Welcome, everybody. I'm Floor Backus. I'm a gynecologic oncology and professor in the Division of Gynecologic Oncology at The Ohio State University and James Cancer Hospital in Columbus, Ohio. I'm very honored to be one of the co-chairs of the IGCS Education Advances and Updates Workgroup and excited for our webinar today that is titled Ocular Toxicity and Management of Other Adverse Events with ADCs or Antibody Drug Conjugates, which is in part sponsored by Immunogen and CGen. IGCS is committed to providing meaningful education opportunities through a unique year-round educational engagement program. This platform provides the level of strategic engagement and exposure needed to educate and inform gynecologic oncology professionals on current and future treatments to optimize patient care. Before we get started, I want to mention a few housekeeping items. Please know that we have a recording of this webinar that will be available on the IGCS Education Portal next week. And we encourage you to submit questions via the Q&A feature at the bottom of the screen or the chat feature, and we will do our best to address as many questions as possible. Now it's my time and my honor to introduce today's speakers, Drs. Gottfried Konechny and Mark Slava. Dr. Konechny is Professor of Medicine and Obstetrics and Gynecology in the Divisions of Hematology and Oncology and Division of Gynecologic Oncology at the David Geffen School of Medicine at the University of California, Los Angeles. Dr. Slava is a Professor of Ophthalmology in the Glaucoma Division at The Ohio State University and also the Vice Chair of the Administration of Finance for the Department of Ophthalmology and Visual Science. Without further ado, our first presentation is on the Mechanism of ADCs with Dr. Konechny. Dr. Konechny, please share your screen. Good morning. Thank you very much, Floor, for giving me this opportunity. I'm sharing my screen. I hope you can see the slides now. I'll put them in presenter mode. Are you able to see slides now? Yes. Perfect. So at the outset, let me briefly give an overview of a new class of drugs that are entering the clinic very recently, which are the antibody drug conjugates that have shown, I think, outstanding activity in patients with GYN malignancies. Their activity depends really on the tumor selectivity. That means targeting a protein that is discreetly expressed on tumor cells only and not in normal cells, giving a selective advantage. An underlying endocytosis allows higher activity at a cellular level. There are new phenomena like bystander effects in the tumor microenvironment, interesting payloads that we can give that we were never able to give to patients before because they're just too toxic. And the interesting thing is really understanding the target expression level and how it associates with drug activity. So a really exciting area, GYN oncology. Now, there are a lot of these out in clinical development. Probably 60 are in clinical trials now with various antibody targets, various linkers, and cytotoxic payloads. And many of these have, depending on the combination of these components, very different toxicities. And we'll talk a little bit about a very unique, a new field for me, at least, dealing with ocular toxicity as a GYN oncologist and medical oncologist was new. So a lot of learning to be done, and I appreciate the opportunity of this educational session. I'll skip these slides because we have an expert speaking to the topic in the later portion of my presentation. And what are the data so far? Well, we have a folate receptor targeting ADC called mirvotuximab suraptanzin, which is, I think, showing incredible activity with minimal toxicity in patients. I've had the privilege to be involved in a number of clinical trials exploring the activity of this drug. And the most recent data that represented in SGO were the Soraya data showing a 35% response rate in pre-treated patients of platinum-resistant disease, 30% response rate with three prior lines of therapy. Moreover, David O'Malley shared data in patients with prior treatments with a combination with bevacizumab, where he saw responses going up between 60 and 70% in recurrent ovarian cancer. So clearly exciting data. There's also been a randomized study which unfortunately changed patient selection criteria in the trial when transitioning from phase two to phase three and diluted the folate receptor high patient population, therefore didn't meet its endpoint. When analyzing with the correct endpoint, meaning folate receptor high, there was a significant improvement in my opinion. However, this didn't suffice for regulatory purposes. And so this study is being done. Again, the so-called Mirasol study. Now, when we look at the toxicity of this new ADC, this is a data set that was put together by Katie Moore, which will be presented in a few weeks at ASCO, which is looking at the safety across three major studies that have looked at miravituximab, 464 patients, but also the Soraya study, the most recent presentation at SGO. So a very, very large data set. And what it really tells me is overall very low toxicity. You can see low single digit incidences of grade three toxicities. But what's new to us is that ocular toxicities occur such as blurred vision, keratopathy, dry eye, photophobia, and eye pain. These never showed up so far in oncology. But I think it's important to state that the severity of these was mild grade, grade one, grade two, again, blurred vision and 42% keratopathy, 26% dry eye, 22% photophobia and eye pain, and 11 and 10%. Very similar to the Soraya data. And I would like to spend a little more time on understanding the frequency and the nature of these toxicities in patients with recurrent ovarian cancer treated with miravituximab Sorayaftansin. If you look at just the blurred vision and the keratopathy listed in the table here, you can see that all grades occurred in 44%. Again, 21% were mild grade that did not need to be addressed or require any attention. It was just reported by a patient, you know, oh, I noticed I have a little bit hard time reading the fine print in the newspaper, for example, and not really requiring any additional attention. Grade two, mild or moderate interference with daily activities, having a harder time reading the newspaper, for example, but only 23% had grade three with severe impairment of daily activities. Same for the Soraya data. If you look at the keratopathy, very comparable data, the majority were grade one or grade two. Again, grade one was solely diagnosed by the ophthalmologist, didn't require any interventions. If you look at keratopathy and blurred vision, these are not separate symptoms, they do overlap, and