Anatomy and physiology of the cornea; intersection of ophthalmology and oncology for patients receiving antibody-drug conjugates (ADCs)

DR LOVE: Welcome to Inside the Issue: Ocular Toxicities with Antibody-Drug Conjugates and Other Cancer Therapies. This is medical oncologist Dr Neil Love.

This program is a follow-up to a recent webinar we conducted with ophthalmologist and cornea specialist Dr Neel Pasricha from the University of California, San Francisco, along with other faculty, and because the concepts we were presenting were new and challenging to process, shortly after the webinar I met with Dr Pasricha for a follow-up one-on-one interview to further explore this fascinating topic.

During the program the use of agents and treatments that are not approved will be discussed, so please check out the package inserts for more, and the conflict-of-interest statements for the faculty can be found in the program notes.

To begin, I asked Dr Pasricha to provide a general overview of the anatomy of the eye, with a special focus on the cornea.

DR PASRICHA: The cornea is the very front-most part of the eye, so it’s the clear, transparent portion. It’s about 500 microns thick, so really, really thin tissue, and it’s completely avascular, so there’s no blood vessels. And it’s kind of in a special state that way, except at what we call the limbus, and that’s important for this antibody-drug conjugate corneal toxicity issues.

So the limbus means the very periphery of the cornea, where that clear cornea meets the blood vessels and the white part of the eye, the conjunctivae and sclerae, and so that’s the only area where the blood vessels are interacting with the cornea. And that’s how we think these antibody-drug conjugates are causing their corneal toxicity, is they’re administered intravenously, they make their way systemically throughout the body, and then they interface with the cornea at that limbus region, the part of the cornea that interacts with those blood vessels.

And as a cornea specialist I deal with both the medical and surgical issues that can arise with the cornea. So for example, dry eye is a big umbrella term. It kind of encompasses any issue that’s affecting the surface of the eye and causing that dry sensation, so I deal with that quite a bit on the medical site. We also have other issues, like Stevens-Johnson syndrome and things that can affect the cornea that way. And then on the surgical side corneal transplantation, procedures like corneal crosslinking for diseases where the cornea starts to become more a mountain shape instead of a hill shape. And then I also do cataract surgery, and the cataract is a different part of the eye. That’s the inside portion where the lens of the eye is, and we get older we all develop cataracts, where our lens becomes cloudy and more thicker, and so we do cataract surgery to remove that and replace it with a lens implant.

So that’s kind of my main medical and surgical focus, is corneal transplantation and cataract surgery on surgery side, and then medical diseases that can affect the cornea and ocular surface.

DR LOVE: And how have you interacted with the oncology team there at UCSF, and what are some of the types of situations you encounter as you see oncology patients?

DR PASRICHA: Yeah. The story of how I got involved specifically with antibody-drug conjugates is interesting. I was very interested in dry eye drug discovery. So I’m a clinician scientist, and half my time is in the medical and surgical side, like we talked about, but the other half of the time I’m in the lab doing different experiments and things.

And early on when I came back to UCSF I was very interested in looking at ion transporters on the epithelium, the surface layer of the cornea, and I was at a friend’s wedding, one of my co-interns, who was going into breast surgery. And I was sitting next to Laura Esserman, the head of the UCSF Breast Cancer Center, and she was telling me, hey, I have these patients who are having corneal issues, do you know any corneal specialists who’d be interested in looking at the corneal epithelium for these patients. And I said that sounds interesting, I’ll take a look.

And at that point I had heard of belantamab mafodotin and the corneal toxicity it had caused, but I wasn’t too familiar with the area. This was about 2 1/2 years ago. And from that moment onwards that really is what got me involved with the oncology clinic, seeing patients who were enrolled in these clinical trials specifically for antibody-drug conjugates but also now for various different treatments, monoclonal antibodies, or even just chemotherapies. They can cause a huge spectrum of ocular issues, and a lot of them tend to be on the ocular surface, the cornea and the conjunctivae.

Association of corneal toxicities with ADCs

DR LOVE: Can you talk a little bit more about your research and your work looking into why you see these corneal toxicities with ADCS and the variation that you see in different ADCs and why you think there is variation?

DR PASRICHA: Yeah. It’s a great question, and it really seems like a lot of ADCs are having this problem. I think that’s the first thing to kind of talk about. And it’s about 50% or so of ADCs will have some degree of corneal toxicity. Now that doesn’t mean it’s the number 1 adverse event for all of them, but for example belantamab mafodotin, it is the number 1 adverse event in that case, and it affects upwards of 75% or more of the patients who are on the therapy.

And what we’re seeing is that it’s an off-target toxicity, and so it’s not like the antibody is binding to something on the corneal epithelium and being internalized, it’s something about the corneal epithelium and specifically that limbus area where the cornea is interfacing with the blood vessels, that tends to have the toxicity where these corneal cells are uptaking the ADC nonspecifically. And the process we think is happening is called macropinocytosis, which just means that the corneal epithelium cell membrane is kind of remodeling and internalizing the whole ADC.

And so in 2018 there was a lab group that published a paper, Zao et al, that kind of showed that for the first time. And so our research has taken that to the next level and seeing is it truly macropinocytosis for various ADCs, does it seem like that’s the mechanism for all the ones that cause this problem, and how can we use different drugs to maybe block that process and help treat this issue or prevent this issue.

DR LOVE: One term you see a lot is pseudocysts.

DR PASRICHA: Yeah.

DR LOVE: How would you define that?

