Developing Story: Triple Negative MBC - Hard Truths, Real Hope with Dr Sarah Premji

Triple negative metastatic breast cancer is one of the most complex and rapidly evolving frontiers in oncology, and this episode is your most comprehensive guide to understanding it.

Victoria Goldberg sits down with Dr. Sarah Premji, oncologist and clinical researcher at the Sarah Cannon Research Institute in Nashville, for a deep dive into what makes triple negative MBC so uniquely challenging and why the treatment landscape is changing faster than ever.

This conversation was recorded a few months ago and has already been overtaken by history. Since taping, the FDA has approved two major new treatments specifically for triple negative MBC, datopotamab deruxtecan (Datroway) and sacituzumab govitecan (Trodelvy) in the first line setting, a shift that Victoria and Dr. Premji saw coming.

Together they break down everything patients and caregivers need to know, including what triple negative actually means and why it is such a heterogeneous diagnosis, the critical role of PD-L1 status and why it acts like a fork in the road for treatment planning, the science behind antibody drug conjugates and how Trodelvy and Datroway compare in terms of efficacy, side effects and administration schedules, the BRCA, PALB2 and PARP inhibitor connection and when germline and somatic testing matter most, brain metastases, how common they are in this subtype and what is being done about them, and the exciting pipeline ahead including bispecific ADCs, new targets like B7H4, and the Emi-Le trial.

Even if you are not living with triple negative breast cancer, this episode matters. The approvals and the science discussed here represent a broader shift in how oncology is thinking about precision medicine for all subtypes of MBC.

This episode is part of an ongoing series with Dr. Premji exploring the major subtypes of metastatic breast cancer. Previous episodes cover ER positive MBC, and the final installment featuring Dr. Erika Hamilton on HER2 positive MBC is coming soon.

As always, nothing in this episode constitutes medical advice. Please consult your oncologist and care team before making any treatment decisions.

Thanks for listening. If you enjoyed the episode, subscribe and leave a review — it really helps. Follow us on social media @livefromstage4 and visit our website at www.livefromstage4.org for show notes and links.

 Your support helps us continue to share important stories and advocate for those living with metastatic breast cancer.

Until next time, take care and keep pushing for progress.

Transcript

SPEAKER_01 0:00

Hello. Hello. You know, I realized I forgot to remind you, but of course you don't need any reminders.

SPEAKER_00 0:07

No, it was on my calendar, which worked out.

SPEAKER_01 0:10

So let's talk triple negative breast cancer, shall we?

SPEAKER_00 0:13

Yes, let's do it.

SPEAKER_01 0:25

Could the cure for cancer be closer than you think? Welcome to Life from Stage 4, where MBC takes center stage as we talk to experts, share inspiring stories, break down signs, and shine the spotlight on what matters most. Because when it comes down to it, this part for us and by us is all about us. Hi everyone, I'm Victoria Goldberg, and welcome back to Life from Stage 4. We recorded today's episode a few months ago, and it's one of those rare moments where the science we discussed caught up with us in real time. Since this recording, the FDA has officially approved two major treatments for triple negative metastatic breast cancer discussed during our interview. On May 22nd, 2026, the FDA approved Detroit, the generic name DATOPOTAMABDERXTICAN or DATO DXD. This approval is specifically for patients whose cancer has spread and who aren't candidates for immunotherapy. It was based on the Trapian Breast II trials, which showed that this targeted approach could be a powerful alternative to standard chemotherapy. Then, on June 24th, Tredelvi, generic name SACIT2Zimab GolvitiaCan, received a significant new approval. While it was already a known toolinau toolkit, it's now approved as a first-line option. This means doctors can use it right away, either alone or alongside Pembrolizimab, depending on the patient's PDL-1 status. This move was driven by the SN3 and the SN4 trials. In plain language, these drugs are antibody drug conjugates. Think of them as a homing device that carries a chemotherapy payload directly to the cancer cell, sparing more of the healthy tissue. Even if you aren't living with the triple negative subtype, this conversation matters. These approvals represent a shift in the standard of care for the entire MPC community. We're seeing the bar being raised for what first-line treatment looks like, moving us closer to a world where a patient gets a treatment tailored to their specific biology, rather than a one-size-fits-all approach. To help us navigate the data and what it actually means for the person sitting in the clinic, I'm joined by Dr. Sarah Premjee. Sarah is an oncologist and researcher at the Sarah Cannon Research Institute in Nashville, where she works on the very clinical trials that lead to these kinds of breakthroughs. It was a timely conversation when we recorded it. And it's even more vital now. So she's become our regular resident medical oncologist, and we are talking about the most complicated subtype of all, I would say, right? Triple negative breast cancer. I'm not gonna ask you to introduce yourself. You've done this already. We're so happy to have you here with us.

SPEAKER_00 4:01

Happy to be here.

SPEAKER_01 4:02

All right, why don't we just introduce the subtype? I just said that it's one of the most complicated ones. So what exactly is triple negative breast cancer? And why is it so much more complicated and difficult to treat than the other subtypes?

SPEAKER_00 4:19

You're exactly right, Victoria. It is arguably one of the most complicated subtypes of breast cancer. It's not as common as the other two subtypes. So triple negative breast cancer comprises about 10 to 15% of all total breast cancers. But it's very heterogeneous because what is triple negative breast cancer at the core? It's a bucket of different types of cancers that just lack the expression of EMR, PMR, and to some degree HER2. They're not driven by HER2. And that is the bucket. But really, that's one large bucket. We think is a field that there's actually multiple subtypes of triple negative. And there's been a lot of back and forth on how do we classify the different subtypes. For all intents and purposes, right now they're being treated in the same way. But we hope that we'll move towards a paradigm in which we identify each of the types of triple negative breast cancer, and they're being treated according to the way they actually behave.

SPEAKER_01 5:24

So this subtype, it sounds like, requires preliminary testing before you actually start treating patients. So we're talking about the biomarkers, the CT DNA. Where are we on that? What are the biomarkers that you would track?

