Introduction: The Patient Experience

DR LOVE: Good afternoon, everyone. I'm Neil Love from Research To Practice, and welcome to Inside the Issue as today we talk about the management of ocular toxicities associated with antibody-drug conjugates and other cancer therapies. We're really excited today. We have a great faculty. Professor Rebecca Dent from the National Cancer Centre in Singapore. It's actually 4:30 AM. She's actually in tomorrow right now. Dr Hans Lee, who was with Ms Richards at MD Anderson Hospital, but now is located at the Sarah Cannon Research Institute in Nashville. Dr Neel Pasricha from the University of California, San Francisco in San Francisco and Ms Tiffany Richards, a nurse practitioner we've worked with many times over the years, who specializes in multiple myeloma from MD Anderson Cancer Center in Houston.

We're going to talk about ocular toxicities from an interdisciplinary perspective. As in all of our work, there will be times that we may be talking about the use of agents and regimens that are not FDA approved. So consult the prescribing information for more.

Here's where we're heading. We're kind of going to just take a breath before we get started and think a little bit about ocular toxicity from the point of view of the patient. And then we're going to spend quite a bit of time listening to a talk from Neel. This is a modification of a talk that he did at ASCO just about the general issues that we're going to talk about tonight. And then we'll follow-up talking about specific ocular issues in myeloma and breast cancer.

So when we put together this grant to do this program many, many months ago, I never imagined that just a few hours before we did the webinar, there'd be a pretty interesting announcement coming out. It came out today from the FDA ODAC Advisory Committee. Not moving forward, at least at the present time, with FDA approval of belantamab, based on mainly concerns about ocular toxicity. I think this is the first time we've seen this happen. This is obviously a very effective agent. Rebecca, I know you're in breast cancer, but this agent was compared to another agent, daratumumab, one of the most effective agents in myeloma in combination about a year ago and was considerably more effective. So a very effective drug that just got at least held by the FDA because of ocular concerns. And I'm bringing that up, and we'll talk a little bit about that, but more to really begin to say, we need to start looking at this issue in a much more detailed and a more coherent way. And I'm hoping we're going to be able to take a step forward, particularly for general medical oncologists. I certainly learned a lot in the last few weeks talking to Neel and others, and I think there's a real story here that I think is important not only for clinicians, but also for people designing clinical trials, which this came up with, again, with the FDA today.

I want to start out — I mentioned that we're doing this program where I'm interviewing a bunch of people, and as it turns out, one of the people I interviewed is a patient of Dr Natalie Callander. She's going to be on this program. And this is a man who's on belantamab mafodotin. And I want you to hear what he had to say about his experience. He's an 81-year-old man. Multiple therapies before this that really did — not very helpful, typical myeloma therapies. He went on a trial of belantamab 3 years ago on trial, and he's still on it now.

MR MIKE GREEN: When I first started getting treatment, I got the full dose that they give to start and I’m pretty susceptible to the corneal little cysts that you get. And so I got it really bad right after the first one. I had to buy myself a magnifying glass about that big so that I could look at anything or read anything. And it took I think probably the full 9 weeks to get so that I was better. But after that, I get cysts but they’re in the corners of my eyes and they distort the cornea a little bit so that if I’m looking at point sources, I can see that there’re a bunch of little point sources overlapping. But your head takes care of that and other than that, I’ve got better than 20/20 vision and so it really hasn’t bothered me.

DR LOVE: Have you ever had any actual discomfort in your eyes?

MR GREEN: I have dry eyes. They make you take tear drops and so 4 to 8 probably times a day.

DR LOVE: When you think about it, how much of a problem has the eye issue been for you?

MR GREEN: Aside from the fact that I have to remember to put drops in, it’s not been an annoyance at all.

DR LOVE: And I'm not trying to say this is a typical case or not, but I will be curious to see how typical these kind of symptoms are. I want to start out first with Tiffany. You have a great paper you put together with your colleagues looking at some of the clinical issues that come up, at least with belantamab. And I think we're going to see this is going to be with many other drugs and mainly ADCs. Any comments you want to make, Tiffany, about what you heard this man describe and how it lines up with what you've heard with other people?

DR RICHARDS: Yeah, I think the keratopathy that we see with belantamab is pretty common. I mean, I think the biggest thing is to make sure that they're keeping up with their eyedrops and that you recognize that even a Grade 1/Grade 2 toxicity, if it's occurring in the field of vision, that can be pretty, have a pretty huge impact on the patient's quality of life. And I would say that I think in oncology, a lot of times we minimize Grade 1 and Grade 2 toxicities, not realizing the impact that it has on a patient's quality of life. And I've said that with neuropathy. And I think we have to get to a place where we begin to pay attention to these Grade 1 and Grade 2 toxicities and the impact that it has on patients.

DR LOVE: And here's, again, a slide from Tiffany's paper. This was a couple of years ago in terms of the algorithm, at least it existed at that time in terms of belantamab. We'll talk more about other ways to do interventions. But, Neel, I'm kind of curious, that story you just heard, is that typical of what you see? And is it specific to belantamab or what you see in general with ADCs that cause ocular issues?

DR PASRICHA: It's a great question. We're seeing that same story play out with the different ADCs that have the corneal toxicity. They all present very similarly with these little pseudocysts in the cornea, the distortion of the vision. And in this case, it actually sounded like it was relatively mild. You heard him say, besides using the eyedrops 4 to 8 times a day, which that's a lot of times to remember to use an eyedrop, besides that, he was doing okay from a quality of life standpoint. So I completely agree with what Tiffany said about the main thing is realizing how much of a quality of life impact these ocular toxicities can really cause.