you can see that I think there's a good overlap between these eye symptoms that add up to, you know, the overall mild ocular toxicity that I see. Now, if we look at the onset of this, this is very interesting data that it happens pretty early in treatment. At an average about six weeks into treatment in the Soraya study and equivalent to this in the pooled analysis, about six to seven weeks into treatment, patients report their first symptoms. However, most importantly, if you look at the dose reduction and dose delays in this large data set, you can see that only a small proportion of patients, 22% required delayed or dose interruption due to the ocular events, and overall, less than 1% of patients really discontinued the study due to ocular events. If we look at this slide showing the resolution of ocular toxicity, you can see, importantly, of all patients that reported blurred vision or keratopathy that required attention, those 20, between 23% that had grade two or more ocular toxicity, 95% and 90 and 93% of patients, these symptoms resolved during the treatment. So, these were temporary ocular toxicities, which is very reassuring. There is a detailed description of the individual patients and how ocular toxicity is resolved for the blurred vision and the keratopathy in the slides below. This slide shows you a summary of ocular events in a tabular form, and what's most importantly is that you can see 50% of patients with this treatment had no ocular adverse events. 50% of patients developed some form of ocular events. However, 90% of these were grade one or grade two. Of those, 20% required management, and the management consisted basically out of a one-time dose reduction, 10%, or dose delays and dose reductions in another 10%. So, a very small subset of patients where you really had to dose reduce or dose delay moving forward. Now, all of this happened while patients receiving prophylactic measurements, measures such as steroid eye drops or lubricants, and we'll get to that a little later. The proactive care, I think, is very critical for managing these, in my opinion, mild to moderate new ocular adverse events. First of all, patients, we recommend them to go baseline eye exams. They should take preventative measures such as avoid using their contact lenses. I think frequent or regular use of artificial tears, daily use, particularly of preservation-free lubricating artificial tears, does reduce the symptoms, and regular use of corticosteroid eye drops, which we'll comment on a little bit later on the various regimens, have shown to decrease these symptoms. Now, as a gynecologic oncologist, we have to learn to grade ocular toxicity, and this is a summary that shows you grade 1, 2, 3, and 4 for blurred vision, keratitis, dry eye, photophobia. And again, keratitis is something that I'd be very interested to discuss with Mark later on. This is not an inflammatory keratitis. In my opinion, these are occlusion cysts that occur that are not something that need to be treated with an antibiotic, for example, but they are reversible, particularly when treated appropriately. Now, grade 2, in general, is something that moderately affects daily activities with moderate impaction of visual acuity. Any grade 3 would be more severe, affecting activities of daily living that are regarding self-care. And clearly, grade 4 would be severe perforation or best corrected vision of 2200, which we'll hear a little bit more to later. Now, I think having had some experience with mirvotuximab soraptansin, I think it's important to message to patients that there are possible novel ocular toxicities, but that these are low grade, that they're very predictable, and that patients can remain on treatment, and that only less than 1% of patients really had to discontinue study treatment. It's actually a typo here. It's not 40%. It's 20% of patients with ocular events had to delay or reduce the dose. And I think it's a key message to say that if bird vision occurs or some symptoms occur with mirvotuximab, that 90% of these patients resolve while on drug, and 100% of these patients have resolution of their ocular toxicity in further follow-up. Now, let's move on to another ADC, which is targeting NAPP2B, a sodium-dependent phosphite channel. It has the unique name of upifetamab vilzodotin, or the acronym UPRI, which is easier to use. The first study presented by Hamilton showed outstanding activity with objective response rates of slightly over 30% in heavily pretreated patients with platinum-resistant ovarian cancer. This is an updated analysis from Deb Richardson at SGO just this year, which shows that there may be an association between activity of the drug and duration of response associated with the level of NAPP2B expression using a score of TPS above 75, and you can see the response rates in those with high NAPP2B expression were 34%. Those with all levels, so unselected patients, 23%. Clearly a promising ADC. Much earlier toxicity data, preliminary data, I would say, that were included in Richard's presentation. As depicted here, there were two dosing cohorts, 36 and 43, with fatigue, nausea, decreased appetite, mild degrees of vomiting, diarrhea, anemia, all mild toxicities. Also, I would say very well tolerated, grade three toxicity is very rare, but no severe ocular toxicity reported. So, I think it'd be interesting to see if this is a distinction of this agent that there are less ocular toxicities. I think we just have to stay tuned for upcoming reports to see the actual data, all mild to moderate ocular events with this antibody drug conjugate, which targets a different protein but also has a different payload, not DM4, as the myrvotexin, sorry, aftansin, but MMAEF or Aristatin F, which could both contribute to different eye toxicities. Now, a third drug which is relevant for gynecological oncologists is the tissue factor targeting to sodomopendotin, particularly in cervical cancer, where the first report by De Bono showed a 26% response rate. And this is the recent publication from Robert Coleman showing the 24% objective response rate in heavily pretreated patients with cervical cancer. This is a GOG NGOT study, which showed promising activity in a real unmet need of patients that have failed preceding chemotherapy. Now, the toxicities for the eye are shown here, conjuctivitis was reported in 26%, grade one to grade two, no grade three or grade four conjuctivitis, keratitis in 11%, no listed in the publication grade three or grade four. However, there was one ulcerative keratitis of grade three, which alarmed, I think, the regulators while conducting this study. And I do think the study has a very cautious prophylactic mitigation strategy for