SPEAKER_00 5:44

Yeah, so at least right now in the clinic, the most important thing to know for metastatic triple negative breast cancer is the PDL1 expression. So that is done on the tissue, and you get a combined positive score, and that tells you to some degree, it's not a perfect biomarker, but for right now, it's what we use to help us determine whether we should be adding immunotherapy to our treatment in the first line setting.

SPEAKER_01 6:22

Okay, let's take a pause here. Because you're going to hear the phrase PDL1 come up over and over again in this conversation. And I want to make sure it actually makes sense before we go any further. So what is PDL1? The full name is Program Death Ligand 1, which sounds very sci-fi, but the concept is actually pretty intuitive. Think of PDL1 like a break that cancer cells can press on your immune system. Normally, your immune system is on constant patrol, looking for anything abnormal to attack. But some cancer cells produce this PDL1 protein and use it to press that break, sending a signal that says stand down, I'm not a threat, and your immune system listens. The cancer gets a free pass. If you want another way to picture it, think of it like a clean-on cloaking device in Star Trek. The cancer tumor is still there, still dangerous, but it has made itself invisible to your defenses. Either way you picture it, the effect is the same. Your immune system gets a false signal and looks the other way. Checkpoint inhibitors like febrolysomab, which you may know as K-Truder, are designed to override that signal. They release the brake and knock out the cloaking device. So your immune system can finally see the cancer and go after it. But here is the catch. These drugs only work if the brake, or the cloaking device, if you like, is actually being used. If a tumor isn't expressing PDL-1, the drug has nothing to block. That is why doctors test for it. Your tumor sample gets scored on what's called a combined positive score, or CPS, that Sarah just mentioned a second ago, which looks at PDL1 staining across both tumor cells and nearby immune cells. A score of 10 or higher means PDL1 positive. And that number is the key that unlocks immunotherapy as part of your first-line treatment plan. This is also exactly why the 2026 approvals are such a meaningful shift and why PDL1 stars acts like a fork in the road. If you are a PDL1 positive, you may now be eligible for Trilvi combined with Pembrolizma K-Trita. That combination was studied in the Asanto 4 trial. And the idea behind it is a one-two punch. The immunotherapy wakes up your immune system while TRDLV delivers a targeted strike directly to the cancer cell. If you are PDL1 negative, or if you can't receive immunotherapy for other clinical reasons, that used to mean falling back on standard chemotherapy. Not anymore. The SAN3 trial for Tridelby alone and the Tropion Breast O2 trial for Dutroway were both specifically designed for patients in that situation. For the first time, there are precision medicine options at the very start of treatments, regardless of which side of that PDL1 line you fall on. That is the gatekeeper role that PDL1 plays in our story. Okay, let's get back to the conversation. Actually, before we do, there is one more trial worth understanding. And it's keynote 522. Keynote 522 is the name of a landmark clinical trial that changed how we treat early stage triple negative breast cancer, meaning cancer that hasn't yet spread beyond the breast or nearby lymph nodes. Before this trial, the standard approach was chemotherapy alone before surgery, what doctors call neoadjuvant chemotherapy. Keynote 522 asked a simple but bold question: what if we added immunotherapy to that chemo? The trial combined Pembrolyzmap Ktruda with standard chemotherapy both before and after surgery. The results were striking. More patients achieved what's called a pathological complete response, or PCR, meaning no cancer was detectable in the tissue removed during surgery. And more importantly, patients lived longer without their cancer coming back. This led to the FDA approving pembrolyzmob plaschemotherapy as the standard of care for early stage triple negative breast cancer in 2021. Keynote 355 is its metastatic counterpart, where keynote 522 was about catching the cancer early. Does adding c truder to chemo help? But for patients whose cancer had already spread, the answer was again yes, but only for patients whose tumors tested PDL1 positive with a combined positive score of 10 or higher. That trial set the previous standard of care for metastatic triple negative breast cancer, and it's the benchmark that every newer trial we're about to discuss is being measured against. Why does this matter for our conversation? Well, because most patients diagnosed today will have already gone through keynote 522 before they ever reach the metastatic setting. That means they've already had immunotherapy and multiple rounds of chemotherapy, which changes which treatments are available to them if the cancer does come back. It's one of the reasons the trials we're about to discuss were so focused on patients who had already been through this regimen. Now let's really get back to the conversation. Okay, and there are others as well, right? I guess we can talk about your low HER2 positive. Those are also newer biomarkers.

SPEAKER_00 12:22

You're right. And that does often come in, especially if we're talking beyond first line. I think it's important to know up front, especially as we're trying to move more towards precision medicine. But yes, absolutely, beyond knowing the PDL1 score, if you know the HER2 status, so that's whether the patient's tumor expresses HER2-1 IHC plus, two plus that's not amplified, or whether it's ultra-low, actually, there's ongoing trials looking at that space as well. And then the BRCA and the PAL B status is important. There's a little bit of ongoing research showing that patients that harbor a BRCA mutation maybe actually do have benefit from using the PARP inhibitor in the first line.

SPEAKER_01 13:17

Before we go further, let's pause on three terms Sarah just mentioned BROCA, FAL B2, and PARP inhibitors. Because they're connected and understanding them together makes the treatment logic much clearer. BROCA1 and BROCA2 are genes whose job is to repair damaged DNA in your cells. You may have heard of them in the context of hereditary breast cancer risk. Angelina Jolie famously made them part of the public conversation. When one of these genes is mutated and not working properly, damaged DNA doesn't get repaired. And that can allow cancer to grow. PAL B2 is a less known gene that works as a partner to BROCA2. Think of ROCA 2 as the repair crew and PAL B2 as the one who tells the crew where to show up. When PAL B2 is mutated, ROCA2 can't do its job properly either, with similar consequences. Now, this is where PARP inhibitors come in. PARP is another DNA repair protein, a backup system that cancer cells can lean on when BROCA and PIL B2 isn't working. PARP inhibitors block that backup system. So if a cancer cell is already struggling to repair its DNA because of a BRCO or PAL B2 mutation, and you then take away its last resort with a PARP inhibitor, the cancer cell can no longer survive. It's a strategy called synthetic lethality, exploiting two weaknesses at once to kill the cancer while leaving healthy cells which still have functioning repair systems largely unharmed. The key thing to know is that this only works if you actually have one of these mutations. That's why testing, what doctors call germline testing in this case, matters so much up front.

