Thank you for joining us today. My name is Dr. Rob Coleman, and I will serve as the moderator for this afternoon's symposium titled Antibody Drug Conjugates as it is an exciting new drug class. Now toward the end of this session, we'll present a few case studies and incorporate several audience response questions. So okay, here's what you got to do. Scan this QR code, and I know some of you are really adverse to doing that, but just scan the QR code, or if you have the app, get it up and going so that you can answer the questions along the way, and we will be able to answer these questions. If you have trouble, please flag down somebody from the staff, and they can provide you with instructions on how to do this. I see phones going up. That's a good sign. Good sign. Excellent. You can't get it? Do you need to come up here really close? Okay, you can. Is it like fuzzy or something? That must be like an iPhone 6 or something. Okay. Fantastic. Okay. So the GOG Foundation and GOG Partners would also like to extend a note of gratitude and thanks to Immunogen who's supporting this symposium. So here's the learning objectives. We're going to introduce the class ADCs and their mechanism of action, present some current clinical data in platinum-resistant ovarian cancer and some future development plans for the antibody drug conjugates, and then review and discuss some ADC-related toxicities and the mitigating strategies. This is going to be important because I know, and I'm going to ask this question in a second about your experience with ADCs, any ADC, but I think if you've not had a lot of experience with this, it'd be really good to pay attention to the toxicity discussion that Dr. Moore is going to present, and then we'll bring up some case studies that will challenge your knowledge of that strategy. So I'm really pleased to introduce our wonderful speakers from the United States and Europe. So Katie Moore is right next to me here, is a professor in the Division of Gynecologic Oncology at the University of Oklahoma. She is an Associate Director for Clinical Research and the Director of Phase I Drug Development at the Stevenson Cancer Center in the University of Oklahoma. She also serves as the Medical Director for Infusion Services, which is like a thankless task. I'm just going to say it here. Director of Infusion Services. Just think what that's going to entail. I know about it because she calls me and says, I can't believe what's going on. And she, of course, is the Associate Director for GOG Partners. Let's see. And then next, at the far end, I have Dr. Keta LaRusso, who's an Associate Professor and Secretary of Gynecology at the, should I just say this, Rome University or University of Rome? Is that enough? Because there's no way I'm going to pronounce all of the names, unless you want to. Policlinico Gemelli. Policlinico Gemelli. Catholic University of Rome Policlinico Gemelli. Okay, so. Twins. Twins Policlinic. As she said. So Keta has been involved in gynecologic oncology research. Actually, everybody up here has been involved in gynecologic oncology clinical trial research for many, many years. And obviously, that's why they're here. They're key opinion leaders globally. And we're so pleased to have Keta join us here. And then next to her is Dr. Anna Walkman, who is the Head of Gynecologic Cancer at her hospital, which I'll let you pronounce. You can pronounce it. Right there. Use the phone, so everybody can hear. Can you do the mic, so that everybody can hear you? Is it working? No, no, it's working. Yeah, go ahead. Valdebron University Hospital and Valdebron Institute of Oncology in Barcelona, Spain. Okay. Do you want me to pronounce in Spanish right now? I'm going to need to learn how to pronounce the Spanish and the Italian. So she's in Barcelona. That's where I know she is. And again, a committed investigator, run a lot of trials, and we're so pleased to have them here with us. Okay, as a matter of a clinical trial, standard of care, or both, have you ever prescribed an antibiotic drug conjugate? Go ahead and vote. Do we have the results coming in? Okay, so no, okay, good. Oh, good, more people are in line. Okay, so, okay, so about a third. 70, 30. Does that mean there's like six people that are voting? 30% of patients. Okay, great. People never experienced with the drug. And then the, okay, this is the last question, so I'm not gonna belabor this. So, which adverse effect most concerns you about antibiotic drug conjugates? So, remember, we did this with immunotherapy, now we're gonna talk about ADC, so of what you know of the ADCs, whether you've used them or not, what is the most concerning toxicity that you've heard about, experienced, worried about? Okay. Kind of the big threes. Although that says nothing, right? I can only see O-thing. Is that nothing? I think it says nothing, yeah. Okay, good, nothing, okay. All right, so ocular and pneumonitis, excellent. So you may see that again. All right, so with that, I'm gonna go ahead and introduce, back up to this podium here, Dr. Cata LaRusso. From polyclinical genetics. Thank you. Good morning, everyone. And thank you for inviting me to speak about this very interesting new class of agents. So, the gynecological cancer treatment is experiencing a new era of treatment. The treatment is becoming more and more personalized. Think about PARP-Inhibitor for BRCA-MUTE, but also for HRD patients. Think about immunotherapy for MSI-High endometrial cancer patients. In this scenario, antibody drug conjugated are the next frontier of personalized therapy. It's a very interesting drug because there are several components in the structure of the drug, and each of them plays a well-defined role. We have an antibody, which typically is a chimeric or a humanized antibody. This is necessary in order to reduce immunogenicity, with high affinity to a target. The target is represented by an antigen with the high expression of the