ocular toxicity, in my opinion, and I'd be happy to discuss this extremely cautious. I'd love to hear Mark's take on this. The recommendations are, again, to have an ophthalmologic exam, including visual acuity and slit lab exam at baseline and prior to each dose of treatment, eye drops regularly, steroid eye drops, as well as lubricating eye drops and vasoconstricting eye drops in addition. Lastly, it's also recommended to use cold packs, something that's new. And I'd be happy to discuss the need for these things and what the rational was and whether really all of these are necessary to minimize the ocular toxicity. And this is a slide set showing you the mitigation strategies based on timelines. You can see the baseline ophthalmologic exam, starting patients 10 minutes prior to infusion, corticosteroid and vasoconstrictor eye drops, then applying cold packs, post-treatment, continuing with corticosteroid eye drops. So, I hope I was able to give a brief overview of the three drugs that are moving forward quickly into clinic in GYN malignancies, an overview of the existing toxicity data and some of the mitigation strategies that have been put into place. And I very much look forward to hear Mark's talk on understanding these new toxicities better and how we can manage them. I stopped sharing my slides, so I hope you can take over now, Mark. Sounds good. Well, I think I'm unmuted. So, give me just a second to pull my slides up here. All right. Does that look like a reasonable presentation there? Very good. I can see them. Yeah. Okay. All right. So, thanks very much for having me. I'll give just a quick note about my background. So, I just work here in the Department of Ophthalmology and I've seen a lot of these patients come through just as mostly as part of the clinical trials that are going on here with Dr. Backus and a lot of the other gynecologic oncologists that work here. So, it's been really interesting for me as well. I've learned a lot about this class of medications and kind of this new whole arena of side effects that's been taking place. So, I'll kind of give my take on what's going on here and how best to communicate both with patients and also other eye providers that you'll be partnering with. So, I do have one disclosure. I have done some work as a consultant for ImmunoGen, who's the maker of mirtotoximab. So, I have that on my disclosure slide there. So, in terms of background, you know, we had a good background here from Dr. Koneksi about kind of the mechanism of action as far as the oncology side of these medications. And it's been a little bit of a surprise, I think, that this kind of new array of ocular side effects has shown up. I don't think this was really anticipated until we started seeing these patients in clinical trials who presented with kind of all these problems. So I want to kind of give a brief overview of how we think about the surface of the eye. So hopefully you can see my pointer here. This is this kind of blown up cellular view of the front surface of the eye, which is where most of these toxicities seem to be taking place. So, you know, in within ophthalmology, we're familiar with lots of different drug side effects. You know, we have classic examples like things that cause angle closure glaucoma. We have a lot of like plaquenil monitoring. There's lots of different side effects that come with drug, different drugs of various classes. This is a relatively new one as far as I'm aware. The reason that we think this is happening has to do with kind of the specific anatomy of the front part of the cornea. It might not be obvious, but the front part of the cornea is very active in terms of its ability to regenerate. You know, for example, if you were to get some type of a laser surgery that wiped out your entire corneal epithelium, that would repopulate in just two to three days. That whole surface will be regrown in that amount of time. That has to be done in the absence of vascularity within the central cornea. And so what you have are these, we call these limbal stem cell areas. So there's these groups of cells that are right at the base where the cornea and the sclera meets. So you can see this little wedge here where this drawing is from. So right at the base of the cornea, there are these populations of cells that are constantly dividing very rapidly. And we'll talk a little bit more about why the mitigation measures that are recommended are recommended. And that is basically aimed at kind of reducing the insult to these cells right in this location that are, again, very rapidly dividing and providing this smooth surface across the corneal structure. Underneath the epithelium, the corneal stroma, which again is a very avascular, somewhat hypocellular structure, that's where if the epithelium starts to break down, that's where bacterial infections can start to occur and that sort of thing. And that leads to more permanent visual sequelae. So Dr. Konechny mentioned that most of these side effects seem to be transient, and that is because they seem to occur primarily in this most superficial layer, which is then rapidly regenerated. The caveat being that if you have severe enough epithelial damage, then you can open up the corneal stroma, the deeper structure, to more permanent damage where scarring can occur and that leads to decreased vision over time. So it is important to make sure that the epithelial integrity is kind of as generous as possible. So in terms of how this works, these cells, again, are constantly dividing in this basal layer. It's not exactly clear what makes them susceptible to this new class of medications. I mean, there's some studies that have been done looking at, like in the case of mirtuximab, looking at folate receptor alpha in antibody receptors. It doesn't seem to be a particularly high presentation of them in that area. Some people have hypothesized that the linker molecule that links the antibody to the payload is actually partly what drives this toxicity. Again, it's not completely clear what's happening. But again, it's what we see clinically. I'm going to forward on my next slide here is this picture here is not a patient on chemotherapy. Rather, this is a patient who is getting amiodarone, which of course is an old school drug for cardiac arrhythmias. But patients on amiodarone will get deposition within these limbal stem cells of this pigment. And then you can see this kind of whorl-like pattern develop because what's happening is that as things are getting deposited out here at the limbus, these epithelial cells are migrating in this kind of centripetal pattern where they're kind of whirling into the center. So you end up with these kind of patterns. So if that