DR PASRICHA: Yeah. It’s gone by the name corneal pseudomicrocysts, or you might see microcyst-like epithelial changes. And basically it just is the epithelial cell, the corneal epithelial cell, has apoptosed, has died, and it’s kind of formed this cytoplasmic vacuole. And that’s why they call it a “pseudocyst”, because it’s not actually a cyst. It’s the dead corneal epithelial cell that has the swollen-up cytoplasm.

DR LOVE: Now is the thinking that the chemotherapy payload is what’s actually doing the damage, and do you see this phenomena with just systemic chemotherapy?

DR PASRICHA: This is a very specific toxicity from ADCs, and so we don’t see this kind of corneal pseudomicrocyst problem with any of the other forms of chemotherapy. So for example with the monoclonal antibodies, and with just plain chemotherapies we’re not seeing this. Something about the ADC specifically is causing these pseudomicrocysts. And it’s interesting because there are — we do think that the payload portion of the ADC is what’s ultimately killing the corneal epithelial cell, but you don’t see this problem with just chemotherapies in general.

DR LOVE: Well, and you’re also saying you don’t see it with all ADCs, so is it the linker?

DR PASRICHA: Right. Yeah. We don’t think it’s the antibody, the target of the antibody. We don’t think it’s 1 type of linker. There is some thought that maybe the more stable linkers would allow the ADC to come as a whole intact ADC and be internalized, and the more unstable linkers would break off that payload portion early and not have this problem, but we see it with both stable linkers and unstable. And it was previously thought that it’s 1 type of payload, like the microtubule inhibitors, so MMAF, MMAE, the auristatin class of payloads, but we’re seeing it with the nonauristatins as well. So it’s really — I wish there was a way we could just pinpoint and say it’s this one component of the ADC, but it doesn’t seem like it’s that simple of an answer.

Dose and schedule modifications to mitigate ocular toxicities associated with belantamab mafodotin and other ADCs

DR LOVE: So before we kind of get into the variations that you see in different ADCs, I don’t know, I have a way of sometimes trying to make analogies, and sometimes they work, and sometimes they didn’t work. I don’t know if you remember, during the webinar I was saying that it kind of reminds me a little bit of neutropenia as a toxicity of chemotherapy in that in general most systemic chemotherapies, not all of them, do cause neutropenia. A lot of them do. You always are kind of looking for it.

DR PASRICHA: Right.

DR LOVE: Some you see more than others. Very sensitive to dose reduction and also a change in the schedule. Is that kind of the way you look at it? And ultimately, in most situations, can you modify the dose and schedule to make this clinically tolerable, or are there situations where you just can’t do that?

DR PASRICHA: I think it’s a great analogy because you’re absolutely right. Just like in neutropenia’s case, for ADC corneal toxicity if you dose delay or dose reduce most of the time that can help solve the issue. So one of the biggest things we’re seeing, for example with belantamab mafodotin, is there really is a component of concentration of drug over time being one of the most important factors for patients developing the toxicity.

And so if you look at even belantamab mafodotin with a dosing schedule of every 3-4 weeks a very high percentage of patients will develop corneal toxicity. If you just space that dosing out, keep the exact same concentration of the dose, but you just space it out, really can significantly reduce the incidence of corneal toxicity. So what they call that AUC (area under curve), that AUC TAU, concentration over time of the ADC, really seems to be a big driving force for the toxicity.

And it’s reversible, so if you dose reduce or dose delay these patients will get complete healing of their cornea. The issue is even though the corneal epithelium turns over every 7-14 days the toxicity can last for many months. So we’re seeing patients who sometimes it’s 6-plus months, but they do get better ultimately. They don’t have permanent corneal damage, at least not what we’ve seen so far.

DR LOVE: And it’s interesting. I’m looking right now at the results of a survey, and we asked 6 investigators a whole bunch of questions, and one of them was if belantamab mafodotin were to become available again do you think that avoiding significant morbidity without the ophthalmic toxicity can be achieved by modifying dose and schedule of administration. And we have 6 of the top people in myeloma in the world, and every single one of them answers yes.

DR PASRICHA: Wow.

DR LOVE: And of course, I guess that was a big frustration with the FDA, that — and I understand the FDA’s position, but still you see that people feel comfortable really doing that.

So thinking about this model, it looks to me — indirectly it seems like ocular issues are much less of an issue with dato than they are with belantamab, but I guess that’s a combination of (a) the inherent ocular toxicity of the Dato-DXd molecule versus belantamab, but also dose and schedule. So maybe if you gave more dato maybe you would see more of this but still not as much as belantamab. And again, thinking back to neutropenia, there’s so many factors that go into that; their prior chemotherapy, did the marrow get beat up, but you’re still thinking about the same phenomena.

And we’ll talk about clinically particularly with dato. I mean everybody’s asking me what do we do and all.

DR PASRICHA: Yeah.

DR LOVE: We’ll get into the specifics. But you think the conceptual model applies to at least these 2 ADCs and a bunch of others?

DR PASRICHA: I definitely think so. I think you’re hitting the nail on the head. If you look at the dosing schedules for a lot of these, I think that’s the main driving force. And right now the main issue that we’re having is, unlike neutropenia and other various forms of adverse events, we don’t have a great preventative treatment. So it’s not like you can say you can dose the ADC more frequently, just use this special eye drop, and it’s not going to be a problem. We don’t have that yet. We’re working on it, and hopefully we’ll have that soon, but for now our biggest thing is we have to look at how can we dose the ADC to get the best objective response for the cancer therapy but also minimize the adverse events.

