Moving Beyond Chemotherapy in Metastatic Triple-Negative Breast Cancer (mTNBC): Are We Clinically Ready? Round 2

Watch Round 3 here.

Kelly McCann: Let's go to round two. Is confidence in toxicity management the real barrier to earlier ADC use in metastatic triple-negative breast cancer?

This is a very busy, colorful slide that demonstrates that confidence in managing ADC toxicity varies widely and is lower among junior clinicians. I would also say that confidence is probably lower among patients, or sorry, not patients, but physicians who see a lot of different cancer types as well. I used to do gynecology and breast oncology, and I stopped doing the gynecology because they started inventing their own ADCs, and then I didn't want to manage the ocular toxicities and all of that. And so let's do this topic next. Clinician confidence is a real barrier.

Jason Mouabbi: All right. So now it gets tougher for me, but we're going to ... I'm still committed.

All right. So, truly, when it comes to ADCs, we need to increase physicians' confidence in prescribing those medications, because the facts speak for themselves. 85% of patients in the US are treated in community settings rather than large academic centers. Community doctors don't see just one type of breast cancer. They see multiple. And when you throw those ADCs at them, these are newer drugs; they come with their own set of adverse events, and they're worried. But I'm here to let them know you shouldn't worry. All right?

So, if you look at the adverse events of the ADCs that we use in triple-negative breast cancer. The first may say treatment, sacituzumab govitecan. That drug has been around for a while now, and many doctors are accustomed to it. The main side effect of that drug is highly preventable. It's neutropenia. But in this day and age, we're going to talk about it in the next slide. You can give growth factors before it becomes problematic. You can prevent it; you can be proactive. In fact, in my practice, I nailed it down. After day one infusion, I give a short-acting, one-dose. And after day eight, I give the long-acting GCSF. And patients do fantastically well. Truly, no problems with neutropenia anymore.

Now, for the other drug that's coming to the market, some of us have some experience for the past year because we've been using it in the metastatic setting of the hormone-positive. That's the datopotamab deruxtecan. When you read the studies, you feel like there are two giants over here that are scaring us. One is mucositis, and the other is ocular toxicity. Those two names scare us.

But let me tell you, these are giants made of paper. It's not an issue. Those of us who tried datopotamab deruxtecan found it very well tolerated. The mucositis is highly preventable. You just give them an oral steroid mouthwash four times a day, the same way we do with everolimus. I mean, we've been doing this for almost a decade now. You do the same thing. Patients are doing excellent.

Ocular toxicity, truly, the name has to change. It's dry eye. Let's be honest. It's just dry eyes. You just give them lubricating eyedrops, and that is it. You don't see any hematological toxicities. You don't see organ dysfunction. They're very well tolerated. Just try it, and you'll see for yourself. So those adverse events, we get scared about them just by reading the study. Once we try them, they're not an issue.

And this is the guidelines for using GCSF. So, you can clearly see that a patient who has one risk factor automatically qualifies. If they have just received prior chemotherapy, or have just received a prior treatment line, a lot of those patients with metastatic disease have received earlier treatment in the early setting because they're recurrent from the early setting. By just receiving a prior treatment, they automatically qualify for GCSF, and you can get it covered by insurance.

So it's truly not an issue to start GCSF. You don't have to wait until neutropenia happens to then be reactive. You have to be proactive. And once you're proactive, it’s no longer an issue.

All right. Let's see how you're going to win that debate.

Seth Wander: I told you all, he's very charismatic. If you're on a plane, you're about to go skydiving, and you're afraid of heights, he's pumping you up. I'm going to scare you a little bit here. Okay?

There are real toxicity concerns with these ADCs. So here are, I think, the results of an analysis of multiple clinical trials published in phases 1, 2, and 3. Look at these death rates on here, worse than skydiving, significantly worse. And some of these toxicities, I'll give my friend Jason a point here. Yes, mucositis. Yes, neutropenia. We're oncologists. We deal with that. But most of you, like me, probably didn't even own an ophthalmoscope when you were in medical school because you were sure that you were never, ever, ever going to use that as an attending. Most of us became oncologists so we don't have to deal with pneumonitis and reading PFTs, EKGs, QTC measurements, and ocular anything.

So I still have some fears of these things. And in all seriousness, when these new drugs come out, and this is not unique to triple negative disease, there are some of these idiosyncratic, unique side effects that push us past the limit of some of these areas that we like to be. Nausea, cytopenia, fatigue, right? Mucositis, etcétera. And you can see some of that on here. Hyperglycemia, things like that. These are challenges we are not thinking about at the forefront of our minds that sometimes require different maneuvers, diagnostics, and different supportive medications. Diabetic changes, eye drops. I don't even count the eye drops when I review the meds on my list. I don't know what any of them are, but now we have to start thinking about these things for this unique drug.