epithelial growth is occurring at a normal pace, again, this front surface is regenerated every two to three days. Something like this turns out to not have really any impact on your vision, even though it looks somewhat dramatic. So this is a patient here. This is just a colored photograph of a cornea in a patient with like severe dry eye. And so what you see here is this kind of fluorescing uptake at the level of the epithelium where that most superficial layer of the epithelium no longer has barrier function. There's not a frank epithelial defect here, meaning that the stroma is not exposed, but the epithelium is very rough. And you often will see this pattern where it's more rough inferiorly than superiorly. And that's really because the upper eyelid will kind of cover this over more of the time than the lower portion of your eye. So you often see this kind of pattern with these epithelial erosions where whatever's affecting the corneal epithelium tends to occur more in this area. So again, this is just a patient with standard, you know, punctate keratopathy is what we would call it. This could be from any number of causes, not necessarily from one of these medications. This is just sort of an overview of what's happening on that corneal surface and why we think these medications affected it in this way. So, you know, back to this question of how common are the side effects? Well, they're actually very common, you know, 40 to 60% of patients, again, maybe half of patients will have some type of inocular side effect, you know, that you could also say, well, it's common enough in the case of Zotimab that they have a boxed warning that comes along with the medication. And it's, if anybody's looked at it, it's a fairly long way, three or four page summary of things to watch out for this very regimented pretreatment thing with including eye drops, cool compresses, that sort of thing. And I'd say also, you know, it's common enough that eye drops are routinely prescribed. And we'll talk more about that in a minute. It's also common enough that you're all paying attention to this webinar. So I'd say it's fairly common and definitely worth knowing about. So in terms of what patients are going to notice, a lot of this has overlap with kind of dry eye type symptoms. So anything that compromises the surface of the cornea is going to lead to sort of a similar set of symptoms. And one of the complicating factors is many of these patients who are going to be eligible, certainly in a clinical trial setting, but even as they become more widely available, they will have already been on other types of chemotherapeutic regimens that can lead to similar problems. So a lot of patients will have kind of chronic dry eye symptoms anyway. So things like tearing, you know, redness, light sensitivity or photophobia, and then kind of a basket term of blurred vision, just things are not clear. You know, when people have dry eye symptoms, they often, if you tell them, look, you have dry eye, they say, no, my eyes are just tearing all the time. They don't understand that the tearing is a reflex due to the surface being irregular. You know, tearing, of course, when you think about high volumes of lacrimation, it's really produced by the lacrimal gland up behind your eyebrow. You know, most of the surface of your eye is actually protected by tear film that is produced like within the conjunctival epithelium, some of the corneal epithelium, and, you know, some of the tear producing glands around your eyelashes. So if those systems start to break down, so the conjunctival epithelium is dried out or the eyelash, you know, the oil producing glands there are not working, then you'll get this, you know, big dumping of watery tears on your eye. So patients that, you know, complain like, well, my eyes are just watering all the time. That's really a symptom of dry eye more than anything else. Redness, you know, again, that can be from a number of causes, just any irritation on the conjunctival surface, corneal surface is going to result in dilation of those blood vessels, sometimes even broken blood vessels and all that sort of thing. Light sensitivity, you know, the, you know, it turns out that two thirds of the focusing power of your eye is just right on that front surface. And, you know, as soon as that front surface starts to get disrupted and it's no longer smooth, lights tend to be very bothersome. You'll get a lot of glare around lights, halos around lights, and can be, you know, make people very sun sensitive, that sort of thing. That's also a very common symptom that patients will notice in response to these medications. Here's a couple of clinical pictures. This is pulled from a paper that just came out last month talking about some of the ocular toxicity. This was actually co-authored by one of our former corneal fellows here. This is a patient who was on Tazotamab who developed this very terrible looking cornea, I would say. In terms of what we're looking at here, you know, the cornea would normally be clear. This kind of like extensive vascularity is a sign that the corneal epithelium is not being resurfaced as quickly as it should. And so what will happen is the conjunctival epithelium, which is a different structure, will start to grow over onto the cornea, which then pacifies it and causes extensive scarring. This can be very difficult to deal with. You know, this is a situation where possibly even surgery wouldn't be that helpful. It likely would be, but again, this can be very challenging. There's, this here is a frank epithelial defect. You can see a little fluorescein stain right in the center there where the epithelium is really, is really in poor shape. And again, this is a patient who was on Tazotamab for this. Again, I want to be clear that, again, I have done some consulting for immunogenesis. I'll take this with a grain of salt. I'm glad that Dr. Conecciani also mentioned this. The patients who are on Mervituximab get a somewhat different type of keratopathy. This is one of my patients actually who was in a clinical trial here on Merv and it's probably a little hard to see on the screen, but there's not any frank epithelial defects here, but there are these sort of epithelial inclusions. And this, I would say the same thing applies here where it's not exactly clear what is in these inclusions. But rather than the epithelial defects that can occur with some of these other medications in Merv in particular, the epithelium is a little irregular, but it's not missing. And so we really have not seen any patients on Merv that have developed like significant scarring or that sort of thing. One thing that we did notice in our patients is that these