And the panel we did with belantamab mafodotin and dato, it was such good timing, right, because the FDA ODAC had just released their statement, and I think it was — it’s on a lot of people’s minds right now, is how can we safely give these ADCs, especially ones like belantamab mafodotin that really are very effective for their target but minimize all the adverse event problems that we’re having.

So I think we’re going to hopefully get better and better at this, and I think you made a really good point that oncologists are also going to start to become more comfortable with the ocular adverse events. Right now anything eye related kind of feels like a black box sometimes, I think, to some oncologists, and they say this is happening, go to an ophthalmologist or go to an optometrist, and I’m not sure exactly what is going on. I think people are going to get more and more comfortable dealing with this. I hope.

DR LOVE: No, for sure. I thought our faculty was kind of keeping their eyes open the whole time while you were talking.

Spectrum and severity of corneal toxicities associated with datopotamab deruxtecan

DR LOVE: Can Dato-DXd actually cause pseudomicrocysts, this phenomena that you’re talking about? You’ve seen that yourself?

DR PASRICHA: It can. It can, but it’s not one of the ones that causes it to a very significant degree. So if you look at their data that they’ve published on it they do show a pretty high corneal toxicity rate at something around 50%. But if you look at the severity of it, it’s very mild for the most part. And that’s been also my anecdotal experience, as well, is that Dato-DXd tends to be pretty mild corneal toxicity, and you do get those corneal pseudomicrocysts, but a lot of the visual complaints and the eye pain and blurry vision complaints are much, much lower than compared to other ADCs, like belantamab mafodotin or mirvetuximab soravtansine. And so I think it’s the same underlying mechanism, just a less severe version.

DR LOVE: And you mentioned 50%. Of course most of those, as you say, are Grade 1, asymptomatic. The package insert says 36%. There are other numbers I’ve seen in the 40%, but I guess all in the same range and all mostly Grade 1.

But it also gets into prevention and diagnosis of this issue. I did a video yesterday, believe it or not, with a very prominent breast cancer investigator, and one of the things we got into was Dato-DXd. And I said do you usually send the patient to an optometrist or ophthalmologist before you get started, because it’s right here in the package insert, and he said no.

DR PASRICHA: Yeah.

DR LOVE: He said well, it’s not a big deal. Some of these people get dry eyes, and you give them a little — drops. And so first of all, do you think it’s worthwhile or important to get a baseline ophthalmologic exam in all people starting ADCs or people who are getting an ADC that’s been associated with microcysts?

DR PASRICHA: It’s a great question, and I think, in my opinion as a corneal specialist, I don’t think all ADCs need to have mandated baseline eye exams, and there’s a couple reasons why. One is just getting that baseline eye exam, it might seem like from an FDA perspective maybe easy and kind of nice to do, but it’s actually logistically not so easy for a lot of places, right? Getting an optometrist or ophthalmologist appointment scheduled, in addition to all their lab work and imaging and other tests that they need sometimes can be the bottleneck for them to actually get their treatment.

And so I think for drugs like Dato-DXd my opinion is it’s probably not necessary. But then drugs like belantamab mafodotin or mirvetuximab soravtansine, where it is their number 1 adverse event, and it can be pretty visually and symptomatically significant for these patients, then in those cases I do think having that baseline eye exam is helpful because then you’re better able to figure out how to dose adjust if and when they develop the corneal toxicity, because you have that baseline.

Role of optometrists and ophthalmologists in screening for and management of ocular toxicities

DR LOVE: And we also got into this issue of optometrist versus ophthalmologist, and also whether most optometrists or ophthalmologists are actually going to be ready to do an appropriate exam and consultation on these patients. How much of a need is there in that community for more education?

DR PASRICHA: There’s a lot of need. I think just like in the oncology space, where it’s people are kind of learning about it, and it’s becoming a hotter topic, the same thing is happening on the ophthalmology and optometry side. So we have our big annual meeting called American Academy of Ophthalmology coming up in October, and we actually have a whole session on these ocular toxicities from oncology drugs, because it’s becoming a bigger and bigger problem that we’re facing. And you’re right that a lot of times even corneal specialists might not be familiar with what corneal changes are happening, and it’s hard to keep up because these ADCs keep getting approved, and you have to kind of stay up to date to know which are the ones that have this problem and which are the ones that maybe it’s not so much of an issue.

DR LOVE: So you also talked about the idea that optometrists can screen patients, they’re much easier to access, and also everyone was fascinated by your in-clinic 20-minute evaluation. Of course maybe it’s different in a center like you have, where you have a lot of patients concentrated with breast cancer or whatever. But can you talk a little bit about the essentials and how you can theoretically, with an ophthalmologist theoretically get it done in 20 minutes maybe in the clinic?

DR PASRICHA: Yeah. I think that is something we’re really excited about doing. Because these ADCs, when they’re getting prescribed, and they need a baseline eye exam, we really don’t want the baseline eye exam screening to be what holds that patient up from getting the therapy. And so even at UCSF, where the Breast Cancer Center is directly across the street from the eye center, we were still having delays of getting patients over, and it was kind of a hassle. They would come in, they have to check in, wait a couple hours. The clinics are running behind. In total it’s about a 4-6-hour ordeal for this patient just to be told hey, this is your normal baseline eye exam.