DR LOVE: And just to point out now, I mean, we've seen an explosion in ADCs of HER2-positive breast cancer. T-DXd just presented at ASCO now probably going to be first-line therapy of metastatic HER2-positive breast cancer. But many of these agents, one of the more recent ones is datopotamab deruxtecan, approved in breast cancer recently now also approved in EGFR mutant non-small cell lung cancer. Rebecca, we haven't really, I think, breast cancer docs haven't seen a lot of ocular issues before. We'll get more into what's been seen with breast cancer. But any general comments about this entity? And also, Rebecca, how patients and family respond to this issue? I hear docs saying, eye is a different story. It upsets patients. What do you find?

PROF DENT: Yeah, and I think first going back to what Tiffany had to say that was a great point that we all look at Grade 1 toxicity, Grade 2, and don't think a lot about it. But in a patient's viewpoint, these are actually really important. Even something like fatigue, we really sort of dismiss it. And I think especially when it comes to the eyes, I think we're all, both doctors and physicians alike, very attuned to be something we actually care about and worry about. And I think even some of our traditional chemotherapies actually have eye toxs that we haven't been so good at proactively treating it or knowing how to manage it or minimizing the impact. So I think this has really highlighted to us that even some of our first-generation antibody-drug conjugates like T-DM1, actually 5% Grade 3 eye toxicity. And so I think there are a lot of lessons that we can now learn from some of these agents that have higher rates so that now we actually can improve the quality of life even in these patients that have smaller rates of eye toxs. We now actually have things that we know work and can implement every day in our clinic and as we'll talk about, such as he mentioned, eye packs and things like that that we'll talk about.

DR LOVE: So Hans, it flipped into my mind the thought of maybe ocular toxicity is going to be the new myelosuppression. Really, just in terms of seeing it as an entity that we really need to understand. And you think about all the things we've done to ameliorate or prevent myelosuppression, I'm not saying we're going to have to do as much of that, but we have the concept of it. And that's really what I want to try to see today.

Here you can see starting back with gemtuzumab this had kind of a rocky course. But the first one is in 2000. And now we're seeing, you can see as we get into 2020, a lot more agents. A lot of great stories in terms of, that I've heard, of cases. Another antibody-drug conjugate in breast cancer, sacituzumab, again, at the ASCO meeting. Looks like it's going to be now part of first-line therapy for triple-negative breast cancer with an IO. We already have in diffuse large B-cell lymphoma, polatuzumab vedotin as first-line. Brentuximab vedotin was first line in Hodgkin and it'll probably come back in there as well. Bladder cancer, enfortumab vedotin, first line again, pembrolizumab. So a lot of ADCs quickly moving up into oncology. And we'll talk a little bit later specifically about breast cancer and myeloma.

Managing Ocular Toxicities Associated with Antibody-Drug Conjugates and Other Cancer Therapies — Dr Pasricha

DR LOVE: But really what I want to do is allow Neel to talk about his vision about what's going on in a lot of these patients and what can be done to ameliorate it. So I'll say that I got hooked up with Neel by talking to, we've worked with Hope Rugo for so many years. I don't know how many of you know but this is kind of like Luka Doncic getting stolen by the Lakers. She went from UCSF to City of Hope. I'm sure San Francisco's in mourning now. But of course, we love working with Hope. But I said, Hope, I've been asking anybody, do you know of an ophthalmologist that could help explain to us what's going on? And she goes, I have a guy for you. Alright. And that led me to watch his ASCO presentation. Here it is. What we're going to do is let him talk for a few minutes and then stop and let the faculty see if they have any comments or questions. So Neel, take it away.

DR PASRICHA: Well, thank you so much to the better Neil, Neil Love, for having me here. And huge thank you to Hope as well. It's been really awesome working with her. And we're definitely still in mourning. But for those who don't know, I am an ophthalmologist, which means we specialize in the eyeball. But specifically, I am a cornea specialist, which is the very front 500 microns of the eye. And I'm going to be talking about the ocular toxicities, mainly from antibody-drug conjugates or ADCs. But we'll also briefly touch on some other cancer therapies as well.

So the key takeaway points I'm going to discuss is, first, how do we explain what are the ocular adverse events from these ADC drugs? The second is, how can we do a better job of grading and screening for these ocular adverse events? And then finally, just briefly, I'll touch on some maybe better ways to do preventative therapy so that we can treat our patients better. So let's jump right in and talk about the ocular adverse events from ADCs.

So this is an ophthalmologist's interpretation of traditional chemotherapies in which you have the toxic drug, and it's killing both the healthy cells and the cancer cells. Whereas in 2000, like Neil mentioned, we had the antibody-drug conjugate first come to market. And it's a really smart idea. Let's link that toxic payload to an antibody and, in theory, have more targeted killing of the cancer cells. So again, that's how the ophthalmologist thinks about antibody-drug conjugates. There's about 15 FDA approved right now, but over 150 in clinical trials. So this is going to be a problem that we're already seeing now, and it's going to keep growing as a bigger and bigger issue for all of us.

So what is the specific ocular adverse events that we're seeing with antibody-drug conjugates? It's a corneal toxicity. And specifically, it's something called corneal pseudomicrocysts. So what I'm showing here is a picture of an eyeball, and we're using our slit lamp microscope to look at it. And when you zoom in really, really fine detail on that slit lamp and look in the periphery of the cornea, you can see these tiny little cysts that are actually not real cysts, but we call them pseudocysts, that are in the epithelium. Like Neil mentioned, a lot of these antibody-drug conjugates are having this problem. So of the FDA approved ones, 3 of them, 20%, have an FDA black box warning specifically about the ocular toxicity. They develop very quickly. So the patient that we heard from, he mentioned that after his first infusion of belantamab mafodotin, he started to develop these pseudocysts. So we're seeing them happen even after just infusion number 1. The good news is they are reversible. So they don't lead to long-term permanent damage to the eye. But the problem is the reversibility can really range in time. It can be as fast as 2 weeks, or more commonly, it's at least 2 months, oftentimes even longer than 6 months. And anecdotally, I've had some patients where they've stopped an ADC, and it's taken about a year for them to get back to normal eyesight.