SPEAKER_00 15:16

However, that also is distinguished by the PDL1 status because that immunotherapy is perhaps not as beneficial in the second line plus setting. And so if a patient has PDL1 positive tumor, you may actually want to use your immunotherapy in the front line and then reserve the PARP inhibitor for the second line plus versus if a patient is PDL1 negative. Now again, this is not approved, but PDL1 negative, BRCA mutated, low burden of disease, and somebody perhaps who is potentially a little frail, you worry about their ability to tolerate chemotherapy, could consider case-by-case basis discussion with your doctor. But really, right now we actually have the approval for the antibody drug conjugate with or without immunotherapy versus chemo with or without immunotherapy for the first line.

SPEAKER_01 16:14

Let's talk about this a little bit because historically, triple negative metastatic breast cancer was always treated in the first line with the systemic treatments. Chemotherapy was the go-to treatment in the past. As you just said, it's changing now. So why don't we talk about this? That's an exciting change, right? And it's fairly new.

SPEAKER_00 16:37

You're exactly right. So really the paradigm up until like last year was the use of chemotherapy plus and minus immunotherapy based on the PDL1. So that was keynote 355 that showed us that. But then we had the readouts of basically three pivotal phase three trials that brought antibody drug conjugates up into the first line setting. And really, now we already have the endorsement for one of those antibody drug conjugates in NCCN guidelines. Basically, we have the Ascent O3 trial, and that was looking at patients that had PDL1 negative tumors. These were patients treated in the metastatic setting who had a disease-free interval of over six months from their curative intent treatment if they did previously have localized tumor. And these patients were randomized one-to-one to either receive sasetuzamab versus chemotherapy. Now, in this triangle, they actually did allow either paclataxol or nanopaclitaxol, which is a broxane as a single agent, or they allow the doublet, gem cytobine and carboplatin, and their primary endpoint was progression-free survival, and they met that endpoint. So they showed an improvement of 6.9 months to 9.7 months with the use of sacetusum abgovotican. And then they also looked at PFS2, so the second progression-free survival, and that was also prolonged from 14 months to 18.2 months.

SPEAKER_01 18:14

Let me just interrupt you for a sec. So for those of you who still don't know it, sacitusum abtican is also known as Tridelvi. There are two names for each drug.

SPEAKER_00 18:26

Yeah, there's a marketing name or a brand name, and then there's often a longer generic name, like we just talked about.

SPEAKER_01 18:32

The doctors tend to go with the longer name for many reasons. But we as patients usually remember the shorter brand names. They usually catch air, but they've become so bizarre. Who can remember them? So for me, it's easy actually. The longer name makes more sense than true cap or tradelvi or god knows what else. So let's go back to this. This is a very interesting study. And you mentioned an endpoint that hasn't been used very widely in trial design. So usually we talk about the two endpoints, the progression pre-survival and the overall survival. But this one you just mentioned has another endpoint that seems to be getting more attention now. So why don't we talk a little bit about that one? Why is it significant, maybe even more significant than progression free survival?

SPEAKER_00 19:28

So it's always important to try to look at, especially because these are global trials. This is conducted all over the world where there's differences in the regulatory approvals of these drugs. And so the question always becomes okay, well, this patient went on to this clinical trial. And then if they experienced a progression, what did they go on after? What happened to them after that? We're always focused on the next line, but what happens after that? And so this did show an improvement in the second progression-free survival. Right now it's trending favorably in the overall survival. So just like you mentioned, Victoria, overall survival is also often a key secondary endpoint that we look at. However, there's a caveat here, and it's very important distinguisher, especially as we talk about the next antibody drug conjugate trial that we'll talk about in a minute. When they were looking at overall survival, we as a field, we may not see that improvement in overall survival because these patients, which is good, were allowed to cross over. And what does crossover mean? So crossover means that when a patient had a progression and they were on the standard of care arm. So they were getting either the paclitaxol or the abraxane or the doublet chemo, the control arm. Those patients, if they progressed, they were then allowed to move up and receive the study drug, the Tridel V. They were allowed to go on to receive that. So then when you go look at how long did patients live, that data becomes very murky. It's very hard to sort that out. And sometimes you don't see an overall survival benefit. But that doesn't mean that the drug is not active. It doesn't mean that it's not a good solution. It's not moving the bar forward in our treatment paradigms. And yes, overall survival is so important, but when you do allow for crossover and you allow those patients to move on, which is great, it's important for those patients to be able to receive that drug, it may interfere with your ability to interpret the overall survival.

SPEAKER_01 21:33

You just explained it so beautifully. Honestly, I have not thought about it this way. I haven't thought about progression free survival too related to the crossover, but that makes such perfect sense. You're absolutely right. And I wish it were more common for trials to be designed in such a way that a crossover was allowed. There's still not that many trials that allow for that.

SPEAKER_00 22:00

Very difficult. I think a lot of times there's various reasons why crossover is or is not allowed. If a drug already has a regulatory approval, sometimes it becomes easier to allow for crossover because there's already an approval out there for maybe perhaps a different indication in the later line setting. So it becomes easier to design your trial in that way, among other reasons.

SPEAKER_01 22:24

Tridelvi was approved for what indication?

SPEAKER_00 22:27

So we were using Tridel V in later lines already. I see. And so now we're looking at can we move it up to the first line? Are we going to get benefit if we do that?

SPEAKER_01 22:38

Okay. So this is our first approved antibody drug conjugate for the first line. And the only one for now, right?