tumor and the low expression of healthy and normal tissue. Then there is a linker, which play a very important role because the linker, the perfect linker, has to be stable in circulation, but has to have an efficient release on the target site. And finally, the payload. The payload is the cytotoxic drug, which are typically high potent drug with a great toxicity sometimes, but the possibility to link it to the antibody allow us to deliver the drug only to the target. And upon, when the antibody meet the antigen, there is a mechanism of internalization through endocytosis. Then the lysosome met the antibody, release the target, the antigen, and the drug is free in the tumor cell and can act. Usually we have two types of cytotoxic agent, one interfering with the microtubules and the other with the DNA. But more, more interesting, the free drug in the cell can pass across the membrane and accept an additional effect, which is called as bystander killing, which is the possibility to the free drug to target also other cell. As I told you, the target is really important. The target works in this mechanism as a Trojan horse. The perfect target have to have two characteristic, high expression on tumor cell and not on normal cell and also should be present on the surface in order to be captured by the ADC. It should be internalized so that the ADC can be transported into the cell. What about the payload? Basically we have two kinds of payload that have been used until this moment with ADC. One class of agent interfere with the tubulin polymerases and the other with the DNA alkylating agent. What about the linker? We have two possible linker. The cleavable linker. This linker are very important because we, through this linker, can increase the bystander effect. And the non-cleavable linker, this linker allow us to have more stability and longer half-life of the antibody. And then there is another important factor that we need to take in consideration. Which is the drug antibody ratio. How many molecules of the drug can be linked to the antibody? Usually this ratio is to be an efficient, in order to have an efficient drug, we have to have a drug antibody ratio of at least greater than two. But it is intuitive that the higher number, the better performance. I will tell you the history of a very successful drug which is trastuzumab derustegam. This is a new class of R2-targeting ADC which is quite, is a new generation, if you want, of ADC. The payload is represented by topoisomerases-1 inhibitor which is a high-potency drug with a short systemic half-life. And this drug represent an evolution with respect to trastuzumab benthansate Tdm-1. Because, for sure, linked topoisomerases-1 inhibitor with respect to antimicrotubule. Because the drug-to-antibody ratio is eight to one with respect to three to one. And also because of a cleavable link which increase, as I told you, the bystander effect. This drug was very successful. All of us remember the results of this trial presented two years ago, the Destiny Breast 03 trial which was a randomized trial between Tdm-1 and trastuzumab derustegam in R2-positive breast cancer. And the trial was powered to demonstrate an increase in progression-free survival. And we were very touched by this case with a significant increase in progression-free survival from 7.2 to 25 months. And a very close to significant increase in overall survival for this patient. And this target is also interesting for gynecological malignancies because up to 30% of gynecological malignancies, particularly endometrial cancer, express this target. And now we have a trial, the Destiny Pantumor 02, which is exploring this drug in three cohort of gynecological patient, the cervical, endometrial, and also ovarian cancer. And in the meantime, we achieved the results of the Pantumor, a preliminary results with this drug in carcino-sarcomas. Uterine carcino-sarcoma has been published reporting 54% response rate in a population of evenly pretreated carcino-sarcoma. Very, very, very interesting. 11 ADC has been already approved by FDA, but a lot of new drug are in the clinical development. And in the coming few minutes, we will discuss very briefly some of them. DS600 is a antibody drug conjugated targeting CDH6. CDH6 is part of the cadherin family involved in cell cell adhesion, organ development, and mainly epithelium methankemal translation. It is over-expressed in several cancer, particularly it is over-expressed in renal cell, clear cell cancer, and in ovarian cancer. In the preliminary results of the phase one trial in a very evenly pretreated population, median number of prior regimen six. 72% of these patients have already received bevacizumab. 70% of them have already received parpinibutors. So a population very similar to the patient that we treat in clinical practice now. Impressive, I would say, response rate was reported. Among the 28 evaluable patients, eight partial response were confirmed. So very, very interesting drug. Upifetamab is a new class of agent. It's the first in class ADC targeting sodium-dependent phosphate transport. This is a very interesting target because it is expressed on tumor cells in two-thirds of patients with high-grade serious ovarian cancer. And it is important because it is less expressed in normal or not expressed in normal tumor. There is a relationship between the expression of the target and the efficacy of the drug. In the phase one trial, two doses were evaluated. 