So what we did is we just did 3 different things that we brought to the oncology clinic. We brought a simple pinhole occluder, and so that kind of estimates what is their best spectacle-corrected visual acuity, but does it in a really fast way. You just put a tiny little pinhole in front of the eye, and you have a vision chart on the wall, you have tape on the floor to say how far away to stand, and you just have the patient do 1 eye at a time pinhole visual acuity. And that gives a really good estimation, again, if they were to have the best possible pair of glasses what would their vision be.

Then we have a simple device that checks their intraocular pressure, and they don’t need any numbing eye drops or anything like that. It’s a handheld device. And then the final one we had was an imaging device that images the front part of the eye and then also can image the retina, the back of the eye, without requiring dilation drops.

And so in total that whole exam takes about maybe 15-20 minutes, and we do it right in the oncology clinic, and patients are able to do it basically in the waiting room while they waiting to have their oncology visit or other test done. And it’s been great so far because you just have all that data go to the cloud securely and HIPAA compliantly, and then it can be reviewed that same evening by the ophthalmologist, like myself, and just kind of get them expeditiously screened for these ADCs.

DR LOVE: Is the idea to try to — maybe this is different with different ADCs, to try to pick this up before they develop — the patient develops symptoms? And what type of symptoms will a patient develop? And theoretically if things continue to get worse, and they’re treated, and maybe they’re not being monitored, what are some of the complications you can see?

DR PASRICHA: Yeah. I think right now, just to make sure we have good data for this, we’re just doing the baseline eye exam. So most of them are completely normal, just saying hey, you have normal eyes, this is your baseline exam. What you just said though is kind of what we envision, is that this could be used as a point of care test for when they come in for cycle 2 or 3 or 4, et cetera, for their ADC infusions. They can say hey, I’m having — blurry vision that I’m noticing or my eyes are hurting, and then we say hey, you can have this screen done here in the oncology clinic. If it’s abnormal and detecting a difference from your baseline we’re going to schedule you an in-person eye exam.

Because that’s what patients really care about, right, is the blurry vision and the eye pain. And those are the 2 main symptoms that they develop. And if they develop them it’s kind of a little late to start treating at that stage, but it’s better than doing these hey, come at cycle 4 arbitrarily for an eye exam. It’s much better to kind of have them tell the oncologist or tell the nurse hey, I’m having some symptoms, my vision’s getting a little blurry, my eyes are starting to feel a little dry, and then get them screened early so that that dose delay or dose reduction can happen in a timely fashion.

DR LOVE: What’s the final endpoint? I think it’s Grade 3, ulceration?

DR PASRICHA: Yeah. If you were to — for some of these ADCs if you were to just not dose reduce, not dose delay, eventually what they develop is a complete epithelial defect. So it’s not just kind of spotty dryness that happens, it’s actually almost like a scratch on the epithelium, and then they become very high risk for infections, what we call a corneal ulcer, so they start to lose some of the corneal tissue thickness. And in the worst case, if you don’t treat that, it can become a corneal perforation, which means a hole has developed in the cornea, and that’s a surgical emergency.

So thankfully it’s extremely rare for the ADC corneal toxicity to develop to that corneal perforation stage, but we have seen some corneal ulcerations and certainly some corneal epithelial defects develop from ADCs. So it is something that for certain ADCs you have to make sure you have some type of monitoring, whether it’s a screening program or a questionnaire, something that’s happening to make sure patients aren’t developing that.

Other ocular toxicities associated with cancer therapies

DR LOVE: What other ocular toxicities, if any, do you see with ADCs?

DR PASRICHA: One of the ones that we’re seeing that’s interesting, and it might be a completely different mechanism, is we’re seeing some conjunctival scarring that can happen. So the example that comes to mind is tisotumab vedotin for cervical cancer. That one does have the corneal toxicity issue, the one we were just chatting about with the corneal pseudomicrocysts. But in addition to that the patients can also develop conjunctival scarring, and it can be pretty advanced in some cases, where they’re getting to the point of having what we call symblepharon, the eyelid is getting stuck to the ocular surface. And that we think is more of an on-target issue because tisotumab vedotin targets tissue factor, and that’s heavily expressed in the conjunctivae, and so that might be a completely different mechanism than the corneal toxicity problem.

And so for that one, same idea. You definitely want to dose reduce, dose delay and ideally catch it very early because you don’t want to have those sometimes-irreversible changes happen.

DR LOVE: So I’m also curious what other types of ocular toxicity you see in general in oncology, or ocular phenomena. When we were doing the webinar somebody in the chat room asked about photopsia with the SERD camizestrant because that was just a huge presentation, it’s not even approved yet, that was used, a big paper at ASCO in breast cancer. I think I only saw photopsia listed with this particular oral SERD. I’m not sure why. There are several other oral SERDs. But what is photopsia, and is there anything you can do to prevent or manage it?

DR PASRICHA: Yeah. That’s becoming a hot topic, too, for us, the camizestrant photopsia. And I think that one has several issues. So first of all it’s about 15% of so of patients on cami are getting these photopsias, which just means flashes of lights in their vision. And from an ophthalmology and optometry standpoint when you hear photopsia, flashes of lights, the number 1 thing you worry about is is there a retinal detachment or retinal tear, some type of retinal issue going on.

The good news for cami is that they’ve done a lot of studies, even in animal models and such, and it doesn’t seem to have any actual retinal pathology that’s happening. They’re just for some reason developing these photopsias. And we don’t know exactly why it’s happening, but it’s happening in some patients. And so these patients are getting full dilated eye exams and kind of making sure there’s no retinal tear or retinal pathology, and nothing’s been detected so far.