And the biggest issue, like Tiffany had mentioned in the beginning, is the quality of life. So these patients are complaining about blurry vision, eye pain. And at least for the patients that make their way to me in the corneal clinic, this is often their number one thing that they're worried about, is that they can't function, they can't drive, they can't do their job anymore because of this ocular toxicity.

So what are these actual pseudocysts? If you look at these pseudocysts in histology, they're actually apoptotic or dead corneal epithelial cells. And you can actually see the ADC drug is inside of the corneal cell when you stain for them. So it's not a true cyst. It's basically killing the corneal epithelium. And interestingly, it's like chasing a moving target. So these pseudocysts initially, in the very beginning, they present right where the blood vessels meet the cornea, so right around the edges like a donut. And then over time, they start to shift towards the center. And as they do that, as these pseudocysts are moving towards the center, the vision is changing as well. So wherever the pseudocysts are, they're getting an effect to their vision that's different. So one day they might say they can't see things far away, the next day they might say they can't see things close up and it fluctuates. Why does this happen? There's been some interesting studies where they've looked at rabbits, and they've administered the antibody-drug conjugates to them. And they've radiolabeled them and seen where they go. And if you do that, and you harvest the ocular tissues only over a 14-day period, one thing they found is really interesting is in all the tissues in the eye, except for the corneal epithelium, the antibody-drug conjugate shows a very normal distribution. So it has a really impressive spike in concentration initially, and then that goes down over about 4 to 7 days, except in the corneal epithelium, where the drug concentration spikes, and then it stays at a really high plateau for at least the 14-day period. So something about the corneal epithelium is sequestering the antibody-drug conjugate, and that's why these patients are having this toxicity present for a long duration of time, even after stopping the ADC.

This was a great study that was published in 2025 looking specifically at mirvetuximab soravtansine, which is an ADC for ovarian cancer. And what they show here is that as you give higher concentrations over time, or AUCtau, so that's more to the right on this graph, the higher concentration over time of mirvetuximab soravtansine is linked to a higher probability of having an ocular adverse event, which makes sense intuitively if you think about it. The more concentration of the drug, the higher the rate of the ocular adverse events. But what they also did, and this was the part that was really interesting, is they did the same thing for their objective cancer response. And they found a very similar description, where the higher the concentration over time of the ADC drug, the better the ovarian cancer was treated. And this is why the ocular toxicity can be a big problem, is in certain ADCs, it can be one of the dose-limiting effects, preventing a higher amount of the agent to be used without causing a higher amount of the ocular toxicity.

This is my favorite table. And what it's showing is it's ranking the ADCs by ocular adverse events that are published with the highest at the top, and it teaches us 3 main lessons. The first is that this is not a toxicity that is only due to certain antibodies or certain antigens that are being targeted. It can happen with various different antigens, and it's off-target, meaning these antigens that the ADCs are targeting are not even expressed in the corneal epithelium in some cases. The other thing is it's not due to one specific type of linker. So the way the antibody is linked to the payload, there's various different linker technologies that have been used, and various ones have shown rates of corneal toxicity that are quite high. And then finally, there has been some thought that only the payloads that are microtubule inhibitors are problematic for the cornea, but what we're seeing is even some other ones, like the TOP1 inhibitors, can also cause corneal toxicity. So it's not just one specific payload class.

So I'm going to pause here and ask if there's any questions.

DR LOVE: So Rebecca, any thoughts or questions?

PROF DENT: Well, first of all, Neel, that was such a great intro. I thought it was fascinating, because I think one of the ADCs that has a DNA alkylator payload had a lot more eye tox, and that one hasn't been developed, is the HER2-directed one. And so in my mind, I was like, okay, well, it's that payload. So it was really interesting to see that regardless of the payload, regardless of the antibody, regardless of the antigen, you're seeing that. So what do we know? I mean, I think we know that these compounds get into the circulation or in the vasculature. So I think we're kind of over that. Even though it's more precise, we actually are seeing these agents being released throughout the vascular system. So what do you think is the cause then, or how can we anticipate that? Is there any predictor of who gets it and who doesn't?

DR PASRICHA: These are great questions. I wish I had a good answer. We don't know for sure is the short answer. What we think is happening is something about the charge structure of the ADC complex and something about the hydrophobicity might make it more likely to be uptaken in this off-target manner.

DR LOVE: So I'm going to let Neel continue, but just sort of like a, here's a palate cleanser, Neel, from the chat room. So Kelly says, it's not just ADCs. What about, we saw at the ASCO meeting, big study, camizestrant, the oral SERD, and one of the side effects, and she brings this out, is so-called photopsia. So what is photopsia? And I was also curious about with crizotinib, they have some kind of weird things that they see. Is that all about the retina or what is that?

DR PASRICHA: That's a great question. And it's completely different than the ADC corneal toxicity that we're seeing. So, for example, in cami's case, camizestrant's case, those are causing photopsias, which just is a fancy term for flashes of lights. And as an eye doctor, when you hear flashes of lights, the number one thing you worry about is, is there something going on in the retina? Like a retinal detachment, which is an emergency, a surgical emergency. But what's interesting is AstraZeneca, who has developed camizestrant, they've done a lot of studies in the retina. It doesn't seem to affect retinal function, and it certainly doesn't seem like it's causing any retinal tear or retinal detachment. So something else about cami is causing those flashes to happen in about 15% or so of patients. And so I would kind of group that as a totally different entity of ocular toxicity.

DR LOVE: So before we move on, Hans, any thoughts or questions?

DR LEE: Yeah, I thought this was really fascinating, that table that you showed at the end, Neel, just showing, again, as Rebecca mentioned, that it's not necessarily target dependent, linker dependent or payload dependent. I guess my question is, do you notice any differences, I mean, is the pathophysiology microcysts and that's it? Or do you notice any subtle differences depending on different ADC? For instance, when you see a patient, if you're blinded, for instance, to the drug, which I know you're not, would you be able to tell which ADC is causing the toxicity? Is there more granularity to that?