36 milligrams per meter square and 46 milligrams per meter square in a neatly pretreated population, four prior line of therapy platinum-resistant. And 67% of patient experience at least a reduction of one target lesion, which is quite impressive. But more impressive, when you look at the response with respect to the expression of NAPITU, in patient with NAPITU-I target, the response rate was 44% when the dose of 36 milligrams per meter square was used. And now we have the expansion of this preliminary research, the uplift trial, which is ongoing, is recruiting platinum-resistant up to four prior line of therapy patient. And this patient will be treated until progression of disease. And another interesting trial is ready to start. The drug in this concept is used as maintenance treatment in platinum-sensitive recurrent ovarian cancer patient who have received at least two prior platinum. I want to show you that for this trial, high expression of NAPITU was requested. Another interesting target is represented by tissue factor. Tisotomabedotin is an antibody drug conjugated targeting tissue factor, which is involved in the physiological cascade of coagulation. Tissue factor is aberrantly expressed in several solid tumor, including cervical cancer, where it is associated with poor prognosis. The main clinical development of this drug is in fact in cervical cancer, where the drug has been used as a single agent, but also in combination with platinum, pembrolizumab, and bevacizumab. But another interesting trial with a single agent in ovarian cancer has been concluded, and we are waiting for the results of this trial. And lastly, the last interesting target is represented by TROPO2. TROPO2 is a tumor-associated calcium translucer, which is involved in tumor invasion and metastasis. It is very interesting for us from gynecological malignancies because it is over-expressed in 96% of endometrial cancer, endometrioid type, and in up to 65% of serious tumor, but also, I have to say, is highly expressed also in ovarian and cervical cancer, where over-expression is suggested to be over 90%. So it's a target very interesting for gynecological malignancies. And now, several, several trials, most of them in phase one or two are addressing the value of antibody drug-conjugated targeted TROPO2. The last target I will introduce, the next talk is represented by folate receptor alpha. Folate receptor is a cell service target, which mediate folate receptor transport. It's expressing limited, it has a limited expression in normal cells, but it is high-expressed in cancer, and this make it as a potent, potent target for antibody drug-conjugated. And in the coming lecture, Anna Wagnin will tell you about the clinical results of this drug. So looking at the scenario that we will face in the coming years, several and several new antibody drug-conjugated are jumping the clinical development. And in the last two or three years, we will have a lot of results exploring this very interesting class of agent in organ ecological malignancies in patient that have been pre-treated with immunotherapy and PARP inhibitor, which is, in my opinion, the most interesting setting in which this drug should be development. And in conclusion, I think that this new class of agent really represent, in my opinion, the most interesting new class of agent in the clinical scenario. Thank you so much for your attention. Thank you. Thank you so much, Dr. LaRusso. Next, I'll invite up Dr. Wagnin to give us a talk on the existing data and expanding into clinical management for the ADCs. Do you want me to speak in Spanish? Yeah, please speak in Spanish. Good afternoon, everyone. Thank you for joining this interesting meeting. So I'm in charge of review the data from Rituximab and other ADCs. So with this, okay, this is my disclosures. So ovarian cancer is a lethal gynecological cancer, and in the past decade, 14 drugs approved for treatment of epithelial ovarian cancer have occurred, all of them led by three drug classes, anti-angiogenic, PAR inhibitor, and TPD-1 agent as agnostic tumor. However, no biomarker-directed therapy is indicated for patient with platinum-resistant disease. And in addition, alternative platinum-based combination that are highly effective and reduce toxicity are urgently required. Therefore, still novel therapy are needed. And in this scenario, antibody drug conjugated are the next frontier in personalized therapy. And why ADC? Dr. Loruso has already explained very well how this drug works, but let me reinforce a few points. ADC allows us to target specific tumor-associated antigens and to deliver highly potent chemotherapy directly to the tumor. In addition, offer patients a differentiated safety profile and more often combination therapy, which may replace a standard systemic chemotherapy. So, in this slide, we have summarized the most frequent target antigens and the corresponding ADC. For the sake of time, I will be focused only in the first-in-class ADC targeting folate receptor alpha, that is to say, myrbetuximab. So, let us start from the beginning. Why folate receptor? Why folate receptor is an ideal target for ovarian cancer? We know that folate receptor alpha is restricted on normal cells and highly overexpressed on the surface of a number of cancer cells. Indeed, high-grade series ovarian cancer, approximately 80% of cells are positive for some expression of folate receptor alpha. And in addition, folate receptor alpha overexpressions allow for delivery of a highly potent molecule of chemotherapy to folate receptor alpha cell. But in addition, via the bystander effect, allows the diffusion of the payload into adjacent folate receptor alpha negative cell. Moving forward, folate receptor is expressed on the surface of serous epithelial ovarian cancer. And this expression is assessed by immunohistochemistry, and immunohistochemistry categorize the expression in three different groups according to the intensity, 1+, 2+, and 3+. I think it's very important to understand the scoring system to interpret in the right way the trial with IDC against folate receptor alpha. In particular, I would like to teach you, to learn you how PS2 plus scoring works. This scoring system determines the percentage of folate receptor positive cells with an intensity of at least 2+. So according to that, we're talking about the low expression with the percentage are between 25% and 