public, right? You don't — I think with bulky disease, you just start to get worried. In a lot of the active CNS trials that we do, which, we're holding off on radiation and we're testing a local therapy or a systemic therapy, we usually use 3 cm as the cutoff. So maybe 2 is a little bit conservative. But I think the point there is that you don't want to be just sitting on large lesions that could very soon cause mass effect symptoms, seizure, things like that.

DR LOVE: So just one other non-breast question, and of course, I always love to ask the lung people about prophylactic cranial irradiation that they do in limited stage disease. I'm curious if you have any thoughts about that. Because I'm not sure I can think of too many situations in oncology where you do preventive CNS radiation therapy. Any thoughts about that?

DR SAMMONS: I believe someone somewhere did a prophylactic whole brain study in breast cancer. And obviously, it didn't become standard. I think whole brain radiation has an immense consequence to it in terms of short-term memory, executive functioning, performance status, depression. Even if you do hippocampal sparing and use memantine. I mean, these patients, if it's between living and not living, we should do whole brain radiation. But we really try to hold off on that for as long as we can.

DR LOVE: So actually we have a video tonight where a doc in practice asks about hippocampal sparing and memantine. I'm curious what your thoughts are about it. Do you use that at Dana-Farber for whole brain?

DR SAMMONS: Our folks use it for whole brain if it's safe. Certainly, if there's any leptomeningeal concern component, then they wouldn't. But if they can, they generally try to.

DR LOVE: Another thing I was curious about is what do we know about PARP inhibitors in CNS mets?

DR SAMMONS: Yeah, good question. We do think that PARP inhibitors have some activity. We did a retrospective case series with Hopkins that was presented at SNO, I think, 2 years ago, that showed a pretty respectable CNS progression-free survival with PARP inhibitors in BRCA carriers. And so we do like either olaparib or talazoparib. We like it for leptomeningeal disease as well. We've had some really nice long-term responses with PARP inhibitors in leptomeningeal disease patients that have been published.

DR LOVE: So you mentioned that you're going to the ASTRO rad/onc meeting. I'm curious what's new in terms of radiation therapy to the brain. You mentioned a paper at ASCO looking at SRS in people with 20 lesions. Can you comment on that?

DR SAMMONS: Essentially the study looked at patients with solid tumor brain mets excluding small cell. So anybody but small cell who had 5 to 20 brain metastases. And they randomized those patients to either whole brain with hippocampal avoidance and memantine or SRS or SRS or SRT, so stereotactic. And the primary endpoint was actually quality of life based. So they used this symptom composite of quality of life, patient reported outcomes and interference, how much is the radiation that the patient had actually interfering with their life, their ability to perform their activities of daily living, all of those things. And they also looked at overall survival. And what they found was that the patients that got SRS had improved patient reported outcomes, improved symptoms, less life interference than the patients who got whole brain. And the overall survival was pretty much exactly the same. So you weren't getting a detriment in survival but the symptom burden was better. And so I think that's going to open up the field to doing SRS or SRT to more lesions. Now, SRS or SRT to more lesions is time intensive. And so that's something that radiation oncologists will have to think about.

Treatment options for patients with HER2-positive breast cancer and CNS-only disease progression

DR LOVE: I'm curious about the, getting back to HER2-positive disease, the scenario that's been, there have been a lot of guidelines about over the years, I think they've kind of stayed the same, of a patient who developed CNS progression, but on systemic therapy, but is systemically stable. So progression only in the brain, where for a long time, and I still think, I think it's still kind of the guideline to treat locally in the brain and continue systemic therapy. Do you still do that, particularly if a patient hasn't had something like T-DXd?

DR SAMMONS: Yeah. So let's say a patient's on trastuzumab/pertuzumab and they develop 1 or 2 brain mets 4 years into treatment or 2 years into treatment and they are completely extracranially stable. It is within guidelines to radiate them and keep them on that. Now if they had another brain event on HP and were still intracranially stable, that's when you might think about whether or not you want to put them on something more intracranially active.

DR LOVE: So —

DR SAMMONS: Repetitive events.

DR LOVE: Right. Also, you were talking about the combination of T-DM1 and neratinib, and it kind of made me think a little bit about where T-DM1 fits in nowadays in breast cancer. Obviously, the post, at least at this point, the post-neoadjuvant setting is certainly there. But in terms of metastatic disease, not everybody is getting T-DM1 early on. But would you use T-DM1 plus neratinib in somebody who had prior T-DM1?