So in terms of how do we prevent it there’s not a great answer for cami, but at least we know that it’s not to our knowledge causing a real treatable retinal pathology, retinal issue. But I think what’s going to be really important for that, for cami’s rollout, is we’re going to need to do a very good job of educating both the oncology side and the ophthalmology/optometry side. Because otherwise it’s going to lead to a lot of these kind of emergency “hey, you must see an ophthalmologist immediately” and ideally a retinal specialist immediately for these patients and cause a lot of alarm for the patients and the providers. So definitely the education component will be big for that one.

DR LOVE: So I don’t know. Again, things just pop into my head. When I first heard about photopsia one of the things that came into my mind, and maybe it’s completely different, and I don’t even know whether you’ve seen this, because this drug’s not used too much anymore, it used to be used a lot more, crizotinib. They have these stories of patients having, I don’t know, hallucinogenic things. Do you know anything about that?

DR PASRICHA: Yeah. I don’t know too much about it, but I know that there’s so many different drugs that are causing different visual disturbances and such. The one that we do see quite a bit of are the MEK inhibitors causing retinal pathologies.

DR LOVE: Right.

DR PASRICHA: And so that is definitely something where a retinal specialists and our optometrists and ophthalmologists were seeing a lot of patients who have the retinal fluid that’s developing. The good news for those, as well, is that that is also reversible, and it’s not something where it’s a permanent problem. And then we’re seeing different levels of the MAPK pathway. When you inhibit those different levels they tend to have different rates of the retinal pathology that’s developing. So the further downstream you are in the MAPK pathway the more severe the retinal pathology is.

DR LOVE: I don’t know if it’s related, probably not, but what about FGFR inhibitors like erdafitinib and central serous retinopathy?

DR PASRICHA: Yeah. That’s definitely one of the ones that can cause it. That’s a little bit kind of higher up on the pathway. And so I myself am not an expert in the pathway, but I am cheating right now, and I have the slide pulled up that I made for the panel, and that one kind of talks about the MAP kinase pathway. So it goes FGFR, BRAF, MEK, ERK, and if you get to the FGFR level that tends to be less severe retinopathy. But if you go down to the ERK level that tends to be the more severe retinal pathology. And then interestingly BRAF, which is kind of the second in line, has more of a uveitis, an intraocular inflammation, than it does retinal pathology. So it kind of breaks the MAPK pathway retinal pathology ladder.

DR LOVE: So just trying to bring in all of the situations, particularly ADCs, where you hear about ocular toxicities. Of course another major one is mirvetuximab soravtansine. Can you talk about what happens there?

DR PASRICHA: Yeah. Mirvetuximab soravtansine, very similar to belantamab mafodotin in the way that it causes the corneal toxicity. And what they’ve actually really, really nicely shown, both in their patient data, but also in rabbit models, is that the ADC corneal toxicity that happens from mirvetuximab soravtansine is definitely concentration and dose dependent. That AUC TAU idea, the concentration over time, just this year they had a nice paper that was published that showed the ovarian cancer objective response rate was better with the higher AUC TAU, the higher concentrations over time. But then on that same graph they also plotted the incidence of ocular adverse events, which in this case is the corneal toxicity, and it almost identically followed the objective ovarian cancer response rate. So both the ocular toxicity, which is the corneal toxicity, and the ovarian cancer got better with the higher — or were higher with the AUC TAUs that were higher.

And then they’ve shown in the rabbit model several really interesting points. One is that when they attach a radiolabel to mirvetuximab soravtansine, and they administer it into rabbits intravenously and harvest the ocular tissues at various timepoints over 14 days, what they found is that all the ocular tissues except for the corneal epithelium show a very kind of normal tissue distribution, where the concentration initially gets very high in the tissue, and then over a few days to about a week the concentration goes back down to normal. Whereas in the corneal epithelium that concentration spikes and then just plateaus, and it stays at a really high level for about — for at least 14 days that they’ve collected the tissues. And so something about the corneal epithelium is sequestering and holding onto that ADC.

DR LOVE: So I believe right now there are 3 ADCs with black box warnings for ocular toxicity, tisotumab vedotin that you mentioned, and mirvetuximab, and I think belantamab even though it’s not approved. Am I right?

DR PASRICHA: Correct. That’s correct.

DR LOVE: And from your point of view, when you think about those 3, because before we were contrasting belantamab and dato, but are those 3, tisotumab, mirvetuximab and belantamab the 3 where you kind of are seeing the most problems? And then for the other ones more like dato where you don’t see so much problems?

DR PASRICHA: That’s right. As far as the approved ADCs go it’s definitely belantamab mafodotin, which is currently not on market, and mirvetuximab soravtansine that are very, very similar in the corneal toxicity they’re causing. Tisotumab vedotin does have the corneal toxicity issue, but like we mentioned it also has that conjunctival toxicity issue, which might be more on target. And then the other ADCs that are approved, like dato, they can have it but to a much milder form.

What we’re actually seeing a lot of, at least UCSF, is we’re seeing a lot of these Phase I/Phase II ADCs that are having, like belantamab mafodotin and mirvetuximab soravtansine, really high rates of corneal toxicity and sometimes even much more severe. So there are some where they come to me, and they’re part of a Phase I escalation study, and they already have an epithelial defect by the time they’ve seen me, and they’ve maybe had 1 or 2 infusions. So some of these ADCs can have a really, really severe presentation of the corneal toxicity even early on.