49%, medium 50%, 70%, and high expression, when we are talking about high expression folate receptor alpha, we are talking about a percentage of 75% at least with an intensity of 2+. So in the right of the slide, you can see the distribution of folate receptor alpha expression in ovarian cancer according to the data that we have so far. 39% are highly folate receptor alpha expression. So here you are, myrvetuximab, I mentioned before, the first in class ADC targeting folate receptor. Dr. Lorusso has already explained, but let me just, you know, a small touch in the mechanism of action. The antibody binds to folate receptor, is internalized, and then release its cytotoxic payload, namely DM4. DM4 disrupts tubulin, resulting in mitotoxic arrest. A very important, the bystander effect. We have said that through the bystander effect, you know, the drug has cytotoxic effect into folate receptor alpha negative cell. So then the clinical development of myrvetuximab. In the early development, as you can see here, you know, the ADC already show promising result with overall response rate between 26% and 28% for those with median and high folate receptor alpha expression. So in light of this result, the FORGAR-1 trial was launched. The FORGAR-1 trial is a phase three randomized trial enrolling patient with platinum-resistant ovarian cancer with folate receptor expression median and high, and patient might have received between one and three prior therapy, and they were randomized in a two-to-one fashion to myrvetuximab or physician-choice chemotherapy, a certification factor folate receptor alpha expression, prior therapy, and choice of chemotherapy, primary endpoint PFS by VCAR. Unfortunately, the trial was negative. In the intent to treat population in the folate receptor alpha high. Then what happened in FORGAR-1? What happened? In the previous study with myrvetuximab, we used the PS2 scoring to determine the expression of folate receptor, and in the FORGAR-1, we used a simplified method 10 times. In this new method, we determined only the percentage of cells with membrane state regardless of intensity, and as a result of that, a number of patients with lower levels of folate receptor alpha expression was enrolled. Then following the result, you know, all the slides were re-read by expert pathologists applying PS2+, and then all the efficacy endpoints were evaluated in the high folate receptor alpha subgroup. You can see here in the slide, all endpoints were in favor of myrvetuximab. According to this, very important trials were launched. In these two trials, one of them, that is the MIRASOL trial, that is the confirmatory trial, is a phase 3 randomized for myrvetuximab in folate receptor alpha high according to PS2 in patients with platelet-resistant ovarian cancer. So 430 patients have already been randomized because the trial has already finished its recruitment and were randomized to myrvetuximab or investigator-choice chemotherapy. As a stratification factor, investigator-choice chemotherapy and a number of prior therapies. The other endpoint, progression-free survival by investigator. We are very eager to have the readout for these trials in the coming year. And aligned with that, the SORAYA trial was also launched. In this trial, we evaluate the efficacy and safety of myrvetuximab in patients with folate receptor alpha high. The patients were patients with platelet-resistant ovarian cancer with one to three prior regimens. Very important, only high-grade serocystology, all tumors must have high folate receptor alpha expression. And one of the criteria, all patients must have received prior mevacizumab. Primary endpoint, overall response rate, and the key secondary endpoint, duration of response. And here, the patient's characteristics in a very brief manner, 51% of the patients have received three prior blimotherapy, 100% of the patients have received the mevacizumab per inclusion criteria, 48% of the patients have received prior PAR inhibitor. And here, the primary endpoint, overall population, overall response rate. The trial met its primary endpoint with an overall response rate of 32%. Five complete responses and 29 partial responses. When we analyzed the overall response rate according to subgroup, the efficacy was maintained regardless of number of prior lines of therapy and regardless of prior exposure to PAR inhibitor. Indeed, the overall response rate was 35% for those with one to prior line and 30% for those with three prior lines of therapy. Interestingly, the overall response rate was numerically higher for those patients who have received previous PAR inhibitor. The median duration of response, 6.9 months, with interval confidence between 5.6 and 8.1. So we can say that these results position myrbetuximab to become a potential biomarker-driven standard of care treatment option for patients with folate receptor-alpha positive platinum-resistant ovarian cancer. Indeed, FDA accepts BLA of myrbetuximab under priority review for folate receptor high platinum-resistant ovarian cancer. Moving forward in the development of myrbetuximab, we have already launched this important trial. It's a single lab, but we're analyzing the role of myrbetuximab in high folate receptor-alpha platinum-sensitive ovarian cancer. Our target is to enroll 75 patients with at least two prior systemic treatments containing platinum-based chemotherapy, and that the investigator considers that this single agent is appropriate for this patient with a sensitive relapse, primary endpoint, overall response rate, and secondary endpoint, duration of response. The trial is enrolling patients through the U.S. and the U.S. So we have already shown the activity of myrbetuximab as a single agent. So the next step is to analyze the activity in combination. And this was done in the forward two, with two important agents, with vevacizumab and carboplatin. We already know the activity of vevacizumab, and we know that there is no overlapping toxicity. So it was an ideal combination for myrbetuximab. Then we analyzed the safety and tolerability of myrbetuximab in combination with vevacizumab in a patient population that is recurrent ovarian cancer, for whom a non-platinum-based doublet would be appropriate. Importantly, we enrolled both platinum-sensitive and platinum-resistant disease. So globally, we enrolled 16 patients, and the main characteristics are summarized here. 55% of the patients had high folate receptor alpha expression. 