DR SAMMONS: So in the study that Rachel Freedman and Nancy Lin did, there was still an intracranial response rate of 29% with T-DM1, neratinib in patients who had prior T-DM1. So there was still activity. And so at that point, once you're reaching for T-DM1 neratinib, these patients are, they're post T-DXd, they're post tucatinib, maybe they're post T-DM1. You're really, really, of course, we're going to look for a trial, but you're really running out of options. And so I would still use it.

Clinical presentation of leptomeningeal disease; management of functional sequelae associated with brain metastases

DR LOVE: So I also want to ask you, you commented a little bit about leptomeningeal disease. And I'm curious maybe about the clinical presentation you typically see, whether it's usually diagnosed in a prompt manner. And also, what you visualize is the pathophysiology. Is there a, I don't know, a CSF blood-brain barrier there? Is this related to a local bone met that erodes into the cerebrospinal fluid? Any comments about leptomeningeal disease?

DR SAMMONS: So in terms of the clinical presentation of leptomeningeal disease, I think that we see it a lot on imaging, especially when we're scanning patients with parenchymal brain mets already, and we're sort of following that over time. And so, a lot of times we'll pick it up on imaging. For the patients that are symptomatic and then we pick it up, those patients tend to be quite sick. Headaches, blurry vision, sensitivity to light. Maybe severe back pain, because you can get involvement of the leptomeningeal areas in the spine. Increased intracranial pressure, so headaches and then if you do an eye exam, they'll have papilledema. Nausea, vomiting. So those are some of the symptoms that you would worry about it.

In terms of the pathophysiology, there is definitely a need for us to know and understand more. I have seen some data about maybe cells moving along the bone, dural channels, but I'm not completely sure about that. Another thing we talk about in clinic a lot is whether or not intracranial resection of a brain met might slightly increase the risk of leptomeningeal disease by seeding. The data there is not very strong, and certainly if you need intracranial resection for mass effect or for tissue diagnosis or for a single lesion, we still do it. But I don't think we know enough about the etiology.

DR LOVE: When you see an asymptomatic patient who has imaging evidence of leptomeningeal disease, do you usually do a spinal tap?

DR SAMMONS: I do because I think it's important for us to sort of know how systemic the process is. So I try to do a lumbar puncture, and we also try to do an MRI of the spine because we don't want to miss it in that area, particularly if we're planning some sort of radiation strategy.

DR LOVE: One other question I was curious about, and that is sort of palliative care of the patient with brain mets. And you kind of alluded to people who have very extensive, progressive, symptomatic disease. I'm curious what some of the functional problems are that people deal with end of life and how they're supported?

DR SAMMONS: Yeah. I think palliative care obviously can be very helpful in terms of helping with issues like pain, anxiety, sleep disturbance. A lot of my patients have issues with memory, processing speed, executive functioning like writing, memory recall. Sometimes, depending on the area where their brain metastasis was, if it was in a motor area, maybe they have problems with utilization of one arm versus the other. Motor problems, I think it's very good to get physical therapy and occupational therapy involved

We have a neuropsychologist here that will see our patients and do very in-depth neurologic exams for processing speed, memory, visual function, hearing, all of those types of things that can be impacted. And then based on that, she'll come up with a comprehensive plan for speech therapy, occupational therapy, physical therapy, things like that. But many people don't have access to something like that. But it can be very helpful. I also think thinking about depression in these folks is really important because we do know that one of the possible sequela of whole brain is depression. And, of course, anybody with advanced cancer is at higher risk of depression. And so that's important to think about.

DR LOVE: It's interesting you mention depression as a sequela of whole brain, which I haven't exactly heard. What other things have you observed or been reported to literature from whole brain?

DR SAMMONS: Memory. So, memory issues. Executive functioning. Interference, just ability to perform your activities of daily living. Short-term memory.

Investigational agents for the treatment of brain metastases in HER2-positive breast cancer

DR LOVE: I wanted to ask you also, you ended there with a bunch of new agents and all. I wanted to ask you about a couple of them. One, this BNT327 VEGF/PD-1 bispecific.

DR SAMMONS: So ivonescimab is owned by Summit Therapeutics. And that's a VEGF/PD-1 bispecific that's being developed in lung and has been developed a little bit in breast. BNT327 is BioNTech's version of a VEGF/PD-L1 bispecific. We are still very optimistic for VEGF inhibition in brain metastases in general. And so I'm actually glad that these bispecifics are coming back because just enthusiasm and money to study VEGF in brain mets has waned over the years when VEGF lost its FDA approval in metastatic breast cancer. Nancy Lin did a study with Pablo Leone that was published in 2020 looking at carboplatin and bevacizumab in active brain mets. And the intracranial response rate was 67%. And so there's something about, there's a lot of data about angiogenesis in brain metastases. And targeting VEGF in a brain mets population is, I think, a good idea.