Prevention and management of corneal toxicity

DR LOVE: So that also gets into the issue of prevention and management of corneal toxicity. And I’m curious, again, maybe using the 2 kind of examples we gave at each end of the spectrum with belantamab and dato, what you recommend and how effective it is, starting with eye drops. What type of eye drops, for example, and do you recommend it with everybody preemptively or just with an agent like belantamab?

DR PASRICHA: Yeah. I’ll preface it by saying we don’t have the silver bullet, unfortunately. There’s not 1 eye drop that tends to work really, really well, but studies have shown that doing preservative-free artificial tears does help, so just kind of lubricating the eye it does help. And that probably helps more with the symptoms, but maybe also a little bit with some of the pseudomicrocysts.

But a lot of these ADCs will also recommend topical corticosteroid drops, and those have been really mixed in the literature. Some studies have shown there’s a small benefit, but most studies have actually shown there’s zero benefit. And anecdotally what we’ve found is that it tends to help a little bit with some of the symptoms for some patients, but I wouldn’t recommend it as kind of a blanket for all ADCs to start topical steroids, and the reason being is those can have side effects for the eyes.

So for example if you’re on topical steroids it can raise your eye pressure, and you’re at higher risk of developing glaucoma, which is irreversible damage to the nerve of the eye from high pressures. And then also it expedites development of cataracts, and that one is tricky because a lot of the patients are already kind of at that older age where they might have some mild cataracts to begin with, and now they’re on a steroid eye drop, and it might just make their cataract develop faster, and that can complicate what is actually a cancer drug toxicity versus just something that would have developed naturally on its own. So even though some ADCs recommend topical steroids I really don’t think it’s a huge benefit, and I hope that’s something that we can change for the next rounds of ADCs that are approved.

And one area that people are looking at, like for mirvetuximab soravtansine, is the idea of vasoconstriction. So just like how for hair loss there’s those cooling caps, they try the cooling eye mask during the infusion and also doing topical vasoconstrictor eye drops. So there’s a glaucoma drop called brimonidine that also has a vasoconstriction effect, so it’s kind of used off label for the vasoconstriction, and that’s been shown in the rabbit model for mirvetuximab soravtansine to delay the onset of corneal toxicity. So it’ll be interesting to see how much of an effect that’ll have in humans and whether that becomes part of the recommended regimen for some of the ADCs.

DR LOVE: What about the use of, again, preemptive eye drops in the ADCs where you see less of a problem? And again, in breast cancer and lung cancer, 2 pretty common cancers, so a lot of people asking questions.

DR PASRICHA: Yeah.

DR LOVE: It seems like not a big deal to do it. I think the nurse on the — nurse practitioner on the program brought up cost, et cetera. Is it really worth doing? For example, if you have a patient on Dato-DXd, do you think doctors should recommend preemptive eye drops or maybe say if you want to or if you get symptoms you can use it?

DR PASRICHA: I think for drugs like dato, where it’s kind of in that middle range, where there is a reasonably high incidence of the corneal toxicity, but when it happens it tends to be mild, I do think just doing a preservative-free artificial tear prophylactically is a good idea. The issue that we run into is that sometimes it’ll be unrealistic the amount that they want patients to use it. So they will recommend things like 8 times a day.

DR LOVE: Right.

DR PASRICHA: Doing any drug 8 times a day is really difficult for patients. And there’s been a lot of studies in the glaucoma literature where patients have to use eye drops chronically for life sometimes, that if you tell a patient to use a drop, for example, 4 times a day 50% or more of patients are not able to stay compliant with that regimen. It’s just too difficult. So I’d say instead of making it something like 8 times a day maybe prophylactically say 4 times a day, and then that we hope that patients can do that or at least get somewhat close to it. But I don’t think saying everyone should do 8 times a day is a good idea.

DR LOVE: So what about management of patients who do develop these syndromes? It would seem that just holding the agent would be a very critical issue and letting the eye recover. Is that really the main thing you’re focused on? Are there any supportive care measures once you get it?

DR PASRICHA: Yeah. I think you’re absolutely right. That’s the kind of key, is catching it early and changing the dose of the ADC. That’s the only thing so far that we have as an effective therapy, and that’s why it’s so important to have the good communication between the oncology care team and the eye care team.

Let’s say someone on belantamab mafodotin comes to me with corneal toxicity, and they’re hopefully going to have many more infusions of belantamab mafodotin to treat their multiple myeloma, if they’re not on a topical steroid I will starting them on one, a low-potency one, just to see if that helps their symptoms. I know it won’t help their actual pseudomicrocysts, but it might help them feel better and then also at the same time let their hematologist know we need to dose delay or dose reduce and go from there and kind of watch it.

But I think that’s the key, is that you have to have that good communication and be able to catch it ideally earlier rather than later.

DR LOVE: I’m not sure if we emphasized this at the webinar, but I’m thinking that actually I guess you could make the argument that any patient getting started on any of these ADCs you ought to ask the patient if they’re using contact lenses.

DR PASRICHA: Yeah. That’s been a kind of controversial thing because a lot of the clinical trials at least will require that patients who wear contact lenses have to stop. And the reason behind it is a good rationale, is that if you have any type of corneal issue, like let’s say that epithelial defect, if you’re wearing a contact lens you’re going to be at higher risk of developing an infection and having complications from that. So I understand why they mandated that.

The problem is one of the other effective therapies that we have to manage the symptoms, the blurry vision and the eye pain, is actually a contact lens. So it’s a hard contact lens called a scleral lens.

DR LOVE: Really?