53% of the patients were platinum-resistant, namely a relapse less or equal to six months after the last dose of platinum. And interestingly, 40% of the patients had previously received vevacizumab. So here are the responses. The total population, the overall response rate was 50%. And then when we look at the responses according to folate receptor alpha expression, it was 64% in the high folate receptor and 33% in the medium folate receptor alpha expression. And when we look at the overall response rate among those patients with a high folate receptor expression, according to platinum sensitivity, we observed really compelling overall response rate. 59% for those with platinum-resistant and 69% for those with platinum-sensitive. In terms of median duration of response, very, very promising results. In the total population, median duration of response, 9.7 months. For those with high folate receptor alpha, the median duration of response was 11.8. And very interesting, when we look at the median duration of response in this population with high folate receptor alpha, the results were really compelling in both platinum-resistant median, 9.4, and platinum-sensitive median of duration of response, 12.7. In terms of median progression-free survival, it was longer in those with high folate receptor alpha compared with the median. And even in those with high folate receptor alpha expression, regardless of sensitivity to platinum, namely for both platinum-resistant and platinum-sensitive, the median PFA was longer in the high folate receptor alpha expression compared with median. So this data in a broader population of recurring ovarian cancer warrants further development of this novel targeted combination and support myrbetuximab as a potential combination partner of choice for bevacizumab. So in light of this result, the GLORIOSA trial was designed. This is a very important phase 3 trial analyzing the combination of myrbetuximab plus bevacizumab as maintenance therapy in folate receptor alpha high platinum-sensitive ovarian cancer. The target of this trial is enrolled 438 patients, platinum-sensitive, one prior systemic treatment. And the patient must achieve a complete response, partial response, of a stable disease after treatment with platinum-based plus bevacizumab. The trial, you know, will be led by my good friend, Professor Lorusso. And the primary endpoint will be PFS and secondary endpoint overall survival. So the other very important combination with glycarboplatin, all of us are quite aware that the landscape in the sensitive relapse is rapidly evolving since we are moving parainhibitor of bevacizumab to first-line therapy. So it's mandatory that we find new combination. And then myrbetuximab and carboplatin was explored in the forward two. It is true that this is a small sample site, but the data are really promising. You know, 18 patients, sorry, with a platinum-sensitive relapse, 35% with a platinum-free interval greater than 12 months, and a heavily pretreated population because 50% have received at least three prior Lyme therapy. What we observed was a 71% of overall response rate and a median PFS of 15 months. And when we look at the responses in those with medium and high folate receptor alpha, the overall response rate was 80%. So this result of that study will be informative as to the promise of myrbetuximab combination therapies as a potential alternative treatment option for the patient with relapsed epithelial ovarian cancer. So according to that, the study 420 was designed. This is a single-arm phase two study of myrbetuximab plus carboplatin followed by myrbetuximab and very important, in folate receptor alpha, low, medium, and high, and patient with platinum-sensitive. The objective is to enroll 110 patients with at least one prior Lyme or platinum therapy, and the primary endpoints is as a single-arm phase two trial will be overall response rate and secondary endpoint duration of response and PFS. So this brings me to the end of my talk, and then I would like to summarize saying that there are several areas of unmet need in the care of ovarian cancer patients. For patients with both platinum-sensitive and resistant cancer, PS2 plus scoring for folate receptor alpha assessment identified patients most likely to benefit from myrbetuximab. Soraya Traya has demonstrated the clinically meaningful activity of myrbetuximab for patients with folate receptor alpha, high platinum-resistant ovarian cancer. And in addition, the confirmatory phase three mirazole has already completed its enrollment. The piccolo trial, a monotherapy treatment trial in later stage platinum-sensitive ovarian cancer, was recently initiated, and it will be very informative. Moreover, myrbetuximab combines in a very good manner with several agents, including bevacizumab and carboplatin. Gloriosia trial has been designed. This 420 study will address carbomyrbetuximab combination in platinum-sensitive. So the strengths of this data and trial in a broad population of recurrent ovarian cancer support myrbetuximab as a potential agent of choice for patients with folate receptor alpha, high ovarian cancer. Thank you for your attention. Thank you, Ana. And so thank you for that great overview. And then I'm going to have Dr. Katie Moore come up and speak to us about adverse events and mitigation strategies for this class of drugs. Katie? Well, good