SPEAKER_00 22:46

For now.

SPEAKER_01 22:47

But let's talk about the other antibody drug conjugates that may be coming out.

SPEAKER_00 22:52

Then there was another pivotal trial that actually, interestingly enough, was basically presented at the same meeting. So these two trials were presented, which was very thought-provoking for the field.

SPEAKER_01 23:05

Unusual, right? To have two pivotal studies for triple negative, but that's really a good sign. Yeah.

SPEAKER_00 23:11

The ESMO last year was huge.

SPEAKER_01 23:13

So this was at ESMO, not San Antonio.

SPEAKER_00 23:16

Both the Tridel V trial, the Ascent O three, and then the one I'm about to talk about, Tropion 02, these were both presented at ESMO.

SPEAKER_01 23:24

All right.

SPEAKER_00 23:26

So basically, this one is looking at a different antibody drug conjugate, but I'll explain the differences and the agents. But this one is called Datapodamab Duroxtican.

SPEAKER_01 23:39

Oh boy. Let's say five times.

SPEAKER_00 23:41

Have you ever heard of that one?

SPEAKER_01 23:42

Dato DXD.

SPEAKER_00 23:44

Yes.

SPEAKER_01 23:45

Do you know its trade name?

SPEAKER_00 23:47

It's called Datroway.

SPEAKER_01 23:49

Yeah. I kind of like that name.

SPEAKER_00 23:51

Datroay, right?

SPEAKER_01 23:52

Yeah.

SPEAKER_00 23:53

Um, yeah. So basically, this was looking at patients also metastatic triple negative breast cancer in the first line. A notable difference of this trial design compared to the one I just talked about is that they did allow patients who unfortunately very quickly progressed from their early stage setting. That's what we call disease-free interval. How long were they without disease? And those patients were allowed onto this trial. And again, they were patients who otherwise would not have been receiving immunotherapy for one reason or another. And they were randomized one-to-one to the data versus investigators' choice of chemo. Now, another distinction here is that the investigators' choice of chemotherapy in the control arm was all single-agent chemotherapies. There was Paclitaxol, NABAClataxol, the abraxane that we talked about, Cape Cytobine or Zalota, Aribulin, Carboplatin, they were all single-agent chemotherapies. They had two dual primary endpoints, overall survival and progression-free survival.

SPEAKER_01 25:04

So taxateer is not one of the drugs that's being offered. Is there any particular reason why taxateer is I mean, I'm so happy it's not because it's one of the hardest drugs, in my opinion. But it seems that was not one of the chemotherapy agents that was used on this trial.

SPEAKER_00 25:22

Yeah, I think when they're designing these trials, they need to try to pick a certain number, but then allow for some amount of wiggle room for the investigator to be able to pick which chemotherapy based on the prior chemotherapies a patient may or may not have received in this situation in the early stage setting, for example, and then based on what's available where a patient is. So to my knowledge, I don't think that taxoteur was one of the drugs.

SPEAKER_01 25:48

So this is another trial for the first line, right? Yes. But you did say that usually, or maybe I kind of inferred that you said that, when they start with an antibody drug conjugate, it's more of a later line treatment, not start right away with the first line.

SPEAKER_00 26:07

Like I mentioned, we were all looking at chemotherapy plus minus immunotherapy first, but there was activity in the antibody drug conjugates after that. And so the question arose that can we bring this up? Will we get more benefit? Because unfortunately, and this is very, very sobering statistics, and there's probably wide variations, but there was some data that showed us that our overall survival in triple negative breast cancer in many cases is not beyond two years, which is devastating. And there was also some data that showed anywhere from a quarter to a third of patients did not survive past six months when they got a metastatic triple negative breast cancer diagnosis. And then there was some data that showed us, I think it was flat iron data, that 50% of patients, I don't know that this is my exact experience as a newer oncologist treating patients now in this age, which is good, but based on historical data, 50% of patients were not going on to receive a second-line treatment. I mean, that's devastating. And so the question comes if we have these active agents after chemo, can we bring them up? And can we allow patients to live longer if we use that strategy? That was the premise for a lot of this stuff.

SPEAKER_01 27:26

That makes so much sense. And as you said, I think it needs to be pointed out that this antibody drug conjugate shows activity in the population that's not PDL1 positive, or maybe PDL1 positive, but not eligible for immunotherapy. This is an incredibly important drug to EST. And so what did we see?

SPEAKER_00 27:48

Yeah, absolutely. So the progression-free survival was also improved from 5.6 months to 10.8 months.

SPEAKER_01 27:56

That's very substantial.

SPEAKER_00 27:58

Yeah, absolutely. And then when you look at that 5.6 months, which is the control arm, and you go back and look at our historical data. Remember, I said the 355 trial, the keynote 355, is what looked at chemo plus minus immunotherapy. It's a very similar progression-free survival when you compare those two. So this makes sense.

SPEAKER_01 28:18

Makes perfect sense. Did they break down by different groups?

SPEAKER_00 28:23

Yeah, so they did look at that actually. That's a great question. They looked at race, they looked at geographic region. Remember, I mentioned that they allowed 15% of patients who were the quick relapsers who progressed very quickly. So they still derived benefit, not as much. Not as much benefit, but they still derive benefit. Now, another key point is that when we start breaking up the subgroups, the trial is designed and powered statistically to look at one specific thing. And in this scenario, it was the PFS and the OS, the progression-free survival, the overall survival. When we start doing the subgroup analyses, these are much smaller groups. So it becomes a little bit harder to be able to say things definitively. But yes, there was benefit, but not as profound benefit compared to those patients that had de novo, they didn't have early stage disease, had treatment, and then progressed. Or they had a longer disease-free interval, if that makes sense. They basically went beyond six months before they had the progression event.

SPEAKER_01 29:25

So at this point, it still hasn't been approved, right? It was reported out at asthma almost a year ago. No, a little less than that.