DR PASRICHA: And what it does is it doesn’t sit directly on the cornea the way a soft contact lens does. It sits on the white part, the conjunctiva, and it vaults over the cornea. And what it does is it soaks the cornea in tears, and it creates a nice smooth surface, and that immediately solves the vision problem. So patients immediately say oh, my vision is completely clear again, and it makes their eyes feel comfortable because it’s kind of like using preservative-free tear every second. It’s just soaking the cornea in that. But the problem is we’ve run into the issue where, especially the clinical trials, they’re not allowed to be in contact lenses, and so we’ve had to kind of talk to the sponsors and see if they’ll make an exception.

And the other big issue with scleral lenses specifically is because it’s a hard contact lens it’s not like a soft lens where you can just put it in and out really easily. You need special training. It needs to be fit for the patient and made for them. And so it takes a few months, generally, for patients to get their scleral lenses and to be able to put them on and off, and by then a lot of times in these trials they’re already off the ADC, and they don’t really need it at that point. So that’s not been our go-to option, but it is an option for patients who need to be on ADCs for a long time.

DR LOVE: Getting back to the cold packs or the use of cold. I always thought that was really cool. I first heard about that with tisotumab vedotin, which I guess now they do that a lot. Any situations where you would use that, maybe a patient who had already had some problems, in the lower-risk ADCs? Example: Dato. Would you ever use a cold pack? Would you have people put — preemptively either if they had problems or didn’t have problems?

DR PASRICHA: I think it’s a good preemptive one because it’s such an easy thing to do, right? You just have these cold eye masks that can have washable or reusable covers in the infusion center, and you just like for the cold caps for people who are using it in the infusion center, you have the patient put these cold masks that generally feel pretty nice anyways, and they just get that for the infusion. The idea behind it is the vasoconstriction. So the cold causes vasoconstriction, and in theory should make less of the ADC drug get to the cornea.

The problem is I don’t know if doing it just for the infusion really makes a meaningful difference, but I know it won’t hurt. It certainly won’t hurt the patient, and it might help them, and it’s an inexpensive, relatively easy thing to do.

DR LOVE: Yeah. Actually I was just flashing on a program we just did on breast cancer. We were talking about dato, and the issue of ice chips was brought up for mucositis, and they said it’s probably not going to work just for the reason you just said, that the half-life’s too long to just use ice chips during the treatment.

Preexisting ophthalmic conditions as potential risk factors for development of ocular toxicities with ADCs

DR LOVE: What about preexisting ophthalmic conditions that should raise red flags? Anything that we should be looking for?

DR PASRICHA: It’s a great question, and the GSK people have looked at this with belantamab mafodotin. So they’ve done studies. Actually at ASCO I saw a nice poster on this, where they looked at patients who were being started on belantamab mafodotin and looked at their preexisting ocular conditions, including corneal issues like dry eye, and what they found is that there was no difference in which preexisting condition caused a higher rate of corneal toxicity to develop.

So I think the short answer is it’s probably not that important to know who has preexisting dry eye or who has preexisting eye conditions except for being able to tell what’s their baseline. Because if you were to just do an eye exam on an entire auditorium of people who are not on ADCs about 50% or so of them will have some type of dry eye. Some of them might have some mild cataracts, things like that. So I think knowing about those preexisting conditions helps to be able to make sure what’s actually a change from their baseline.

DR LOVE: What is the pathophysiology of what’s going on in those 50% of people, and is it age related?

DR PASRICHA: Definitely. So age is a big factor for getting more dry eye, but then the other one is our lifestyles. Right now so much of us — so many of us are in front of computer screens or phones, and when you’re looking at a computer screen or looking at your phone you are not blinking the same way you normally do. And so that alone, just kind of the decreased blink rate and that focus, that’s going to lead to more dryness, and also you’re straining your eyes more than you would if you were just walking outside or in a classroom type thing.

DR LOVE: And do most of these people have normal exams?

DR PASRICHA: They have relatively normal exam, but when you look at their corneas they do have kind of spotty staining of the cornea, where there’s a little bit of breakdown of the epithelium, what we call epitheliopathy, and that’s kind of how dry eye presents. It shows up as little areas of the corneal epithelium that are not fully intact and normal. And one of the issues that we run into with the ADC corneal toxicity is it also develops these patchy epithelial changes too. And so I think for that reason it's important to know that 1) there’s a really high rate of just normal patients who have mild forms of dry eye with that corneal finding, and then also to know that ADC corneal toxicity also can present in a similar fashion. But what’s different is that dry eye will not have those little pseudomicrocyst changes, and it won’t be something where it should be progressively getting worse and worse the way that with an ADC the more they get over especially shorter periods of time the worse their toxicity will get.

DR LOVE: I don’t know if you would call this age-related dry eye, but in this benign syndrome any supportive care? Do you recommend artificial tears? Does that help? What do you do?

DR PASRICHA: Definitely, so using that same type of preservative-free tear that we would say would be a good prophylaxis for these ADCs. That also helps with people who have just mild dry eye. So I myself as a corneal specialist usually carry around a preservative-free artificial tear and from time to time will give myself a drop of that. It helps. And things like traveling and allergens, that can also worsen it, so it’s something good to have. And definitely as we get older your eyes — we know that the dry eye issue gets worse and more prevalent.

DR LOVE: I’ve seen, and actually I’ve used artificial tears that are individual things that you open.

DR PASRICHA: Yeah.

DR LOVE: Do you recommend that? Is that what you recommend?

DR PASRICHA: So that’s the preservative-free one, those ones that are in the little vials. So those are great.

DR LOVE: Right.