little inclusion cysts that show up on these corneas, one of their main effects is not what you might expect. It really changes patients' refractive error. So it tends to make them more farsighted actually. So they do actually often complain of the inability to read because when they could read before, now they cannot read. They need maybe several pairs of glasses or something like that to read. And it can be very frustrating for the patients because as these epithelial inclusions migrate across the cornea over every few days, it changes their refractive error on like a day-to-day basis. So we might see somebody on like day zero of their treatment with zero refractive error. And then we might see somebody day 10 or something like that, and their refractive error has shifted fairly dramatically. But then by day zero of cycle two, it'll be back down to something different. So it's this very kind of fluctuating blurred vision. I had one patient, for example, who was a pianist for her church. And she knew that on certain weeks of her cycles, she could play the piano. In certain weeks, she could not play the piano because she couldn't see the music. And that was really because her refractive error was fluctuating so dramatically. So the blurred vision with mirvotoximab appears to be a little bit different. In the papers that were already shown, you know, they kind of lump this together as keratopathy, meaning sure the corneal surface is not normal, but it's not really the same type of keratopathy as with Tizotimab, for example. So it's not that the epithelium is missing. It's sort of aberrant, but it's still there. And that, again, prevents these kind of long-term complications that we might otherwise run into. So in terms of the mitigation strategies, we talked about this just briefly. So cold packs, vasoconstrictors, lubricant drops, and then topical steroids. We're going to spend a few minutes talking about the topical steroids in particular. So with regards to the cold packs and the vasoconstrictors, I'm showing the same picture again here. You know, recall the cornea is one of these rare avascular structures in the eye. And so, you know, but the limbal stem cells are being regenerated in an area that's highly vascular. And so these strategies, my understanding is that they were put in place to reduce the amount of drug that's exposed in this location, again, by kind of restricting the blood flow to that area. You know, restricting these during the time of infusion by kind of reduce the payload there. So, you know, whether that is very effective, it's hard to say exactly. And it seems like it has helped some, but it also, if you look closely at the data, like in the MRF trials, for example, patients who were not given mitigation strategies had a trend towards doing worse than those who did, but it wasn't that statistically significant. So again, these mitigation strategies, I think will be something that is probably evolving, especially with the steroids, because there can be some significant comorbidities that come along with chronic use of topical steroids, depending on how many cycles patients have been treated with, that can become an issue. Lubricant drops, I would say, you know, that is probably the most straightforward and probably most effective thing that patients can really do. You know, when we think about lubricant drops, we just think about over-the-counter artificial tears, lots of different brand names. You know, if you go to your drug store, there's a huge section of them. You know, one thing that people might not be aware of is that there's maybe two broad categories of drops. There's ones that have preservatives in them. There's ones that do not have preservatives that are preservative-free. And when we really feel strongly about protecting somebody's surface, using a preservative-free artificial tear can be much more effective. With preserved tears, the preservative in those tears does tend to build up and it can, you know, if you're using them a lot, you know, let's say more than three to four times a day, we generally would recommend switching over to a preservative-free artificial tear. There's also things like gels and ointments. There's, you know, more, even more protective substances that can help. Those tend to blur vision a little more, so patients don't like them as much. But just, you know, getting people on a preservative-free artificial tear and telling them to use it frequently will go a big, long ways in the right direction to keep people more comfortable during those treatments. So in terms of the, you know, monitoring recommendations, there's different ones for different medications, but basically it's going to involve likely a baseline eye exam of some sort, especially, you know, I'm kind of thinking about this in two distinct categories. So in terms of the monitoring, you know, we're kind of thinking about direct drug effects, but then we're also thinking about monitoring of these mitigation strategies. And specifically, it's really the steroids that probably require monitoring. So for the baseline, you know, we're thinking about direct drug effects. You know, we're thinking about the corneal surface. And as I mentioned before, patients have already been on several cycles of chemotherapies often. They might have some underlying dry eye, some underlying surface issues. So kind of getting them in with an eye care provider, whether that's an ophthalmologist or an optometrist, you know, somebody who can really take a look at their corneal surface and say, you know, this, you really need to be careful here. Or, you know, if they haven't used artificial tears in the past, kind of go walk through that with them. And then as far as other things that we're looking for from a steroid monitoring standpoint, the eye pressure and then cataract monitoring is important. My experience with these patients in the clinical trial has been that they are very familiar with the idea of side effects from their chemotherapy regimens, whatever those have been. You know, they've been through a number of different things often. And so people are very aware that side effects can happen. And they're accepting of that as long as they are kind of given a heads up. And I think that's really key is in communicating with the patient to say, look, these are going to likely have, you know, ocular side effects, or at least possibly. And these are the things that we're going to do to watch out for that. But you really need to be aware that, you know, some of these steroid drops can have other side effects that go along with them. And it's just important to have that discussion up front. And then again, the monitoring recommendations with