SPEAKER_00 29:34

A little less than a year ago. And I know that it's being evaluated now, but I will say both of them are being looked at. There's the Food and Drug Administration that approves the treatments that we often use that we're able to get for our patients. When I explain to my patients what is on the shelf, and I can pull off the shelf and give you access to.

SPEAKER_01 29:53

Right. That's the FDA-approved drugs.

SPEAKER_00 29:56

Yeah, and then there's the NCCN. A lot of the guidelines that we use and is often a guiding force for the oncology community, and they regularly meet and look at the data and then provide guidelines. So, yes, exactly to your point, the Tridel V has NCCN, it's incorporated into this latest iteration of the guidelines. There's a lot of questions as to why the Datroay was not. You know, we don't know exactly, but a lot of times the groups that are involved in this, they're looking at all the data. They're looking at everything that's out there, and they're often looking at the full publication that's out there. And to my knowledge, Ascent 03 had a full publication.

SPEAKER_01 30:39

So, you know what we did not talk about, and maybe it's worth talking about. Let's just go back. And I think everybody knows what an antibody drug conjugate is, but maybe it's worth explaining since we're talking about two different antibody drug conjugates. Maybe it's worth explaining to our listeners what an antibody drug conjugate is and how these two differ from each other.

SPEAKER_00 31:03

Absolutely. So, antibody drug conjugate, I kind of describe it as fancy chemotherapy. It's still chemotherapy.

SPEAKER_01 31:11

It's so funny because most people they start, oh, it's a smart bomb, it's a this and a that, and you went right to the heart of it. It's a fancy chemotherapy.

SPEAKER_00 31:22

That's what it is. Yeah, exactly. And so there's really multiple components of this fancy chemotherapy. So it has a target. In this case, both of them have the same target. It's called trope 2, which is often a marker that exists on the cell surface of triple negative breast cancers. And then it's linked to chemotherapy. So that's where the fancy chemotherapy comes from. The chemotherapy is a very strong, potent chemotherapy that's designed to kill cells, but in a molecule that's designed where you have the target that is linked to it, and then what we call the payload, which is the chemo, they're all together packaged in one molecule, and that's given to the patient. And so both of these, like I mentioned, have the same trope two target. And then the payload, slightly differences in the type of metabolite, but for the all intents and purposes, they have the same type of payload. They basically do the same thing in the cell, the taupe one that we talked about.

SPEAKER_01 32:28

So there are actually three components in the antibody drug conjugates. There is a linker. Do they have the same linker?

SPEAKER_00 32:36

There actually is slight differences in the stability of the linker. You basically, how well does it do when it's inside the body? There's also a difference in what we call drug to antibody ratio. So, how much drug is on the antibody? Like how much of the chemo were they able to fit on there, right? And so datopodamab dirextican, the one we just talked about, the datraway, that one has what we call a four to one drug antibody ratio, but the payload is very, very, very strong. And then the Tridel V, it's like almost eight. I think it's like 7.6 or something like that to one antibody that they fit on there.

SPEAKER_01 33:19

That's a lot.

SPEAKER_00 33:20

Yeah. Yeah. There are differences. There's differences in what we call the half-life.

SPEAKER_01 33:25

Explain that to people.

SPEAKER_00 33:26

Yeah. So the half-life is how long is it getting halfway metabolized in the blood? So how long until it reaches its peak and then starts dropping of basically the amount that is circulating around your body. And then there's differences in the stability, right? So the question is when you infuse this treatment into somebody, how stable is it? Does it break apart before it does the job that it's intended to do? Or how on target is it? And our newer wave, which we can talk about in a little bit, the newer wave of drugs, the antibody drug conjugates that we're getting out there are even more strong, more direct, more stable than even these.

SPEAKER_01 34:08

You know, it just occurred to me that we were just talking about the two antibody drug conjugates, but we also mentioned in the beginning of our conversation that one of the biomarkers is to test for HER2. So that usually comes with another antibody drug conjugate, right? It's trastisum of drugs to can as we all know it, and HER2. Was that approved for triple negative? Are they trying to bring it up? Is there a trial that is trying to bring it up to the first line?

SPEAKER_00 34:41

To my knowledge, there's not an ongoing phase three trial. There's a number of early phase trials looking at all sorts of combinations of all sorts of drugs. But to my knowledge, I don't know that there's any phase three trial. I could be wrong too, I'll admit that. That is looking at bringing in HER2 in the first line triple negative breast cancer space. But the trial that showed that it was beneficial for patients with triple negative, that was Destiny Breast04.

SPEAKER_01 35:12

I'm actually surprised you remember the number. I just talked to Dr. Weiner and he said the same thing I was thinking. Who can remember those numbers?

SPEAKER_00 35:21

All the numbers, I know it's a lot. And every single one is a different number for a different thing they looked at. So it certainly can be tricky. Um, but it was Destiny Breast O4. That was the trial that looked at her too low tumors, and they were either hormone positive or hormone negative. So the hormone negative, her too low, that it's triple negative breast cancer. That's some subset of them. But then the question is how many? How many of those patients were actually triple negative? And it was about a tenth of patients. I think it was 11% exactly. It's low, right? And so, yes, is it a reasonable strategy that's something that you can do? Certainly. But we have a lot more data now for these trope two antibody drug conjugates compared to in her two, which is a HER2 targeted. So the target is different.

SPEAKER_01 36:13

The target is different. So let me ask you this we test for HER2, but we'll never tested for TROP2.

unknown 36:20

Yeah.

SPEAKER_01 36:21

Do you have an idea? What is the percentage of the triple negative population has this on the surface?

SPEAKER_00 36:29

It's believed to be highly expressed. Okay. We think that you need HER2 expression for TDXD to work, but why are we not testing for trope 2? And there was some data that has shown us that you actually don't need to show a certain amount of trope 2 expression in order for Tridel V to work.

SPEAKER_01 36:46

Okay, well, thank you so much. So I guess this would be a good time to talk about sequencing. We've just rattled off a lot of different options. So if a triple negative patient came to you and they do, how do you start the treatment process? What do you do first? And then how do you sequence the treatments?