DR PASRICHA: That's another great question. As far as the corneal toxicity from ADCs, they all present with that corneal pseudomicrocysts. I will show one little example of an ADC that has the corneal toxicity, that corneal pseudomicrocysts, but also has some conjunctival changes. And that's more thought to be an on-target effect, slightly different than the corneal effect.

DR LOVE: So I'll let you keep going, Neel. Now we're talking about prevention strategies. I was bringing up before we started that I was always fascinated by the ADCs used in cervical cancer, tisotumab vedotin, because from the beginning I heard about people putting ice packs on their face, and I'm like, why aren't they doing this with other ADCs? So anyhow, I think Neel has some insights about that, but you're going to talk about prevention strategies.

DR PASRICHA: Yeah, it's kind of a sad story because unfortunately, prevention-wise, we don't have a great answer. So you'll see some of these patients are on artificial tears, like the gentleman we heard from, up to 8 times per day, which think about giving yourself an eyedrop 8 times per day. That is a lot. And also on corticosteroid eyedrops as well. And despite being on both of those, patients can still have very high rates of this corneal toxicity develop. And one of the big issues is this can lead to the ADC having to be interrupted. So either a dose delay, up to 50% of cases, up to 35% can have a dose reduction and in the worst of cases, we're seeing some patients have to just completely discontinue their ADC.

Vasoconstriction, like Neil mentioned, that has been one thing that has shown some efficacy. And so you can vasoconstrict by either doing the cold eye masks, or you can use some topical eyedrops. There's a glaucoma drop called brimonidine, which is also a vasoconstrictor as well. And that has shown efficacy both in a preclinical setting, so again, in those rabbit studies where they administer the ADC to the rabbits, they've shown that those pseudocysts get delayed in their onset when you do vasoconstriction, but the rabbits still develop the corneal toxicity if you wait long enough. And then in patients on tisotumab vedotin, which is for cervical cancer, really high rates of corneal and conjunctival toxicity. But when you add a regimen that includes vasoconstriction, you do see a reduction in the ocular adverse events, so from 80% to 60%. And then specifically on the conjunctiva, it goes from 80% down to below 30%. But what's important to note here is that tisotumab vedotin causes both corneal toxicity and conjunctival toxicity. So it also causes the scarring of the conjunctiva. And we think that that is more related to its targeting of tissue factor, which is heavily expressed in the conjunctiva. So it's more like an on-target mechanism.

The other things that have been tried that were really smart ideas is seeing whether you can give systemic or topical antibody ahead of the ADC drug to basically saturate or quench those receptors. And unfortunately, they did not work, at least when they tried this in non-human primates. So they tried first giving the systemic monoclonal antibody, so not the whole ADC, just the antibody component. And giving that ahead of time had no effect on the corneal toxicity. And then same thing with topical eyedrop formulas. So trying the topical antibody on the surface of the eye or the topical antigen on the surface of the eye did not reduce the risk of corneal toxicity.

So why is this happening? This kind of gets to Rebecca's question on, what is the underlying etiology here? We think it's this off-target mechanism called macropinocytosis, which is basically just a non-selective endocytosis. And what that looks like is the ADC is in the blood, and these corneal cells are rapidly remodeling their membrane and taking up the whole ADC inside the corneal cell. And there's been studies dating back to 2018 that have really nicely showed this in vitro. That giving a gold standard inhibitor of this process of this macropinocytosis reduces the rate of corneal toxicity by reducing the amount of ADC that's entering into the cells. And so that's shown here as less of that green, fluorescent ADC inside of corneal cells with higher concentrations of this inhibitor. And then as far as inhibiting macropinocytosis, this idea has been tested now more recently in 2 papers last year, and both have shown very similar effects. Adding this macropinocytosis inhibitor in vitro in corneal cell culture seems to do a good job of reducing the corneal toxicity.

I'm going to switch gears very briefly and just touch on other cancer therapies that are not ADCs, but that also have ocular adverse events. So one class of them are these immune checkpoint inhibitors, and a good example of that is pembrolizumab. We're seeing about up to 3% of patients can develop some ocular adverse events. By far the most common is dry eye, and it's different than the corneal pseudomicrocysts dry eye. It's just more of a classic dry eye targeting the corneal cells. But then also these patients can develop uveitis, which is a term for intraocular inflammation. The good news is that more than 90% of these patients can be managed effectively with just topical eyedrops or local steroids and don't need to actually stop their immune checkpoint inhibitor.

And then the other big class of drugs that we're seeing ocular adverse events with are MAPK inhibitors. And it's kind of interesting, I've put the MAPK pathway there on the side, but it goes from FGFR to BRAF to MEK to ERK. And where you target the drugs, they have a different ocular adverse event profile. So if you target the BRAF, like dabrafenib, that causes a uveitis in about 5% of patients. But interestingly, if you target any of the other points along that path, so FGFR, MEK or ERK, those tend to cause a retinopathy. And it's the further downstream you target. So if you target ERK versus MEK versus FGFR, you get higher rates of the retinopathy, the lower down you target. So the ERK inhibitors are the most likely to cause this problem. And the good news is that they can improve over time, even while patients remain on the drug. So it's not something where it's going to affect all the patients in terms of their actual drug. And only 50% of patients are symptomatic, which is great. Any questions there?

DR LOVE: So we'll get more in — yeah, we're going to get more into some of the specifics, but I do want to dive a little bit into this issue of preemptive in a second. Neel, I'd like you to talk about right now, specifically for very practical purposes, what would you recommend if a patient, for example, you have a lot of patients with ER-positive breast cancer and eligible to get Dato-DXd, what would you say to — how would you think about — would you suggest a cold pack? Would you suggest eyedrops? What type of eyedrops? First, I want to come back to Tiffany and ask what your experience is with patients taking eyedrops and also any experience with cold packs, how the people like it, don't like it?