DR LOVE: Yeah, actually, you just triggered a memory. I was thinking, oh, you guys don't use bev but now, I think that when the adjuvant trastuzumab trials were presented in 2005, Kathy Miller also presented the bev study. I forgot that bev was actually used for awhile in breast cancer. That's really interesting.

DR SAMMONS: It was, and it's still used in Europe. It's still approved in Europe.

DR LOVE: Really?

DR SAMMONS: Mm-hmm.

DR LOVE: Wow. Interesting.

DR SAMMONS: Still used with a taxane in Europe.

DR LOVE: A couple other, most of these new agents, I was just curious in general about breast cancer. One, zanidatamab, which is, I think, approved right now in biliary but it looks like it has a lot of other activity. What do we know about — I think it's a bispecific. What do we know about that in breast cancer and brain mets also?

DR SAMMONS: We don't. We don't know anything. It's in a Phase III trial in breast with chemotherapy. They actually allow active CNS disease. So we'll probably learn something from that trial. But we don't know anything yet.

Case: A 65-year-old woman with ER-negative, HER2-positive metastatic breast cancer (mBC) develops a single 6-mm brain metastasis after 4 years of maintenance trastuzumab/pertuzumab

DR LOVE: Alright, so what happened with this 65-year-old woman?

DR SAMMONS: Yeah, so this is a 65-year-old woman who had de novo estrogen receptor negative, HER2-positive metastatic breast cancer. And she was treated with the standard of care CLEOPATRA regimen and was on her maintenance trastuzumab, pertuzumab, doing really well for 4 years. So she was a long-term responder. And around the 4-year mark, she developed a new small 6-mm brain metastasis. We wouldn't have known about it, but she had an unrelated fall and had her brain imaged. And so then we learned about it and because we're not screening for brain mets right now in the US, and we should talk about that too.

And so she had stereotactic radiosurgery. She had controlled extracranial disease on scan. So we just continued her HP. And I figured that she would do really well for a while because she had this 4-year disease-free interval. But sure enough, we scanned her brain 12 to 16 weeks later, and she had 2 new small brain metastases that were treated with SRS. And, I mean, at that point, you could think, some might just continue her HP. But I was a little more worried about her now that she's had 3 brain mets in what is a really relatively short period. And so we talked about our options. And she really preferred oral therapy. So we switched her over to tucatinib/trastuzumab/capecitabine. And she's been on that now with no new brain lesions for about 11 months, tolerating the therapy well.

DR LOVE: So I am curious in HER2-positive situations, it seems like when we ask people that it's interesting a few years ago everybody said HER2CLIMB and now recently when we ask people what they do, they say T-DXd. But theoretically, you still have both options. Here, the patient preferred oral therapy. But from your perspective, how do you think through which way to go first?

DR SAMMONS: Yeah. Now that we have DESTINY-Breast012, not 012, DESTINY-Breast12, I think we have very high-level evidence, both for CNS PFS and intracranial response rates. So for most patients, I will choose T-DXd. But there are a good portion of patients, especially the ones that — this lady was just on HP coming in for injections with no side effects for 4 years. And to move right from that to an IV ADC, the substantial amount of side effects can be really challenging for people. And so we talked about both. And I said that probably at some point you'll have both. But she was really interested in an oral option first.

Screening for brain metastases; radiation necrosis as a side effect of radiation therapy

DR LOVE: So you mentioned the issue of screening for brain mets. Any thoughts?

DR SAMMONS: Yeah, I have a lot of thoughts. The ESMO guidelines say that it's reasonable for HER2-positive metastatic breast cancer. The NCCN guidelines say that we don't have enough data yet. For HER2-positive and triple-negative disease, I mean, the rates of developing them are so high, 30 to 50%. What level of data do we really need to say that we shouldn't screen the brain? If we screen the brain, we know we're going to catch them smaller. And we know if we catch them smaller, and we know if we catch them before there's many, that we're going to either allow them to get SRS, mitigate side effects, mitigate morbidity, reduce seizure risk. Now that we're using ADCs, we know that radiating lesions smaller reduces the risk of radiation necrosis, where if you radiate larger lesions, you're at much more risk of radiation necrosis. So what more data do we need to say that we should catch brain mets smaller? I really just don't understand. I think we should be screening HER2-positive and triple-negative patients at baseline and then maybe every 6 to 12 months. But the guidelines have not endorsed that yet.