Here are high-grade, serious discontinuation and death-related events published from ASCENT and TROPION-Breast02. And you can see when you look, compared to chemo, almost across the board, numerically, there are higher rates of high-grade or serious adverse events with ADCs compared to chemo. Though I will acknowledge, and Jason's going to be very quick in his rebuttal, to point out that the discontinuation rates are not necessarily higher, which I agree. And I think that's a testament to the point we're discussing. We're getting used to using these drugs as these trials move along. You think about T-DXd and the pneumonitis rates in the phase 2 setting in the more heavily pretreated HER2-positive; they were high, and there were multiple deaths on that study, which we haven't seen borne out in some of the later phase 3 studies.

So, despite our reluctance, we are becoming better pulmonologists, better ophthalmologists, better endocrinologists, and better cardiologists, and we're anticipating and acclimating, but that doesn't mean these aren't real challenges.

Now, as Kelly alluded to a minute ago, there are studies that have demonstrated different rates of adoption, for example, of immunotherapy. And I can remember when I was a fellow, my father-in-law was now partially retired, but he was in community practice for 30 years, seeing every kind of disease, when all I could do was breast cancer.

And I remember when I was a fellow and Pembrolizumab was coming out, and we were using it a lot in clinical trials at Dana-Farber, he was terrified to give Pembrolizumab to his first patients. This is a person who has received heavy-duty R-CHOP and R-EPOCH, all of which I would be absolutely floored by today. He was terrified to give pembrolizumab, where we were using it all the time in the context of the clinical trials for lung and melanoma.

ADCs are not dramatically different from that concept, right? Totally different kind of drug, totally different toxicity profile. So here, in this study, looking at practice location (independent versus academic), practice size (small versus large), there are differences in uptake, for example, of immunotherapy. And it's harder for doctors in rural locations, for doctors outside academic systems, and for doctors in much smaller practices where the resources, pharmacy support, and other things may not be in place.

I lean on my pharmacist, breast specialty pharmacist, all the time to help me think about med interactions, to help me think about GCSF dosing in certain contexts, et cetera. And I would have a really hard time adopting some of these newer drugs as quickly without all of that support from pharmacy, from nurse practitioners, from nursing, et cetera. Okay. Back to Kelly.

Kelly McCann: All right. So, in round two of the discussion on clinician hesitation due to anticipated ADC toxicity, what do you think makes ADC-associated AEs feel more challenging than chemo?

Jason Mouabbi: So, mainly because they're new, everything that's new for us, we feel it's more challenging because we haven't tried them yet. When we sit at conferences and hear speakers talk about them, we start thinking about those side effects in our heads and over-amplify them. We tend to do that as human beings. We tend to over-amplify everything until we try it, and then it doesn't feel as bad. So I think that's the main challenge and barrier, because they haven't been there for long. A lot of people don't have experience with them.

But once I start experiencing them, they will see that they're not terrible. Actually, they're a lot better. You mentioned earlier the KEYNOTE-522, the regimen we use in the early setting. Yes, patients respond well, but it's a tough road. It's tough to give this regimen. You must always support your patient. The amount of work you need to do when you give chemotherapy is huge. A lot of the time when you do the ADCs, the work is front-loaded, right? Reassuring patients, start them on the preventive therapies, and then it's cruise control from there on out.

So, it’s a challenge early on because they're new, but later they become much better. And the best metric for assessing whether a drug is better or worse tolerated is the discontinuation rate. That's when side effects are problematic: patients are discontinuing their treatment because of them. And the answer is clear. It's not worth it in chemotherapy. It is not.

Kelly McCann: I do think, just to play devil's advocate, that because the ADCs have a longer half-life, sometimes when those side effects do get out of control, that is more problematic because you can't do anything quickly with them.

Seth Wander: This is a two-on-one debate. I see that. I see that. That's the count on your vote.

No, I concur. I mean, I think again, it's a bit of a moving target. Certainly, if you look at some of the original phase 1 studies and earlier experiences with multiple ADCs, we see higher rates of these toxicities. We've learned to anticipate and adapt to them. But we're also entering a world where there will be a whole arsenal of new ADCs, antibody targets, payloads, and linkers, with all kinds of side effects we may not anticipate.

And the last point I would make about this is, and I think we're going to talk about this in the last section, that the nature of the chemical structure for ADCs makes it more complicated, right?

So for my own practice and my own research, I'm focused on resistance to antiestrogens and targeted therapies that have kind of a defined mechanism of action. When you think about an ADC, you have an antibody, a linker, and a payload, all of which can be modified. And those modifications can result in unanticipated effects, such as antibody side effects and linker cleavability-related diffusion rates. What's the payload? What are the resistance mechanisms and the side effects of the payload?

So, in terms of understanding response and resistance, and in terms of anticipating and adapting to side effects, it's a much more complex type of drug. And Jason definitely has to agree with me on that because here you actually have multiple drugs combined into the same element. And I think that’s part of the hesitancy.