Vazutimab are every cycle. Mervituximab, they are still kind of in arguments about what that will look like. But likely will be something similar with, you know, fairly frequent eye exams. Again, the Mervituximab keratopathy that you see is a little different in that they develop this kind of very blurred vision. But it doesn't seem to cause any underlying scarring problems. So that might be less important to monitor over time. But that I think we'll see as time goes on. And then in terms of the monitoring recommendations, again, I really split this out into two categories. And those would be this first box here, direct drug effects. And these are the things that will become apparent within days to weeks of infusion. And patients will likely report them. So again, the dry eye symptoms, the redness, tearing, the blurred vision, those will all, you know, present to the oncologist who's treating them. The second box here, the mitigation monitoring is what I'm calling it, is again, the steroid effects. This is an area that is going to really require eye care providers who are aware of what to look for and kind of will be given a heads up about what their treatments are going to look like. And this will take weeks to months to become apparent. And so as far as the, you know, the steroids go, really a couple of things here. The eye pressure issue, I'm technically a glaucoma specialist, so this is near and dear to my heart, but just in all comers, this would be not restricted to cancer patients or anything like that, but steroids can lead to elevated eye pressure in probably 30 to 40% of patients. And it's somewhat unpredictable. It is dose dependent. So for example, patients that are on a low dose of steroid for a short amount of time will almost never develop high pressures, whereas patients who are on high dose steroids for long periods of time, and I'm referring to topical steroids here, most of them or a majority of them will develop eye pressure issues at some point. Now, the steroids that are used for topical treatment, there's at least four or five that are available on the market in any given time. So prednisolone or predforte is probably the most common one that's available. That is a topical steroid that has a fairly significant ocular penetration. And so one thing that we have talked about is whether it would make sense to use a topical steroid that has a more potent surface effect, but less penetration into the eye, which is where you run into problems with eye pressure and glaucoma. One thing about the steroid effect on eye pressure is reversible. Generally within a week or so of stopping a steroid, the eye pressure will come back down to normal. Probably the most tricky thing about this is it is undetectable by patients. They will not be aware if their pressures go up, they won't be aware of that happening. And they can develop permanent damage due to glaucoma. So this is where monitoring with an eye care professional, again, whether that's an ophthalmologist or an optometrist is really important. And I think having the eye care person be aware of what the expectations for their steroid regimen is going to look like is important just to make sure that everybody's on the same page about how much steroid and for how long. As far as the cataract thing, you know, this is more certain, I'd say, you know, if you're treated with a steroid regimen, let's say you're on it four times a day for a year or something like that, you will dissolve the cataract. It's not really a might kind of situation, but it is dependent on cumulative dose, length and frequency of treatment, still steroid specific, again, different amounts of ocular penetration for different steroids. So that is something to keep in mind. This, unfortunately, is not reversible. This is detectable by patients because they'll be aware that their vision is getting blurred. You know, on the upside, this is something that can be fixed with surgery. So as opposed to the glaucoma, which can result in permanent damage, it's not fixable. This can be fixed. I have operated on a number of these patients within the kind of confines of their clinical trials. It is kind of a hassle because you have to often hold their treatment for at least a cycle or so to get them through the surgery and then get back on, but they generally do well. So this is one of these things that, you know, again, it's a problem. The only patients that I had who were kind of irritated by this were patients that weren't really aware that this was a possibility. So again, I think communication is really key here. So what should we be telling the patients? You know, again, I think ocular side effects are common. There are these strategies to reduce the visual impact, but they also have their own issues and specifically the steroid one. And I think that's a question that is probably not completely answered yet, like what the correct risk benefit analysis of the steroid treatment is. You know, in some ways, ophthalmologists are like dermatologists, where if we see a problem, we'll just throw a steroid at it and see what happens. And so that I think kind of happened here in some ways. It's definitely helpful. But again, whether that offsets the risks, I'm not totally sure yet. Definitely symptoms cannot be ignored. You know, if patients are complaining of problems, they're going to need to be seeing somebody who's kind of familiar with these problems. And then I'd say in terms of talking to eye care providers, I would not assume that your local ophthalmologist or optometrist is going to be familiar with these medications. You know, again, they are, we are generally good about understanding side effects of systemic medications on the eye because it comes up all the time. So again, you know, developing that rapport with somebody who, you know, say, look, this is a, this is the plan for this patient. They're going to be on, you know, however many cycles, they're going to get steroid drops for a week around each cycle. You know, can we just screen them for dry eye symptoms, eye pressure problems, cataract problems, that sort of thing. And then in terms of the corneal checks, you know, they really need the corneal checks periodically. That is fairly dependent on symptoms, I would say. In the absence of symptoms, patients really aren't going to probably have a significant problem. There have been other medications in this same class that are not FDA approved that have shown, you know, significant corneal scarring in the absence of symptoms, but that I think is unusual. But again, getting on a regular monitoring schedule is important. And then MIRV in particular, it has an unusual profile to the blurred vision because they