afternoon, everyone. All right, we're going to take a step back from just talking only about myrbetuximab and just sort of talk about antibody drug conjugates as a class and some of the toxicities that we see across some of the different agents and how the mitigation strategies actually apply to multiple agents. These are my disclosures. So what I'm going to do today is really discuss the differentiated toxicity profiles of available and emerging antibody drug conjugates and the mitigation strategies that I mentioned. So we have a lot to talk about, so let's get going. So I think we've heard today already, and I can breeze through this, that antibody drug conjugates are here to stay, finally, in gynecologic cancers. It's exciting for us to have this new class of agents emerging not just in ovarian cancer, but in cervical cancer as well. So I'll start the talk with just Tizotimab-vidotin. As we've already heard, this is the mechanism of action, antibody drug conjugate targeting tissue factor. And it works quite nicely in recurrent cervical cancer and led to an accelerated approval in the United States, which will hopefully be confirmed based on this strong response rate in second and third line recurrent cervical cancer of 24%. But it does have some key treatment-related adverse events that we have to be aware of and understand so we can mitigate them to the best impact on our patients. And these include ocular treatment-emergent adverse events, bleeding, which is a unique one here, and peripheral neuropathy. And so we'll talk about those as we move through the study. So that's our only FDA-approved antibody drug conjugate so far. Hopefully we have one coming soon in Mervituximab. And you've heard just a master class talk on Mervituximab preceding this. So I can just sort of not belabor the point that we believe it works. Here's the overall response rate. But otherwise, has differentiated toxicity. Again, we have some ocular toxicity. What I'm showing you here is the data from Forward One. And in general, you can say about 50% of patients receiving Mervituximab will have some sort of ocular toxicity, albeit the majority of it is grade one or grade one-two. And at the bottom, you can see a table that I'll dive into a little bit later. There was an integrated safety population that we reported at ASCO with some of the other toxicities that we see, just to complete the picture for Mervituximab. And we do see some neuropathy, 14%, but very minimal hematologic toxicity, as I'll run through in a moment. And then other sort of emerging antibody drug conjugates. Again, you heard about Upafetamab, Rilsdotin. This targets the sodium-gated phosphate channel, which is a lineage marker for ovarian cancer and so highly overexpressed, much in the same way as foliar receptor alpha. It's kind of ubiquitously expressed across epithelial ovarian cancer, but there are variations in the amount of staining. And that's still being worked out. This one has a little bit of a different drug-antibody ratio. So it is a different drug with a different payload. Early reports by my partner, Dr. Deborah Richardson, in multiple meetings have shown early signals of efficacy, as you can see here, and was already presented. And so this has moved into an accelerated approval run in the United States and some other countries with a confirmatory study that's just launched with UpNext. But like the others, it has key treatment-related adverse events that are distinct to this class of agent. Most notably is pneumonitis, which has been controlled with more appropriate dosing, but still needs to remain front of mind when you're using this medication, along with some other unique toxicities that I'll take us through. And then there's some that are in phase one. You know, we see, you heard about DS-600, or DS-6000, which targets cadherin. This is the early stage one, phase one data presented just at ESMO a few weeks ago by Erica Hamilton. And we do see here a little bit of pneumonitis and some neutropenia. Again, much of this may be reduced with further dose optimization, so we still have to kind of watch the development of these earlier drugs, but you see kind of a pattern emerging of adverse events we can see with antibody drug conjugates. Trastuzumab durextacan you just heard about. This is a phenomenal achievement in breast cancer, and it's common for us, for our patients in uterine at least and probably others. We have early data that suggests it's quite active. And so we're gonna need to know how to use it. And so we're gonna have to learn really a lot about pneumonitis and the mitigation strategies, pay attention to left ventricular ejection fractions, and also the other associated side effects that are associated just with chemotherapy as we'll go through. So this is something that medical oncologists know quite well, and gynecologic oncologists are gonna have to get used to, and we're good at learning new things. So let's just take them one by one. How about ocular toxicities? So we'll look at Tuzotamabvidotin, because ocular in one isn't ocular in another. They're different toxicities. Here we see conjunctivitis, and so there's a little picture here. This is something you can see. You and I can see that the patient has conjunctivitis, and they will also complain about it. So it's pretty common. You'll have about half, 50%-ish, a little bit more of patients with any grade ocular event on Tuzotamab, and you can see this here, about 31% though is conjunctivitis, and then you see a myriad of other things, dry eyes, keratitis, blepharitis, but itises. It's an inflammatory sort of side effect. And so the mitigation strategies have been well borne out for this agent, and it shows benefit here. So 5% of patients, only 5% discontinue because of ocular toxicities, which is important to note. But 20% require dose reductions, and so you do have to mitigate somewhat frequently, but very few discontinue, and this is the strategy. So