DR LOVE: So you mentioned radionecrosis. Can you remind us how you make the diagnosis? And I don't know, do they use bev there to treat, or how do you treat them?

DR SAMMONS: Yeah. Radiation necrosis is becoming, I think, more of a problem, particularly in HER2-positive brain metastases. And it's a complication of mostly stereotactic radiosurgery. And sometimes, and it can be really hard to tell, the lesion is getting larger, and it can be really hard to tell if it's from radiation or if the area is truly progressing. But sometimes, you'll see edema surrounding the area, more sort of rounded edges, more so than nodular. This is really where I rely heavily on our radiation oncologists with expertise in brain metastases to help determine the difference between radiation change and true progression. But it's really becoming a challenge. Memorial Sloan Kettering put out a paper about 2 years ago showing that patients with breast cancer brain metastases that got ADCs close to the time of their SRS had a higher risk of developing radiation necrosis than patients that were not treated with ADCs. And so it has made the field think about that a little bit more. In that paper, it also showed that the smaller the lesion is, the lower the risk of radiation necrosis. So I think, for me, that speaks to an etiology in itself for us to be screening to treat them smaller to try to prevent some of these problems, which really become major problems. The treatment is steroids, bevacizumab, sometimes we do surgery. But it can be challenging to manage.

Case: A 39-year-old woman with ER-negative, HER2-positive mBC develops 7 new brain metastases 6 months into treatment with a taxane, trastuzumab and pertuzumab

DR LOVE: Alright. 39-year-old lady.

DR SAMMONS: So this is a 39-year-old patient. She is on her taxane, trastuzumab and pertuzumab. And we do staging scans and she has 2 new liver lesions. She's having some mild headaches so we do a brain MRI and she's got 7 small brain metastases. So they're all less than 2 cm. There's no mass effect. Somebody started her on steroids and her headaches went away. And so I would say that she's asymptomatic. And so she's got 7 new small brain lesions. And I have to change her therapy anyway because she has liver progression. And so I presented her at our brain mets tumor board. We all knew that the plan was for me to start her on T-DXd anyway, which we know has a 72% intracranial response rate. So the question was, do we have to radiate those lesions now if I'm putting her on T-DXd? And we decided not to. And we decided to just watch her really closely and start T-DXd, do a brain MRI 6 weeks later. And she had an excellent response in the brain on the 6-week MRI. She had a 45% reduction in the sum of all of the lesions in the brain. She was quickly tapered off steroids in the beginning anyway. And then at 12 weeks, she had a CT chest, abdomen and pelvis that showed a partial response. And so we're going to just keep her on T-DXd and watch her brain for now. And see how long we can go without having to radiate the brain.

DR LOVE: So same exact case except HER2-low. Would you still be comfortable using T-DXd?

DR SAMMONS: So if it was HER2-low, I would radiate because the intracranial response rate for HER2-low, as far as we know right now, is only 25%. And I'm not, it depends on, I guess, if you think 25% is good or not. But I don't think it's good enough to defer radiation when we have a highly effective treatment option like radiation. So I would probably radiate a HER2-low patient. The other reason to consider not radiating for this patient that has HER2-positive disease is because of the data that we just talked about with radiation necrosis. So I was going to start her on T-DXd regardless. And so if I radiate and then a week later start her on T-DXd, she'll have that risk moving forward. Whereas if I can hold off for awhile, maybe we won't have to deal with that problem.

DR LOVE: What about using systemic therapy during radiation of the brain, whether it's SRS or whole brain? What are the situations where they can overlap and when do they need to be separated?

DR SAMMONS: Yeah, I mean, I almost never give any therapy with radiation. I usually at least hold the therapy on the date, during the radiation. There is some safety data with giving tucatinib during radiation. But generally, I tend to just hold it during radiation and start after. There's very few times that I can think of where I would continue.

DR LOVE: Incidentally, I noticed you didn't mention what this patient's ER was. She's HER2-positive. But what was her ER? And I'm kind of curious what you're doing about that in HER2-positive since the PATINA trial. We've been asking investigators and they seem like they're on board to give palbo for HER2-positive. Was this lady ER-positive?