developed this refractive change where again, their glasses prescription just shifts around a lot. So these patients might show up with vision of 2200 or something, but if you change their glasses prescription, you can get it right back down to 2020. But again, that glasses prescription is not stable, so we don't normally prescribe it. But that's, that's something that was a new, that was a new side effect to me, certainly something that probably the average eye care provider is not going to be aware of. So in conclusion, you know, these, these new class of medications definitely have significant ocular side effects. It's going to be important to coordinate with somebody who can really help out and provide that monitoring. Pre-existing conditions that need to be looked at, dry eye, again, a lot of patients will already have some of those symptoms just from their prior treatments. And then again, these other things are really monitoring of the, of the steroid drops, so the glaucoma, elevated eye pressure and cataracts. And again, these symptoms generally manageable. I think, you know, when I talk to these patients, I tell them, look, this is a hassle. Patients hate having blurred vision, but they know they have a bad problem. And it's, you know, I tell them, look, this, this is not causing permanent damage. You know, we know that when you stop these medications, your vision is going to return to normal. You know, if you can hang with us, we'll, you know, we'll work with you and figure something out. But it's definitely important to have that communication up front. So that's the end of my slideshow. So I think we'll probably do a little bit of Q&A and I'll kind of turn back over to Dr. Beckes. This is really, really a great two talks. Great on to hear the background and some of the concerns that all of us have. And I certainly feel much more comfortable with understanding this now after your talk. So thank you for that. We do have a couple of questions in the, in the chat. And so it from, as I understand it, so the side effects with the Tysotemab Fidodensis Morda Conjunctivitis, which we as providers would be able to easier recognize, is that a correct understanding with the red eye and, and discomfort. Then the side effects that we see, for example, with the Mervitoximab with the ocular cyst. Well, that's, that's being described conjunctivitis as such as not being described for Mervitoximab. And I, I don't know, is it because tissue factors expressed in the conjunctiva? I think we don't know, you know, whether the target proteins are differentially expressed. And it's clearly not a symptom. I think for Mervitoximab, particularly these punctuate inclusion cysts are key. And those are not described in the same way in the Tysotemab Vendotin. So I think getting to standardized ocular toxicity language is also important because sometimes you get reports from outside ophthalmologists, words are thrown around like keratitis, dry eye, blepharitis, et cetera, conjunctivitis. I think standardization would help in comparing ADCs against each other. And I think my experience has been, there are big differences between ADCs. Clearly, some have minimal eye toxicity, some have higher rates of more moderate eye toxicity. Yeah, I would say that's, I mean, that's a fair, that's a fair statement. I think part of the issue with, within a clinical trial, you know, you operate with certain verbiage that's given to you. So, you know, whether it says keratitis or keratopia, I mean, what's, you know, what does that mean exactly? And so, you know, we get put in this position where you're sort of like, well, there's something wrong with the cornea. We're just not sure what it is. But I think, you know, your question was sort of about whether you might more easily recognize the conjunctivitis versus the keratitis. I think that's fair. I mean, if their eyes turn beet red while you're doing the infusion, then you know, you know, you've got a problem on your hands. But, you know, the patients will probably complain of both things. The MIRV toxicity is very unusual. I had never seen anything quite like it. And again, patients would present with blurred vision. I think one of the tricky things about that specific finding is you really have to look closely to see it. And again, the picture I showed was probably the best picture I have, but it's still not very easy to see. You know, again, we've tried to describe it a little bit as, you know, only viewable when you like retro-illuminate the eye. You can see it in a certain pattern, but it's not very obvious. But then again, you just get these wild shifts in people's vision. But, you know, that tends to be kind of more annoying than problematic, I would say. Patients can usually kind of deal with that. Again, with the conjunctivitis, you know, the ones that I've seen, you know, tend to respond pretty quickly to, you know, fairly mild topical steroids. And, you know, we often will switch classes of steroids. So instead of the prednisolone, we'll put on like flormethylone or dexamethasone, something that has much less ocular penetration. And that can be very helpful as well just to treat the surface more aggressively, but then you're not dealing with all the intraocular effects of the steroid. Right, and I think that answers one of the questions in the chat also. Which one, which ocular steroid would you use and recommend here instead of prednisolone because of that? Yeah, there's probably two medications. Well, there's probably two medications that are at least as potent on the surface. So Lodamax or Lodaprednol is one, and then flormethylone or FML. Flormethylone is very cheap. Lodamax is not cheap, but they both are fairly potent on the topical side, but they don't penetrate the eye nearly as much as like prednisolone. In some of these clinical trials, I speak more to the MIRV trial, because I have more information on that. But, you know, they also put people on Durazol or Difluprednate, which is probably four to six times more potent than the prednisolone even. And that has very high ocular penetration. So you end up with, it can work really well for the surface, but then you end up with really kind of bad ocular side effects. So I wonder if, you know, going forward, we won't switch more to these kind of surface specific topical steroids. Lawrence, you know, I don't want to end off on a note that the audience has the impression that this is, you know, a huge problem. I feel reminded a little bit about toxicity discussions with neutropenia. Oh, wow. You have grade one neutropenia. You have grade two neutropenia. No one cares about frequent mild toxicities. And because it's the eye, it's a new area for us. And that is