DR RICHARDS: Yeah, I think that's a good question. I mean, I think the one thing to keep in mind with these eyedrops is the expense to the patient. Because if insurance is not going to pay for it, and I think for the majority of patients, not just here in the U.S., but in Europe and around the world, that's a significant expense, and particularly if there's not great data that shows that it's actually doing anything. And so to ask a patient to invest the amount of money that they're being asked to invest in for something that's not really going to do anything, to me, that's not, to me, it's not really ethical to do that to a patient, right? I think the ice, the cold packs is a great idea. I mean, I think that is something that's really easy to do, and if that is actually making a difference, then we should be switching how we're managing our prophylaxis and move away from the eyedrops, unless a patient has dry eyes, but moving towards the cold pack. And probably most women are familiar with eye cold packs, so, I mean, it'd be something super easy for people to do.

DR LOVE: So, Neel, again, practical purposes, you're about to start a patient on Dato-DXd or maybe belantamab, if it comes back on the market, or any other ADC that you saw on that list, on your list. In what situations would you recommend preemptive eyedrops? What type of eyedrops? And what about ice cooling?

DR PASRICHA: I think it's a great question. We don't have a great solution right now, so I would say for the ones, the ADCs where we know they cause high rates of corneal toxicity, including Dato-DXd and belantamab mafodotin, I would say preservative-free artificial tears at least 4 times a day and a preservative-free artificial tear ointment at bedtime. That would be kind of the standard regimen at home. And then during the infusion, doing something simple like the cold eye mask to cause some vasoconstriction, that would be great. Doing the topical steroids, there's been multiple studies now that have shown that that really does not have an impact on the actual event of the toxicity. But anecdotally, if patients are very symptomatic and have the corneal toxicity, you can put them on a topical steroid to see if that helps with some of their symptoms. And I found it helps about 50% of the times with some of the symptoms. But I wouldn't prophylactically put patients on it.

DR LOVE: So Rebecca, I mentioned ER-positive breast cancer, but also you're running a big trial in triple-negative. Hopefully we're going to see results with Dato. Have you been recommending ice packs to your patients on these trials? And any thoughts about what about Neel's saying?

PROF DENT: So yeah, so I mean, I think there's a wide range here. So the first thing is, the majority of patients, as he alluded to, compared to some of these compounds that we're seeing given the hematology space and maybe in cervical cancer, we've been fortunate, I would say, in the breast world that we haven't actually seen a lot of toxicity. So other than, because we're enrolling patients in trial, we know that baseline, we get an ophthalmologist assessment. Ironically, so many of my patients at their baseline assessment already have evidence of Grade 1 toxicity. And so I call the ophthalmologist. That's the most important thing is get to know your ophthalmologist. And they said, oh yeah, yeah, they're just using their contact lenses too much and they're not using their eyedrops. And I say, okay, so they haven't even started on drug and they already have Grade 1, which is what we know is asymptomatic keratitis. So I think that's the first thing is get comfortable with a little bit of the language, get to know your ophthalmologist. But what so far we're seeing is a lot of it's Grade 1. When we see like anything, these things rolled out in a more real-world setting where like you said, people are not as aware, I think my worry is that we are going to see a lot more of it and we're not going to know what prevention strategies. And as Tiffany said using an eye mask, it'd be very comfortable to sit in chemo in your ATU suite and put an eye mask on. And then I think, there are actually some compassionate programs of the eyedrops that some of the companies that are making these compounds are providing. So I think we need to make sure that those are accessible for patients and available. And I think, as I said, the final thing is knowing how to adjust to when you're getting these side effects. So for breast cancer and Dato, Grade 4, you stop the drug, Grade 3 you dose reduce after you've seen it come down, Grade 2 you rest the eyes and then you stop the drug and then you can restart. So I think we just have to get a little bit more comfortable with that. But I think getting that baseline assessment for me and knowing about these prophylactic measures are so key to preventing it from progressing.

DR LOVE: And again, you ask an oncologist about Grade 1 hematologic toxicity or other toxicities, they're not going to know it. We need to start learning these. Neel, any thoughts about what Rebecca said? Also, Neel, ophthalmologists versus optometrists?

DR PASRICHA: I'll start with that second part first, the ophthalmology versus optometry. I would just group them all together as eye care provider. And for purposes of corneal toxicity or any of the ocular adverse events that we're dealing with, any eye care provider, ophthalmologist or optometrist will be totally equipped to be able to handle this. And I think that's an important distinction because sometimes patients will say, I must see the ophthalmologist only. And specifically, it's an oncology drug, so I need to see an ocular oncologist only. And that is not necessarily the right person for them to see because those are people who are oftentimes doing surgical management of conjunctival melanomas or intraocular tumors. And you really just need someone who's well-versed in the eye to just do an eye exam and figure out what's going on. So that's to that part. And then I agree with what Rebecca said is that if we can get the sponsors of these drugs to invest in actually providing some of these preventative therapies, to me, that seems like a win-win. It's going to help the patients feel more comfortable and help them use their drug more effectively.

DR LOVE: So Hans, I'm curious about your thoughts, but just to add, the man on the video actually has been followed by an optometrist. And he brought up something that, you talk about examining them, but he talked about how helpful the optometrist was in helping him use the eyedrops and encouraging him to use the eyedrops. So it wasn't just diagnostic, but his relationship was kind of therapeutic. Again, before Hans comments, what about, I just saw this very pretty disturbing article in Women's Health Journal about LASIK. I don't know, we could probably get into that, but what about people who've had LASIK or contact lenses that are going to get an ADC?

DR PASRICHA: I think it gets to the point that Rebecca had made, I think, about how most patients, if they come in to the, or get screened for these eye toxicities at baseline, will have a Grade 1 toxicity already there at baseline because of how they're wearing their contact lenses and things like that. So dry eye is very prevalent. LASIK or any type of refractive eye surgery, those will increase the risk of having dry eye, but I don't think it's a reason to say these patients can't get the ADC drugs.

DR LOVE: So in a second, I'm just going to let you go through to the end, Neel. Anything you want to bring up, Hans?