SPEAKER_00 37:08

Yeah, very good question. And I will also say between all of these antibody drug conjugates that we're talking about, these ADCs, even though, like I mentioned, their designs are slightly different, they also have differences in their side effect profile. And that's critical because all of our patients, not any one patient is the same. They're all experiencing differences. And so right now, if a patient comes to me in clinic and they have metastatic triple negative breast cancer, I'm looking first at their PDL1 status. And if they're PDL1 positive, I can give them Tridel V plus immunotherapy. If they're PDL1 negative, I can give them Tridel V alone. Or off-label use can use Datroay.

SPEAKER_01 37:55

I think I've tried in one of my previous episodes explain what off-label is, but I would love to hear it from you. As a medical professional, what is an off-label drug?

SPEAKER_00 38:06

So that is something where as a clinician you see benefit of a drug, but it hasn't been approved yet. It hasn't reached full approval. It might be being evaluated, but it hasn't reached full approval. And that's very tricky. In order to get approval to get the drug paid for for a patient, approved by insurance. I mean, insurance follows regulatory approvals. If an investigator prescribes something off label, then they don't have the backing of the approval, perhaps yet. They technically at that point in time don't have the backing of the approval, and yet they try to get access to the drug for the patient. And there's a number of ways to do that, but that's essentially in essence what it is.

SPEAKER_01 38:48

So that's a lot of work on your end as well, when you try to get insurance approve something for a person.

SPEAKER_00 38:57

It can be depending on where you are, what state you live in, the actual insurance company. There is so many variations across the country, and how if you get a drug off label, how you then get it for your patient.

SPEAKER_01 39:10

These drugs are so incredibly expensive. You can't really pay out of pocket for them.

SPEAKER_00 39:17

Right. That's first line. So we're still at first line. So the distinguishing thing is PDL1 positive versus PDL1 negative. And then PDL1 positive, right now we have the Tradelvi plus the immunotherapy, or we technically also had the chemo plus immunotherapy from the keynote 355 that I mentioned.

SPEAKER_01 39:35

Is there a reason why you would give chemo plus immunotherapy instead of an antibody drug conjugate to a patient?

SPEAKER_00 39:44

That's a good question. I would worry that a patient would significantly struggle with the side effects of Tridel V. What would that be? That would be if somebody is already having a lot of issues with their blood counts going down, because we know that's a side effect of Tridel V, or they're having a lot of GI issues already. You may want to be careful. However, I will also caveat, we've gotten a lot better at managing the side effects of these drugs, right? So now we're using growth factor support with the Tridel V. So we're using that with the Tridel V to help boost up the blood counts to try to mitigate that.

SPEAKER_01 40:23

So interesting though, that it's something that you're just starting to use. As you well know, when you have chemotherapy, everyone gets that. This is not even up for discussion. You get that stuff. Why are they taking so long to figure out that that would work for an antibody drug conjugate?

SPEAKER_00 40:41

It's a good question. I think as a field, we're all learning about these molecules so much. And a lot of times when a new molecule is new to people, we just don't know enough about it and we go off of the way the trial designed it. And that's often the way that we can get things approved too, like I mentioned. So, and then it's the experience, right? Over years, everyone comes together at these conferences, on podcasts, on all sorts of things, and they say, I keep having this experience with my patient. I keep having this experience with my patient, and then things evolve over time. And then there's certain chemos, right? Like Dosa Taxil, for example, where we know we need growth factor support. Like we absolutely need growth factors support. There are certain chemos where we know that we absolutely need growth factor support, and there's others where it's conditional. You don't necessarily have to give growth factor support. However, if you're having that issue and you've looked at all other potential causes, then you can certainly incorporate growth factor support. And so there is that nuance there. And so I think as a field, we have learned that that we absolutely for Tradel V, we should be using growth factor support.

SPEAKER_01 41:48

Okay, so we started talking about side effects. So there are two more side effects that are very common with antibody drug conjugates. There are many more, but the three most common. So you mentioned one, but the other two are nausea, any sort of GI issues, plus fatigue. People often complain about being very, very tired. So, what do you guys do about those two now?

SPEAKER_00 42:17

Yeah, yeah. So I think we've also gotten better at trying to use medications to help mitigate diarrhea. That's one thing. And then fatigue, you bring up such an important point with the fatigue because fatigue is very different for everybody. If you ask a patient, they feel fatigued, and then you're saying, Well, I'm also tired, but what is their tired? Their tired might be completely different. Their tired might be, I can't leave my house. I can't go do the things that I used to do. That is my fatigue, and that is very debilitating. So on the other episode we did, I mentioned kind of looking at alternative causes to, you know, what else could be there that we're missing? Is there a vitamin deficiency that we didn't know about that we can correct? And maybe that helps to some degree. That's one thing to do. The other thing is sometimes you look at dose reductions. We shouldn't be scared of dose reductions if we have to try to help mitigate some of that. And then I think last time we talked about there's some other drugs that are being looked at, other supportive care medications. So that's important. And then the data weight, that side effect profile is different. It's a different side effect profile.

SPEAKER_01 43:21

Is it how different?

SPEAKER_00 43:23

Yeah, it's different compared to the Tridel V. It's more of dry eyes, what we call keratitis, and then what we call stomatitis. It's completely different, right? And so you don't run into as much of the blood count issues that you do with the Tredelvi. And so that's where, you know, you mentioned how would you pick one over the other.

SPEAKER_01 43:43

Right.

SPEAKER_00 43:43

Patients can't wear contact lenses with data.

SPEAKER_01 43:46

Really?

SPEAKER_00 43:46

They have to be very aggressive about the eye drops. It's like a six time a day protocol for eye drop usage, which is very cumbersome to people who are trying to live very full lives. No, I know. There's mouthwash protocols. So So it really depends if a patient is already struggling with GI issues. Maybe you lean more towards the data, if they really value contacts or they're already having issues with their eyes, or they've already dealt with mouth sores and you worry about their intake and their nutrition, maybe you swing a little bit the other way. And then their administration schedules are different as well. The Tredelvi is a day one and a day eight. You come back a week later, whereas the data is once every three weeks. So there's differences there.