they all need a baseline ophthalmologic exam. You can see this moving left to right. The day of infusion, pre-infusion, they get corticosteroid and vasoconstrictor eyedrops, so at least 10 minutes before, and then you put a cooling pack on their eyes, and that stays on until 20 minutes post-infusion, and then for 72 hours post-infusion, they're using corticosteroid eyedrops as well as lubricating, preservative-free lubricating eyedrops as indicated, and then other recommendations for good eye hygiene, like not wearing contact lenses and not using perfumed soaps on your face. Patients really do have to be counseled how to minimize eye toxicity with all of these agents. And so what you can see here is they've developed patient handouts. This is an FDA-approved medication, and so we already have patient handouts. You can see that at the top with kind of easy-to-follow guidelines on what kind of cooling mask to get. You know, if it doesn't block your eyes, it's not gonna help, and so it has to be the one on the left, but it's helpful because patients may come in with the one from home that they can see through. So this is a nice picture. I got this off the Memorial Sloan Kettering website. And since the mitigation strategies have gone into place, you know, they work, and so they've looked at this. So on the top, you can see patients enrolled before mitigation. On the left side, on the right, you can see after. You go from 80 to 60% all types of ocular toxicity, and for conjunctivitis alone, you drop it down to about 28%, the majority of which is grade one, two. So mitigation strategies are important to keeping our patients on these medications so they can benefit from the antitumor activity that they offer. So that's conjunctivitis. With myrbituximab, we see keratopathy, and so this is completely different. So just for those of you that forgot the I, here's the I, because I always have to remind myself. So here we're talking about the cornea and the corneal epithelium right here. So it's a surface event. So you can see it again. Here's a sagittal view of the eye. This is what we're talking about. We think the damage occurs at the limbus of the cornea, although that is still being studied, and so you damage it, and what happens is that these damaged cells, kind of like a burn on your skin, kind of ball up and migrate across the cornea, and you can see in the upper pictures, if you can squint, you see these tiny little dots, and they're microcysts, and they give the patient blurry vision. If you look at the bottom histograms, you can see these are rabbit models, but in the middle is a normal cornea. You can see everything's nice and neat and lined up, and on the bottom, you see one that has keratopathy, and so it's just kind of a mess because they've had some epithelial injury, and it's flaking off and making these microcysts, but we see this toxicity is limited just to the epithelium, so the deeper corneal layers are not affected, and that's incredibly important because it makes it reversible. So you see regeneration of the corneal epithelium. You shed the areas just like if you burn your skin with an iron, and it flakes off, and then it's nice and healed afterwards. That's what happens on the eye, so it's completely reversible, and it's very much related to peak doses in that first 24 hours after we give the drug, which is what led to the adjusted ideal body weight dosing. So we do have well-borne-out mitigation strategies here, grade one and grade two. So a patient with grade one, really what we wanna do is a complete eye exam. You monitor for worsening symptoms, but you really don't have to change the dose. They can keep dosing, and so this is someone that maybe has some dry eyes or just a little bit of symptoms, but not really anything impacting any of their activities of independent daily living. Grade two, they're coming and going, hey, I can't read real well today. I can't read the paper, and this is very common, and you just set expectations so they know to tell you that. Their night vision's affected, so they have trouble driving. That's a grade two. Then you need to hold the drug. They need a complete eye exam just as above. You have to hold until they resolve to grade one. In that point, you can restart the drug. If it resolves within a short period of time, like a week, you can restart the drug at the same dose, but then they have to get every other, sorry about that, every other cycle ophthalmologic exams kind of for the rest of the time they're on the drug just to watch for further worsening. Certainly if you see, say, recurrent state grade two or grade three, you have to hold until resolved, and then dose reduce, and then grade four, which I don't think we've ever seen, you would discontinue drug, and so this works. So this is data from a long time ago where we just went from ideal body weight dosing to adjusted ideal body weight dosing, so pre is on the left and post adjustments on the right, so we avoided these big peaks in dose that patients would get, and you can see the reduction in the frequency and the severity of ocular toxicity just with modifying the pharmacokinetics of the drug. This is why PKs are so important, and that leads us to this. I've already shown you from Forward One. About 50% of patients will have some sort of ocular complaint, but the vast majority is grade one to two and easily reversible, and this is from the integrated safety data that I mentioned to you earlier. So when we have patients with ocular toxicities, about 28% don't need any modification. 