DR LEE: Yeah, I mean, I would just like to echo the use of preservative-free artificial tears. And so this is something I highly recommend to my patients, for instance, starting on belantamab mafodotin. And it doesn't necessarily get to the root of the issue, but it does help with the symptomology of the dry eye, gritty eye feeling. And so I do feel that patients benefit from that symptomatically. And I think this kind of just highlights the importance of the multidisciplinary collaboration needed between the eye care specialists and the oncologists. And so, again, just as oncologists, the eye is kind of a black box. But I think, Neil, as you mentioned, we're very comfortable managing myelosuppression, neuropathy, and this will become more of our oncology vernacular to manage eye toxicity.

DR PASRICHA: That's what I hope.

DR LOVE: Alright, Neel, let's talk a little bit, and particularly as what you're about to talk about, grading and screening, I think most of us are not too familiar with that or where it needs to be.

DR PASRICHA: Absolutely. And this was an issue that came up early on when I started working with Hope Rugo and some of our colleagues on the oncology side is, how do we better grade and screen for these toxicities? So first, I'm just going to show you the common terminology criteria for adverse events or CTCAE. This was what was given to me when I first started seeing these patients. And there's a couple of problems. The first is you look at the terms. So for example, dry eye and keratitis are separate scale terms for CTCAE. They both kind of represent the same entity when we're talking about ADC corneal toxicity. The other is that they include a lot of words and a lot of signs and symptoms mixed together like vision and the symptoms. And the other one is that they have no recommendation on what to do with the oncology drug. So those were kind of the main 3 points that we found as limitations is the mixing of visual acuity with clinical findings, no representative photos, just words, and these ambiguous terms on what to do. And then the FDA kind of sent these modified ocular adverse event scales, which were a little bit better, but had the same type of issue. But one thing that they did is they included a dosing recommendation for each ocular adverse event grade. And what we were finding is that even at baseline, patients were having a lot of this technically Grade 1, or technically Grade 2 even, corneal toxicity and that was being recommended that they needed to delay their dose. And so we were having this disconnect about what do we do with this information? Because I would tell the oncologist, this is a Grade 1 or a Grade 2. And they'd say, well, based on this, we have to delay the ADC or unnecessarily basically causing dose delays. So we still thought that there was a limitation here.

So this is what led us to create this multicenter interspecialty consensus scale where we got together a big group of oncologists, ophthalmologists and importantly, we also included the FDA leadership to say, what can we do better and how can we make these better? So we came up with 6 different new oncology drug-related ocular adverse event scales. And I'll just show you one example. This is the cornea one. And so just looking at it, it's very clean. So for those who are just on audio only, it has pictures in the middle, it has very simple clinical findings on the left and it has drug recommendations on the right side. And we appreciated that now it was very easy for me as an ophthalmologist and my colleagues as other ophthalmologists or optometrists to come up with the same grade consistently and to give the oncologist accurate dose recommendations for each level. So it separated the visual acuity from clinical findings, included representative photos and most importantly it had appropriate dose delays listed.

The other issue we wanted to tackle was how do we better screen these patients? So a lot of patients who are about to start an ADC that has high rates of corneal toxicity need a baseline eye exam. And we were finding that even at UCSF where our eye clinic is right across from the oncology clinic, there was a huge delay in getting patients screened for that exam. So we thought, what if we brought the eye clinic to the oncology clinic doing these portable eye exam screenings? And so we just simply checked 3 things. We did a pinhole to check the vision acuity. And pinhole basically represents what is that patient's best vision with the best pair of glasses. And it does that in a very simple, cost-effective, easy way by just putting a pinhole in front of the eye. We had a portable eye pressure checking device and then a portable eye imaging device that did the front of the eye and also captured the retina without dilating the patient's eyes. And these are some representative photos that show really nicely that even just with this handheld device, you can get some pretty high-resolution images. And we found that this was very efficient, so it took about 20 minutes, which a lot of these patients have their lab visit, their imaging visit, the oncologist. They have a lot of this downtime, so this was able to nicely tuck into their waiting room time. It was effective. So we found that we were able to efficiently and effectively see all the pathology we need to for a screening purpose. And it was easy. So high patient and technician satisfaction. So now we're trying to roll this out at UCSF and hopefully across the country for different trials as well.

What are some ways that maybe we can be more effective in preventing the ADC corneal toxicity. So I'm just going to switch gears and talk about some of the research on the lab side of things. I spend about 50% of my time in the clinic and operating room and 50% of my time in the lab. And we've developed a protocol where that same corneal tissue that I'm transplanting into patients for corneal transplantation, if it gets downgraded to research use, we can set up this in vitro cell culture of patient-derived corneal cells and we can test antibody-drug conjugate corneal toxicity in those cells. And so I want to show some really interesting videos that have come from that. So this is using something called holotomography, which basically is looking at the cells without adding any dyes or any type of labeling. And on the left, you'll see corneal cells just kind of nicely moving around on the Petri dish, not really doing much and not really internalizing anything from the extracellular fluid. But on the right, when you add an antibody-drug conjugate, in this case, belantamab mafodotin, you see this macropinocytosis process where those black vesicles are coming into the corneal cell now because of the addition of the ADC. And I'll zoom in here just to show that one more time. On the left, just kind of normal cell migration. On the right, you see that macropinocytosis process occurring after ADC addition. So this is how we think the ADC is actually getting into the corneal cell in this nonspecific process. And we've done studies to look at these patient-derived corneal cells. Adding a macropinocytosis inhibitor called EIPA significantly reduces this toxicity in vitro. And so we're hoping that we can develop this into a better therapy for patients.

So I'll just end on some key takeaways. The ocular adverse events from antibody-drug conjugates are these reversible corneal pseudomicrocysts and they cause patients to get eye pain and blurry vision. The grading and screening can be improved so we can use these consensus grading scales that work a little bit better and maybe think about doing portable eye exam screenings to improve our screening efficiency. And maybe we can target the root cause macropinocytosis to better treat this ADC corneal toxicity in the future. So thank you so much again, Neil, for this and thanks to Hope for introducing me to you. Appreciate it.