SPEAKER_01 44:30

So we're still on line one.

SPEAKER_00 44:32

Okay, let's move to the next line. Remember, we mentioned the PARP inhibitors. We have data to support germline BRCA. So germline meaning a patient was born with this, it's inherent to their DNA versus somatic, what is that? That is a mutation that is unique to the tumor. Maybe the patient wasn't born with that mutation, but the tumor has that mutation. And so we know based on data that germline BRCA and then somatic BRCA and then germline PAL B, those are all the mutations that you can try to consider use of PARP inhibitors. So that can be the first line. Remember, I mentioned that small nuance, otherwise, you bring it into the second line. And then there's the inher to that we talked about. There's always chemotherapy. What is the benefit that you get from chemotherapy? I'll be honest, it's very low. The ascent trial group looked at how much progression-free survival were patients getting off the single agent chemotherapy. It was two to three months. It's very low. So it just highlights, in my opinion, the biggest areas of unmet need are in triple negative. I mean, there's lots. But our patients who progress quickly after keynote 522, because the other caveat I didn't mention is that all of these trials we just talked about, they had extremely small proportion of patients who had received keynote 522. The treatment that we now use in early stage triple negative breast cancer. So we still don't fully know in this landscape, these drugs are being studied, but how well are they doing truly after these patients had already received a four chemo plus immunotherapy regimen? How much are we getting? And yes, we're curing more patients with keynote 522. We kind of yaunted the cure idea. We're getting more of that, but that singles out those patients who have very bad tumor biology that are progressing quickly. That is a very much an area of unmet need. And then now that we're moving these antibody drug conjugates up in the first line, what do we do after that? That's another issue in an area of unmet need. And that's where the research is coming in. We have new types of drugs that are being developed, which that is exciting, not approved yet, being studied that are entering the scene.

SPEAKER_01 46:49

We just mentioned the unmet needs. Let's talk for a few minutes about brain metastasis, how common they are, and how do we treat them now with triple negative breast cancer?

SPEAKER_00 47:00

Yeah. So just like you mentioned, uh they're HER2 positive, it can happen in hormone positive, but HER2 positive and triple negative have a higher predilection for brain metastasis. And this can look very different. And while right now, I do not believe we have, you know, uh entered in guidelines to at the baseline get a brain scan, I think we should be doing it. Because if we find a metastasis in the brain, while of course that's terrifying, it's so scary for the patient, it's scary for the doctor that's treating that patient. If you can do something about it, such as surgery or radiation, if you can do that early, that makes a big difference, right? And so if you can control that, and sometimes we're doing that more now. We're we're rate, we're zapping, we're radiating a spot in the brain so that we can then move on to continue our treatments. And then what we're trying to do is have more treatments that have what we call CNS penetration, central nervous system penetration that can enter the blood-brain barrier and have activity in the brain. We are trying to develop more of those molecules. There's a little bit of data that supports Tradelvi, uh, data is being looked at. Uh, so all of these are being looked at more and more. We know when HER2 reaches the brain, so that's great that we that we at least know that. But that's also very much an area of unmet need, is that we need better molecules that can go into the brain, and it's actively being looked at.

SPEAKER_01 48:32

What is the story with these trials? Do they allow people with uh brain metastasis?

SPEAKER_00 48:38

Both of them did. Both trials did allow patients with brain metastasis.

SPEAKER_01 48:42

Treated, treated, right?

SPEAKER_00 48:44

Treated, yep, treated. What we call is like treated or state, treated and stable.

SPEAKER_01 48:48

Stable, and stable, right? Absolutely. All right, so before we go, and this has been a little grim. I mean, there is no way you can talk about this subtype and not sound a little grim, but let's let's try to end on the positive notes. What's so what's in development? You kind of you kind of alluded to that.

SPEAKER_00 49:10

And I will say, I mean, triple nigga breast cancer was even more grim before this to for us to reach this point, also is incredible. Like I think it's always important to celebrate our successes and how far we've come, but it also is motivating, it's sobering and it's motivating to see that we have a lot more to do in this area, and it gives us a lot of impetus as investigators that we have to develop good drugs for our patients who are dealing with this. How, what can we do and how can we benefit these patients most? So, really, what we're looking at now is we're looking at looking at the specific mutations that a patient has. So we do that's the molecular profile, looking at the mutations that are unique to that patient's tumor and trying to target those. Now, we actually have approval for some of those, and they're very rare, I'll tell you. It's NTREC fusion is one, ret fusion is another. Those are what we call pan-tumor approvals. So that a patient has that mutation, regardless of what cancer they have, they have that drug available, those are exceedingly rare. What we're looking at is one of some of the more common mutations. Can we target those? We're also looking at, remember, I mentioned the antibody drug conjugates we have. We're looking at a new generation of antibody drug conjugates that are more stable. They have more stability, they're able to more precisely do what they're designed to do. We're also looking at antibody drug conjugates that have two payloads. One of them, I'll just throw out, there's many of them, but I'll throw out one name. It's Ezebren. Is the easiest way to remember it, and it has two payloads. It has the HERD3 payload, which is different from HER2. It's her three and EGFR. We also have different antibody drug conjugates that have two chemos attached to them.

SPEAKER_01 51:02

Hold on a second. The one you just mentioned, those were the targets, not the payloads, right?

SPEAKER_00 51:07

Those were the targets.

SPEAKER_01 51:08

Okay, so the first one we just talked about, what was it called? E'Zabren. E' Zabren has two targets, right? It's EGFR and her three.

SPEAKER_00 51:19

Got it, exactly.