DR PASRICHA: Those are really good. They do have ones that are actually a bottle with a special cap —

DR LOVE: Right.

DR PASRICHA: — that’s a multidose preservative-free cap. Those are also great options for people who don’t want to carry around a bunch of different vials. So either one of those tends to be good, but I’d say the safest one are the little vials because they’re single use, so they’re much lower risk of having issues.

General clinical pearls on the management of ocular toxicities with cancer therapies

DR LOVE: Any other clinical pearls that you might want to share that a medical oncologist would find useful? Any misconceptions out there or anything else that you think would be worth chatting about?

DR PASRICHA: I think one of the biggest things that you mentioned that’s really good to reiterate is who to send these patients to from the oncology clinic. Going to a corneal specialist sure, that’s great, but they can also go to a comprehensive ophthalmologist or to an optometrist, and in any of those 3 situations, the corneal specialist, comprehensive ophthalmologist or optometrist, they’re going to be able to do the full eye exam that’s needed to diagnose the corneal issue that’s going on, the corneal toxicity. And so I think that’s a thing that we’re trying to educate the oncology community, is that you don’t need to only send these patients to an ophthalmologist. Optometrists are also totally capable of managing that.

The thing that’s a little tricky is that sometimes from a patient standpoint they might say oh, well I want to go see an ophthalmologist, I want to see an MD doctor for this problem. And if they kind of demand that, and the oncologist says that’s a good idea, they can have a really significant delay, and sometimes they get put in the wrong subspecialty of ophthalmology. So for example, if they go see an ocular oncologist, in theory that makes sense, right? It’s the ocular oncologist, they deal with cancers of the eye, but a lot of times those ocular oncologists are dealing with intraocular tumors, which is very different than a corneal toxicity from a cancer drug. So sometimes they are very familiar as ocular oncologists, but sometimes they are completely the wrong person to go to. And so I don’t want that misconception out there, that patients who have these ADCs and get ocular problems can only see an ophthalmologist.

DR LOVE: Just to finish out, any cases that you’ve had of people that you might want to comment on, people who’ve gotten belantamab, Dato-DXd or mirvetuximab you think would be instructive?

DR PASRICHA: Yeah. I think one of the things that you did that was really nice during our panel discussion was you actually had that patient video of the multiple myeloma patient who had belantamab mafodotin and developed corneal toxicity.

DR LOVE: Right.

DR PASRICHA: And just hearing the patient perspective because his case, thankfully he was saying yeah, I had it, it was a little bothersome, but once I used the eye drops and we changed the dosing it was manageable. It didn’t really affect his quality of life. One of the things that I’ve seen, and again I’m biased because I’m on the eye clinic side, right, so generally if they’re coming to me a lot of times they already have pretty significant problems.

What I’ve seen is kind of the opposite end of the spectrum, where patients have told me in their actual own words this is the worst thing about my cancer is this eye problem, and if I had known about it I would not have ever signed up to take this drug. And a lot of times these are patients who are enrolled in clinical trials for Phase I or Phase II drugs, and they’re saying this is something that I didn’t know about ahead of time, or I didn’t fully appreciate ahead of time, and I’ve felt like I’m a vampire.

I had 1 patient who used that exact term. He said, “I feel like I was a vampire when I was on treatment. I just closed all my doors in the house, closed all the windows. I was in my own room by myself, eyes closed in complete darkness, and I felt miserable.” And he ultimately ended up stopping that ADC and got better, thankfully, but he was saying it was the worst thing he had to deal with, and he was saying this is not how he wants to spend his last few months or few years of life dealing with.

So I think knowing that there is a big spectrum and that quality of life can be a huge issue for these patients because we all use vision, right? We all want to see people and watch our TV, watch our TikToks and things, so if you can’t do that, and you can’t do that comfortably, that can be the thing that makes your cancer journey one of the worst parts of it.

DR LOVE: Yeah. That was really impressive when these agents first came out and I first started to hear about ophthalmic toxicity. I kept hearing from docs patients really do not like the idea of it, not just patients who’ve had problems, but just talking to somebody about the potential. And I guess you’re right, it’s such a critical function. It’s very scary to think about anything happening.

DR PASRICHA: Oh, yeah. And I think another thing that’s good to educate both the oncology and ophthalmology/optometry field is these changes, while they can be very significant and reduce quality of life, it’s important to let the patient know that these are reversible. Because right off the bat if you tell someone you might develop these problems that happen, it might affect your vision, and it might cause you to have eye pain, but the good news if it happens it’s going to be fully reversible; you’re going to get better. Just knowing that completely changes their mindset when they do develop the corneal toxicity, because now they’re not coming into the eye clinic in tears saying I’m never going to see again. And I’ve had a couple of the early patients who were like that, where they came in, and they weren’t told that this is reversible, so they thought they’ve kind of — they’ve ruined their eyes, and it’s done. So just knowing that ahead of time does help too.

DR LOVE: Yeah, I mean that man on the video — I chatted with 10 myeloma patients, so he’d been on belantamab for 3 years. Of course he described the initial time, as you heard, when he had a lot of problems with vision, et cetera, but now has been cruising along for 3 years, nothing. He had not responded to anything before that.

There was another patient I also talked to, we didn’t show it on the webinar, who’d been on belantamab for 4 years, again no ophthalmic issues. They had just reduced the interval between treatment. So yeah, I mean at least some of these drugs have tremendous potential to benefit patients. You hate to see it getting railroaded because this is kind of a new problem to deal with.

DR PASRICHA: Yeah. I totally agree.

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