DR LOVE: And thank you. And we do have a few more minutes. We're going to talk a little bit about myeloma and also breast cancer as kind of examples where this might play out. But just real quick again from our great chat room. So Rachana wants to know, what should be an ideal ocular exclusion criteria for a patient getting Dato-DXd? Would a Grade 1 CTCAE keratitis be an exclusion criteria? Sutini wants to know, does a history of Sjogren's syndrome mean a patient shouldn't get an ADC? And then Juliana wants to know, what about the nasal spray, varenicline, for dry eye from ADC?

DR PASRICHA: So all 3 are great questions. So the first 2 are kind of similar. Is there any type of prescreening criteria that can rule out patients? So, for example, Sjogren's disease they get really bad tear deficiency and that causes a pretty severe aqueous deficient dry eye. And then if they have really severe dry eye or like, Neil, what you mentioned a history of LASIK, should that be a criteria to stop them from getting ADCs? My take on it is that they should still be allowed to proceed because this is a different mechanism of corneal toxicity. It's not just a classic dry eye where it's causing aqueous deficiency or a lipid problem where the tears are evaporating faster. It's a very unique and specific corneal toxicity and I think that even in Sjogren's patients who have very severe tear deficiency, they're still at the same risk of developing these corneal pseudomicrocysts as someone who has a normal ocular surface to start. And then varenicline, it's a nasal spray that increases tear secretion kind of like when you sneeze, sometimes you get more tearing, same idea. It works great as a really good preservative-free artificial tear because it's your own natural tears on the surface, but, again, it doesn't get to the root cause of preventing the corneal pseudomicrocysts. So it might have a role in increasing lubrication and improving symptoms, but it won't actually prevent this toxicity from happening.

Ocular Toxicities in Multiple Myeloma

DR LOVE: So Hans, let's talk a little bit about myeloma. And you and your group put out a paper looking at real-world data with belantamab how it was actually playing out in clinical practice using the Flatiron database when belantamab was approved. And then, of course, it got pulled off the market, not because of toxicity but because it didn't outperform a standard therapy. And then about a year ago all of a sudden we saw these 2 Phase III studies, the DREAMM studies, DREAMM-7 and DREAMM-8, comparing belantamab first to bortezomib and then to daratumumab showing great benefit. And there was a lot of data that came out at the ASCO meeting. There were 2 big posters just on data from the DREAMM studies and other Phase III studies quantifying and also looking at the reversibility. These are all in the slide deck. We're not going to go through these. These are the 2 posters. And then, again, you had this really great, and here's the FDA document that you can also check out, a lot of data that they put together by the FDA looking at the incidents, looking at how often people are examined. Huge amount of data that they reviewed coming up to this document today where it sounds like things are getting held up. There's another study out there looking at different doses of belantamab. I know different intervals are being looked at, longer intervals, Hans, between therapy. And then your work again looking at the real-world play out of this and what you saw there. Again, this is all in the slide deck. But kind of looking like a lot to me like a lot like the research study results. But what do you take away from this whole scene, Hans?

DR LEE: Yeah, I think there are several really important key takeaways. So, I think, based on the DREAMM-7 and DREAMM-8 study, belantamab mafodotin is a highly effective drug. These were 3 drug versus 3 drug randomized Phase III studies where there's a very significant benefit in terms of progression-free survival with a bela/maf based combination. And so it was really not just the benefit but the magnitude of benefit that really stands out and seeing progression-free survival of 30 to 40 months with a bela based combination was quite impressive. But I think, one of the key aspects of belantamab that's important, I think this kind of goes with the real-world study that you highlighted, Neil, is that we know that BCMA is an important target in myeloma and, of course, we know that BCMA bispecific antibodies and CAR Ts are very effective for our patients. But access largely remains limited for patients in need of BCMA targeted therapies. And that real-world study with that Flatiron study was important because the majority of patients actually included in that data set were from the community. And so I think this is so important that this is an off-the-shelf drug that can be administered readily in the community setting and I think, to your point about some of the different dosing sort of intervals, that's the piece that we're learning a lot more about. And I think in my own personal experience with belantamab is that we don't need to dose it every 3 to 4 weeks, actually we spread it out to every 8 to 12 weeks and the ocular toxicity is significantly mitigated through that less frequent dosing interval and that's ultimately the way we often give it in the real-world.

DR LOVE: And this is such — we see this over and over in oncology, dose reduction really can be a very effective way to keep people on therapy without sacrificing any efficacy. Tiffany, any thoughts? And also the issue of the team dealing with this, the oncology team, not just the physician, particularly in terms of nurses and nurse practitioners, all the logistics that — I'm fascinated by this in-clinic type assay. Any thoughts, Tiffany? And this is not just about myeloma and belantamab but about this whole generic issue.

DR RICHARDS: Yeah, I mean, I think being at an academic center we have a lot of luxuries that most community practices don't have. And I think about the nurse practitioner or the PA who's living in a rural area and is trying to get their patient set up with an optometrist or an ophthalmologist and you're trying to coordinate all this. I think this mobile eye thing is really fascinating actually because you almost could create a situation where you could do something telemedicine-wise, right, where you have the mobile, the technology in the oncology clinic but maybe your ophthalmologist or your optometrist is located in a different area. And so that makes that coordination so much easier and the patient isn't having to drive around trying to get to these different doctors' offices because that is cumbersome for a patient, particularly our patients who live in the rural areas. I think of our patients in Texas who live in the valley or live in west Texas. Those are luxuries that they don't have that we have here in Houston.