SPEAKER_01 51:28

I want to take a quick time out here. Because we're again using a lot of scientific short ends. Terms like EGFR, her three by specifics. It sounds like alphabet soup, but it's actually the key to how these new treatments work. Most of us in the MBC community have heard of HER2. To understand how these new drugs work, you have to visualize the HR family. Think of them as four sisters HER1, HER2, HER3, and HER4, who live on the surface of the cell. Their job is to act like antenna, catching signals that tell the cell to grow and divide. In triple negative breast cancer, the most famous sister, her two, is missing. That's actually why we call it negative. But the cancer is smart, it doesn't stop growing just because one sister is gone. Instead, it starts leaning on the rest of the family to do the work. It recruits the first sister, her one, which doctors often call EGFR, and the third sister, her three, to catch those growth signals instead. Even the fourth sister, her four, is part of this network, though we don't hear about her as often. By targeting these other sisters, we are finally able to cut off the growth signals that triple negative cancer has been using to thrive. Now, we've been talking about antibody drug conjugates or ADCs. These are like smart bombs, they have a GPS tracker that finds a specific protein on a cancer cell and then drops a payload of chemo directly inside. But the newest drug we're watching is called Isabran, or I will probably get this all wrong isolant BrangetCan takes this a step further. It is what we call bispecific. Instead of having a GPS for just one protein, it has two. It looks for EGFR and her three at the same time. Think of it like a key that has to fit into two different locks simultaneously to open the door. By grabbing onto both of these growth receptors, the drug makes it much harder for the cancer cell to hide or resist the treatment. In these right trials, this double lock approach showed it could keep the cancer stable longer than standard chemo for people with metastatic TNBC. The reason this is so exciting is that it's essentially taking the smart bomb for her two positive patients and tailoring it specifically for those living with triple negative disease by targeting the receptors they do have. It's a more sophisticated way. And it's why the standard of care is changing so rapidly right now. The significance here is huge. It means that if your cancer doesn't have a high amount of R2 or PDL1, we're finding new doors to go through. We're moving toward the future where no matter what your specific subtype is, there is a targeted delivery system waiting to be used. It's another reason to stay hopeful about the pipeline of what's coming next. Okay, let's get back to Dr. Premji. And you just mentioned now they're also doing two payloads. Oh wow.

SPEAKER_00 54:58

They're looking at that. They're looking at if you use a completely different target and different payload. Actually, Dr. Hamilton presented that at ASCO last year. Oh yeah? Is that the drug? Yeah, the drug was called Emily. That's one way to remember it. It's it's a longer name, but the short name is M E E-M-I-MLE.

SPEAKER_01 55:16

Emily. Nice.

SPEAKER_00 55:17

Yeah, the target was completely different. It was called B7H4. That was the target. And then the payload was what we call orostatin. So it does something different to the DNA of tumor cells. So the idea being if you change the target and you change the payload, if the cancer found a way around the first one, can you still get it the second way?

SPEAKER_01 55:39

That is exciting. We have spent a lot of time today talking about the HER family, EJFR, HER2, HER3. But science doesn't stop there. Researchers are constantly looking for new flags on the surface of a cancer cell that they can use to guide our treatments. One of the most exciting new targets being studied right now is a protein called B7H4. Think of B7H4 like a specialized shield that cancer cells use. It's often found in high amounts of breast cancer cells, but it's rarely found on healthy tissue. This makes it a perfect target for an antibody drug conjugate. There are currently several trials like the SGN B7H4V and others testing new ADCs that are specifically designed to find the B7H4 FLAC. One of the more interesting studies in this space right now is the MLE trial, which is testing a new drug called amylotog litotocin. This is another powerful antibody drug conjugate. What makes MLA different is its payload, which is a medicine called orostatin. While the drugs we have often focused on breaking the cancer's DNA, orestatin actually acts more like a scaffolding wrecker. Once the drug hitches a ride on the B7H4 protein and gets inside, orostatin payload destroys the internal structures. The cell needs to physically pull itself apart and divide. The Emily trial is showing us how we might be able to treat cancers that have become resistant to everything else in our current toolbox.

SPEAKER_00 57:44

Yeah, there's other types of immunotherapies under development. There's actually multiple, but there's one looking at PDL1 and VEG F, which is a different target as well that works on blood vessels. So we're looking at that too.

SPEAKER_01 57:58

Okay. That sounds good, right? Is this a good way to end? I think it is.

SPEAKER_00 58:04

I think so.

SPEAKER_01 58:05

Well, thank you so much. It was so wonderful and interesting as always.

SPEAKER_00 58:11

I love being here. Take care of you.

SPEAKER_01 58:13

So wonderful to see you. Thank you so much. All right. Bye. And that's a wrap on today's episode. And what an episode it was. We covered a lot of ground. Triple negative breast cancer is arguably the most complex and the most urgent frontier in metastatic breast cancer treatment right now. But as Dr. Prem just showed us today, the ground is shifting, and it's shifting fast. From the first approvals of antibody drug conjugates in the first line setting to the precision medicine horizon just coming into view, patients living with TNBC have more options today than ever before. And more coming. This episode is part of a series we've been building with Dr. Sarah Premjeck, a deep dive into each of the major subtypes of metastatic breast cancer and what the latest science means for the people living with them. If you haven't listened yet, we have a full episode on air positive metastatic breast cancer, another subtype where treatment landscape has been completely transformed in recent years. I will link to it in the show notes. And coming up, our final episode in this series, Dr. Pramge will be joined by Dr. Erica Hamilton for a conversation on her two positive metastatic breast cancer. That one is coming soon, and I think it's going to be extraordinary. Stay close. A huge heartfelt thank you to Dr. Sarah Pramgey for her time, her clarity, and her compassion. Sarah, you have a rare gift. You make the most complex science feel not just understandable but hopeful. And for our community, hope backed by science is everything. Thank you. Before I let you go, an important note. Everything discussed in this episode is for informational purposes only. This is not medical advice. Every patient's situation is unique, and treatment decisions should always be made in close conversation with your own oncologist and medical team. Please do not use anything you heard today as a substitute for that relationship.