DR SAMMONS: This lady was ER-negative. But I think the PATINA data is very compelling. For those in the audience, PATINA is basically patients who had the CLEOPATRA, taxane, HP induction for 6 to 8 cycles without progressive disease and who are on HP with endocrine therapy. And then they were randomized to either placebo or get palbociclib. And the median progression-free survival was 44 months, almost 4 years with a chemotherapy-free regimen, which is just astounding. And so I have moved to that in my practice. It's not NCCN or FDA approved yet, but I've been able to appeal and get it approved. So I'm already using that. A secondary endpoint in PATINA was to look at brain mets free survival, but we haven't seen that data yet.

DR LOVE: So I know our topic here is brain mets, but anytime I talk to a breast cancer person nowadays, I've got to ask them about DB09. And I'm curious how you're thinking about applying it and particularly the issue that everybody's talking about is, are you going to give it indefinitely? Are you going to stop it? Use maintenance therapy? What kind of maintenance therapy? And again, are you going to use palbo, for example?

DR SAMMONS: Yeah, I mean, the field is becoming complex, and I think that's good, because that might mean I still might have a job and AI won't take over my job. Because there's definitely still an art to medicine and everything is going to become just more highly individualized and patient-specific and that's not necessarily a bad thing. It's just a more complex thing. So nobody is surprised that DB09 is a positive study. Nobody is surprised that T-DXd and pertuzumab has more efficacy than taxane HP. The question is, who really needs, if anyone, continuous T-DXd with pertuzumab up-front? And I think the main question to that is sort of who does really well with THP up-front? So we know that people that do really well with THP up-front are PIK3CA wild-type, HER2 3+, de novo people do better, people with non-visceral disease, non-brain mets, so sort of low volume, HER2 3+ de novo patients do really well with THP up-front. So I don't know the answer, Neil.

DR LOVE: I just want to know what you're going to do?

DR SAMMONS: Yeah, I have to be honest, I don't have a problem with giving induction T-DXd to everyone, but I'm not going to continue T-DXd for 3 and a half years for everybody. I think we're missing the mark in terms of the quality of life that people have on regimens like HP and even HP and endocrine therapy and PATINA, which is chemotherapy free and has a PFS of 44 months. I mean, people do really, really well on that. And yes, the side effects of T-DXd can be manageable, but it's still chemo for 3 and a half years. And I just think that that's not going to be what we give to the majority of people.

People that I plan to start on T-DXd with or without tucatinib, or pertuzumab, once it's approved, is rapid recurrences, heavy visceral disease, maybe even brain mets patients. All of them I think it's a good idea to potentially consider T-DXd up-front. But lower volume disease, de novo patients, I just, I don't know that they need continuous ADC for a long time. And so I'll probably do some sort of induction and then meet a maximum response and then still think about maintenance.

DR LOVE: But still T-DXd and not chemo, pertuzumab, trastuzumab, CLEOPATRA?

DR SAMMONS: I think so. I just, I don't, I think T-DXd is just as well tolerated as docetaxel, and it's probably more effective. So I don't have a problem with inducing people with it.

DR LOVE: So you just said something I hadn't heard before. I didn't realize that PIK3 has anything to do with HER2-positive disease.

DR SAMMONS: It does. So we have data showing that patients with PIK3CA-mutant HER2-positive breast cancer have inferior outcomes with the CLEOPATRA regimen. And so, those patients, I think reasonable to think about T-DXd up-front for them.

DR LOVE: So again, we're talking about HER2-positive, PIK3-positive and ER-positive also?

DR SAMMONS: They could be ER-positive or ER-negative and PIK3CA mutant. We know they have inferior survival on the CLEOPATRA regimen. There are some ongoing studies looking at adding inavolisib and PIK3CA inhibitors to HP that are in Phase III right now. But as for right now, we just know they don't do particularly well on CLEOPATRA.

DR LOVE: So I didn't actually realize you can be PIK3-positive and ER-negative. And I guess you could be HER2-negative as well. For example, have PIK3 inhibitors been used in those patients? Is it a Phase II study? Did they respond? I always thought it was just ER-positive, PIK3-positive.

DR SAMMONS: No, about 30% of patients, I think, with HER2-positive disease have PIK3CA mutations, 25, 30%. So there is an appreciable number. And, in fact, I believe DESTINY-Breast09 even stratified for PIK3CA mutations.

DR LOVE: This concludes our program. Special thanks to Dr Sammons, and thank you for listening. This is Dr Neil Love for Oncology Today.