Jason Mouabbi: But I would say that's what's exciting about those drugs because they do come. I'm going to use your own argument here, which I'll use next as well. This is like a heat-seeking missile, all right? You're trying to target the cancer and spare the healthy. That's the closest we've ever been to the silver bullet, where you can target the cancer and spare the rest of the body. And that's why those are exciting. He's nodding. That's point number three.

Kelly McCann: I mean, we've had a lot of these ADCs go through in clinical trials, and it's not that we don't have novel payloads and targets and linkers. It's that they're just unpredictable sometimes. And then I must be the ophthalmologist in the clinic doing the eye chart, and that is not my social.

Seth Wander: And I would make the point that these first-generation and second-generation ADCs are far more similar than they are different. Wait until you start having totally different targets and payloads. We're talking about distinctions between Dato-DXd, T-DXd, and saci. And the joke is always that if sacituzumab and T-DXd had a child, it would be Dato-DXd, right? You have the antibody from one and the payload. But these drugs are way more similar than they are different, and still, the toxicity profiles are dramatically different. Wait until you have a totally unrelated antibody, a totally unrelated payload.

Jason Mouabbi: Seth, you might not know it yet, but you made my argument for the third round.

Kelly McCann: Some of the proactive strategies we use: one important thing to note is that, for sacituzumab govitecan, the FDA changed the label to say you should use prophylactic GCSF. So that's very important. That was within the last year. And then we use eyedrops and dexamethasone swish and spit for the datopotamab deruxtecan. What systems do you have in place, and what would be optimal for community practice? We don't, for example, have a pharmacist in our clinic to ask patients questions or counsel them. I don't have an APP. It's just me. So I'm like a community practice.

Jason Mouabbi: Yeah. So I'm going to talk about the two drugs. So first, if you look at EG, there are side effects like chemotherapy. We're very accustomed to dealing with those, right? Mainly, it's neutropenia and the other one's alopecia. Those we deal with them, or nausea, vomiting, diarrhea. These are the stuff we always deal with chemotherapy. So, community oncologists are very well-versed in managing chemotherapy side effects, which remain the same.

For datopotamab deruxtecan, they're a little different, but community doctors are also accustomed to them. For example, mucositis is the same mucositis we had to deal with when we were overaligning. And again, we've been using those steroid mouthwashes for about a decade now. Since the SWISH study by Dr Hope Rugo was published and the guidelines were updated to recommend the steroid mouthwash with everolimus, everybody has been doing it. Here's the same thing, you're going to do it.

So we're left with this ocular toxicity. Again, it's dry eyes. It's truly, there is nothing structurally wrong with the eye. In fact, at MD Anderson, when this drug was first approved, everybody was sending their patients to optometrists and ophthalmologists. Over the past six months, nobody did. We don't do it anymore. It's truly dry eyes. That's it. Everybody deals with dry eyes at different points in their life, at different seasons. It's the same thing. You just must tell your patient: "Don't wear contact lenses.” That's when you can damage your eyes; you can get corneal abrasion because dry eyes plus lenses is a recipe for disaster. Just consult them not to use contact lenses, but to use lubricating eyedrops.

Yes, the guidelines are four times. The majority of my patients do them once a day at night before bed because they have learned that the worst time for dry eye is in the morning, when their eyes are shut all night. When they wake up in the morning, they feel like they have a sandy feeling. But when they lubricate before bed, they don't have it in the morning, and they do great. Occasionally, they have to do it again during the day, but that's about it.

So truly, when they start experiencing the drug, when they start prescribing, they'll understand it's not a big deal. You don't need much help. And in the future, I highly anticipate that many of us will not even be sending, as we see in academia right now: we don't even send them to optometrists or ophthalmologists anymore.

Seth Wander: It's nice and warm and humid in the south. A little colder and drier in the northeast in the winter, when it's 20 degrees.

Jason Mouabbi: Thank God we're in Miami.

Seth Wander: I think we've been integrating more preemptive GCSF use here. We have to be aware, depending on which drug we're using, in terms of EKG and echo monitoring, right? If we're using T-DXd in terms of the ocular stuff, for Dato-DXd in terms of the mucositis.

I think we have a dedicated pharmacy team and some protocols for teaching before we start these drugs, which have been beneficial. But again, for smaller practices where you don't have a subspecialty pharmacy, it may be harder to get a baseline optometry jam. Even though Jason's downplaying the ocular stuff, we still must send them for an optometry exam at baseline per the guidelines.

Luckily, when the drug was approved, I think the guideline says once a year. During the trials, they were supposed to see the ophthalmologist every couple of months. And I was worried that if it came to market with that kind of requirement, it would be a real challenge.

But I think just being cognizant of what you need at baseline for clearance, and the frequency with which you need to intervene and monitor, is important.

Kelly McCann: Perfect.