an organ of certain sensitivity. And I think we have to address an issue of how do we, you know, communicate toxicities with patients that involve the eye. That's very different. And if you don't do this correctly, you create anxiety towards, and hesitancy towards using a drug that has incredible activity and a phenomenal safety profile. The ADCs are drugs you can give chronically over 12 months without seeing any of the chemotherapy related side effects. And we have to be careful that we're not moving the eye toxicity discussion out of proportion. Again, if you look at the data, the majority were mild. There was also a question, you know, about dose delays. Most of the eye toxicities and inclusion cysts were reversible just over time. They were observed, but redosing, I mean, we saw the, you know, the epithelial, how quickly it recycles. After three days or seven days, you have a completely new cornea. So I think it's important really to be cognizant that these pictures we saw today are the absolute exceptions. And I think the mitigation strategies that we developed are very proactive and they're very important to do. But having used a lot of ADCs, I think I'm always worried a little bit about messaging the right way to patients that this is a huge advantage and access to a new effective treatment with very, very manageable toxicity. Yeah, I think you're absolutely right. The agents are very active and the side effect profile is definitely, the side effects are low risk for severe toxicity. So I think this lecture is very helpful to get us more comfortable. And I think to reassure providers that we can manage these so we can manage these drugs. So in your opinion, do you think it's more important to, is our dose reductions really so important or just doing the preventative care and making sure that these patients get their steroid drops and get monitoring? Yeah. I mean, Mark pointed out, we don't really know. There's no high level evidence of does it help or doesn't help. I mean, the Mervitux, the early studies, Katie Moore did introduce the prophylactic measures and saw a slightly lower incidence of these. So I think until we know better, we should use them, but clearly dose reduction, dose delays resolve the Mervitux toxicities that you see that are those that are grade two or higher. So, and again, what is a dose reduction? You go down from six milligram to five or four milligram with a second dose reduction per kilogram or delay for a week. We do that all the time. I mean, and you have resolution of some of these toxicities in the majority of cases. So clearly it's manageable. And personally, the patients I have treated, I've not taken a single patient off drug because of ocular toxicity. Absolutely. And lastly, as we're getting a little short on time here, how do both of you feel about working together with your eye care provider and how do you prepare to set up a network of experts around you so that you can make sure you can safely give the agents and monitor? Well, I think it's great that you have your own institutions, ophthalmologists on this call, because I think building that relationship with your eye care doctors is key and it's not always easy to get someone to see patients quickly considering that, you know, these clinics are getting busier and busier. So I think getting together and working with ophthalmology and creating some contact person that is, I think, interested in particularly focusing on these toxicities is helpful. Yeah, I mean, no question, it'd be hard to find somebody everywhere that will be willing to do that quickly, but it's not particularly challenging. I mean, this is again, not some terrible toxicity that we're completely unable to deal with. You know, these are all sort of routine kind of surface of the eye complaints that we're accustomed to dealing with from many different things. So again, I think just the education, just saying, look, this is a new class of medications that has this. And, you know, there's the companies are also developing literature around, you know, just how this should be screened and that sort of thing. So I think it's, you know, it's all a work in progress, but again, just developing a relationship with somebody who can help you out on a short-term notice would be important if that's possible. I also think messaging to patients is important. So if I talk to a patient who I offer a clinical trial, you know, I extensively discuss eye toxicities, but I, you know, I don't necessarily approach them to say that there is a risk of a severe keratopathy or cataracts. I do counsel them that regular eye exams are necessary, that blurred vision is very likely, but the reversibility of these things is key because it's interesting if you talk about hematologic toxicities or neuropathy or things like that, there is a much higher threshold of anxiety if you talk about eye issues and the ability to change in visual acuity or vision. So I think developing a sensitivity in counseling patients that there's no unnecessary anxiety, you know, and that seeing an ophthalmologist either at baseline, I mean, we don't send them to an ophthalmologist at every treatment cycle, it's baseline, and then the clinician monitors eye symptoms. So do you have blurry vision or do you have change in your visual acuity? And that leads us with myrvituximab. With tesotumab, it's different. There it's recommended to see an eye doctor every visit, but sort of taking the anxiety from that, that there is an impending risk that something bad is going to happen, you know, I think that's key. Yeah. No, I think it's great as our patients get more informed, but really weighing those risks and benefits. And with the benefits being so great, I think we're very fortunate that we have these agents that we can use. And as we use them more, we'll all get more comfortable with it too. Unfortunately, that's all the time that we have for today. And I would really like to thank Dr. Konechny and Dr. Saba for their time, their insight and expertise. And thank you to Immunogen and Cigen for supporting this webinar. I would all like to thank everybody for attending and the recording of today's session will be available in the IGCS members education portal by the end of the week. Please also join our IGCS in New York City for the annual global meeting, which will be September 29th through October 1st. And this is in New York and visit IGCS 2022 for more information. We wish you all safety and health and please, we will see you hopefully in New York. Thank you. Bye.

ocular toxicity

ADCs

gynecologic oncology

mechanism of action

conjunctivitis

keratopathy

blurred vision

mitigation strategies

monitoring

healthcare professionals