Ocular Toxicities in Breast Cancer

DR LOVE: Let's talk a little bit about breast cancer and again, Rebecca, this became an issue with the TROPION-Breast01 study looking at Dato-DXd. This is in ER-positive, HER-2 negative patients. As we mentioned, you're running a trial in triple-negative that everybody's very anxious to see. There was a benefit seen. Enough so that you can see here hazard rate of 0.63 in terms of progression-free survival, maybe not statistically significant but also well, I guess at this point no survival benefit. You can see the tolerability issues. But also, again, and here we have another issue that came up with Dato-DXd that we're not going to talk about today is stomatitis where I think preemptive steroid mouthwashes are being used. But any thoughts, anything that you've had as you've listened to this whole process here today, Rebecca. I think this drug is recently approved just in January. People are still trying to figure out exactly when and where to use it. It seems to have some advantage potentially in terms of toxicity. We have 3 other or 2 other ADCs, well 3. We have sacituzumab, we have T-DXd in HER2-low patients that are also considerations. Any thoughts about what you're hearing today, Rebecca, in management of these patients?

PROF DENT: So I think there's a big learning curve with any new agent and as you said medical oncologists have to now be equipped to know how to manage. Specifically in breast cancer, we were a bit late to the game with immunotherapy and so now I think we all feel very comfortable and are very quick to identify and not shy about treating with systemic corticosteroids. And so fortunately in my practice we're not seeing this as much now because we know how to act on them. And so I think the same thing with the compounds like Dato-DXd and other Trop2-directed ADCs. We see this profile actually is a little bit different between them all. And so selecting them may be based partly on side effect profiles or schedules. And so for Dato, we're seeing mucositis and some of these ocular events. In the stomatitis and the mucositis realm, we absolutely see ice chips, prophylaxis mouthwash really significantly reduces that and so we've got people doing it and in our trials we're just not seeing it. With the eye, it's the same thing. When you're sort of doing this appropriate prophylaxis and basically making sure you rest the eyes and stop the drug when you need to, the majority of the trials as I said we're not seeing it. As I said as we're seeing it in broader populations and especially in TNBC where it's a much more aggressive disease, people will be much more reluctant to stop the drug. I think we've got to be very cautious and make sure we get them in to see eye doctors. Now that we have Neel on the line I really want to optimize our ability to ask him questions. A lot of the times a lot of my colleagues say to me, okay, we've got natural tears, we've got lubricating non-preservative eyedrops, we have steroid eyedrops and we have vasoconstrictors. Neel, can you help us? When do I use those? When are they used prophylactically? When are they used as treatment in sort of this related eye ocular toxicity and maybe in other toxicities related to other chemos that we use?

DR PASRICHA: It's a great question, Rebecca. I would say to make it simple to keep it broad category as any preservative-free artificial tear lubricating drop that'll be good as like a prophylaxis level. And then for the topical corticosteroid, if they develop symptoms, you can use a low potency one. So there's one that's called, abbreviated FML but it's fluorometholone. That one is a great one for these ocular surface adverse events. But, again, it doesn't actually prevent the toxicity, it just, like Hans mentioned, might treat them symptomatically and make them feel better. And then I would also add a preservative-free artificial tear ointment. Again any of the preservative-free artificial tear ointments as a group will do a good job for that. And those are over the counter, whereas the fluorometholone steroid and any of the other steroids, those are prescription based. And vasoconstriction, at least during the infusion doing something like a cold eye mask, I think would be great. The brimonidine eyedrop I had mentioned, that's approved for glaucoma. It's not an approved vasoconstricting eyedrop for this purpose so that might be difficult to get across the board. But at least the cold eye mask will be something as a low bar to do.

PROF DENT: Great. Thank you.

DR LOVE: Give a panel a couple more questions. Tiffany, any questions? Any issues about the type of eye mask? I mean can you use like a bag of frozen corn or something or anything special about it?

DR RICHARDS: Yeah, I mean, is there a difference between or is it just having the cold pack?

DR PASRICHA: Yeah, any type of cold eye mask will work, right? We use ones that you get on Amazon. So you can just go on Amazon and say, cold eye mask, you put it in the freezer, and then it has, it looks like one of those sleep eye masks but it has the ice pack on it. You can also use a bag of frozen peas or something that'll just retain the cold better. What doesn't work well is cold water on a towel because it just gets not cold very quickly.

DR LOVE: Hans, any closing —

DR LEE: Yeah, Neel, I had a quick question. I think the model that we, when we administer belantamab, for instance, is we give the drug, hold it when there's toxicity, restart it, et cetera. Do you have any insights on potential long-term toxicity of that approach and is there potentially any permanent issues with limbic stem cells, for instance, and things like that that this has been discussed probably in some circles?

DR PASRICHA: Yeah, initially — it's a great question. Initially we thought there might be some limbal stem cell damage because the corneal limbal stem cells live right at the edge where those corneal pseudomicrocysts start and you can see a pattern of staining on the cornea that looks like limbal stem cell deficiency. But what we found is that it doesn't cause, at least so far, long term damage to those limbal stem cells. So they recover completely normal, have normal wound healing, all those things. So I think what you mentioned about belantamab mafodotin about just extending the intervals, so instead of every 3 to 4 weeks do it every 8 to 10 or 12 weeks. If that can be effective for their myeloma, that's great. That's going to be hopefully preventing them from developing severe symptoms in the eyes as well.

DR LEE: Great. Thanks.

DR LOVE: So this has been a really exciting experience. Final question back to you, Neel. What's going on in terms of education of optometrists and ophthalmologists about this?

DR PASRICHA: These same types of webinars that we're doing here we're trying to do the exact same thing on the ophthalmology and optometry side because this is still a growing hot topic, but a lot of people in the eye community are still not aware of this specific ADC corneal toxicity issue that we're facing. So we're trying our best to really spread the news and educate from optometrists to ophthalmologists across the board.

DR LOVE: So Neel, Rebecca, Tiffany and Hans, thank you so much. Audience, thank you for attending.

Be safe, stay well and have a great night. Thanks so much, Neel. Thanks, Rebecca. Thanks, Tiffany. Thanks a lot, Hans.

DR PASRICHA: Thank you guys.