20% have some dose delay, 12% need a dose reduction, and less than 1% across almost 500 patients discontinue due to ocular toxicities. So the mitigation strategies work to allow our patients to stay on study, and we do believe that these are 100% reversible and can be mitigated with strategies, and we're continuing to work on how to do this better even moving forward. Now I will point your attention to this really nicely done manuscript that I actually discovered when I was preparing this talk, and this is for Tazotamab, but it takes you through the ocular toxicities for Tazotamab, but it also gets you kind of familiar with the language of grading ocular toxicities, which I think we're all gonna have to get better at. So in general, it's just a nice paper at how you think about the terminology you use and the questions you ask a patient who comes in complaining of any sort of eye disorder and takes you through the grading for here conjunctivitis, but it's a nice general overview just for your reference. So it's really well done. I would recommend you take a look at that. I can guarantee one will be coming out for keratopathy soon. So moving on to pneumonitis. Now pneumonitis is a little less frequent for us, but I think with these newer agents, we're gonna have to understand it and really pay attention. So if we pay attention, we can keep patients on safely. If we don't pay attention, patients can be really harmed, and we've learned that from trastuzumab durexacan. So what I'm showing you here on the left is that this isn't like an early thing. You don't get through a couple cycles and go, phew, I'm done, no pneumonitis. You can see those rates of pneumonitis really still increasing. The cumulative probability increases to about a year, and then it starts to level off. So this is something you have to be paying attention to on the CT scans, looking for ground glass opacities, and asking your patients about respiratory symptoms really for the duration that they are on these medications, and that's a little bit new for GYN oncologists. As with many things in breast cancer where they're kind of far ahead of us because there's so many more patients, they have developed very specific mitigation strategies for pneumonitis or inflammatory lung disease, ILD. And so asymptomatic ILD means on the CT scan you see ground glass opacities, which you really have to have confidence that your radiologist is calling these. And for certain drugs, not all, but for certain drugs, and this one in particular, if you see that, you start steroids. And you hold the drug until they're gone, and then you restart it as long as it resolves within a month. For symptomatic ILD, which is grade two or higher, you start the steroids, but it's discontinued. So for this drug in particular to be used safely, it's a very conservative run with dealing with the pneumonitis. Now other ADCs aren't as severe, and so we may have to be flexible with kind of starting and stopping, but for this particular drug, when we use this, we're gonna have to follow these mitigation strategies because they worked. Again, ooh, something's, maybe I'm taking too long. It's like someone's telling me to go faster. Because they work, as you can see here, when you, the mitigation strategies really went in place in 2020 after they really were seeing these severe pneumonitis events and they did have grade five events. These can be fatal if not managed appropriately. But once they instituted the mitigation that you see in the middle, the whole, all grades went down, which is kind of hard to explain because you're mitigating something as it happens. But be that as it may, the percentage of recognition went down from 15% to 6%, and then the percentage of those having grade three reduced from 7% to 2%, and then grade five went down as well. But we still could see grade five. So we do need to be really careful and continue to learn about ILDs. Now, how about neuropathy? Tuzotamab, Vidoitin, while we like these differentiated safety profiles of doing the Trojan horse and getting the drug into the tumor, there is bystander effect, and you do still see on-target, off-tumor toxicity on the nerves because some of these conjugated medicines are microtubule toxins, and that's just what they do. And so we see this in about 30% of patients on Tuzotamab. Now, and only 21% resolve back to baseline, and so it's not super high, but a lot of patients come in already with baseline neuropathy, so this is something you have to pay attention to with patient selection, dose holds, dose modifications, and appropriate medications to try and help modify what is largely grade one, 17% is grade one, but nine and 7% are grade two and three respectively, and that's not a small number when you think about it. So neuropathy remains an issue here. We do see neuropathy with Mervituximab as well, but less than its comparator, which would be Paclitaxel, and so you see Mervituximab in blue with about 27% neuropathy, the vast majority grade one to two, versus 44% for Paclitaxel, so less than the other microtubule toxin, but more than PLD or TOPO, which makes sense. So again, something you have to watch for, mitigate appropriately, and select appropriate patients for this medication. And then for Upafetamab, we actually don't see neuropathy, which is interesting, but we do see fever, and it's associated with the drug, and so this is something you have to know, because when we have patients with cancer on a drug and they get fever, we worry about infections appropriately, and call them in and start antibiotics and do all the things, but here we see pyrexia associated with this medicine, and so you have to pre-medicate with antipyretics, you can use whatever you want to use, and then you can use that post as well, as long as you're sure it's not an infection. So this is one of those things you have to work out clinically, but know it can be related to the drug. And so this is sort of the differentiated safety profile for these agents. Here's Tuzotamab, you can see across the board the different toxicities. There is some alopecia here, you have to warn patients. It's grade one to two, but their hair's gonna thin, and so we can't just say, oh, there's no hair loss. You can't have hair loss, but negligible heme, which is important, because sometimes our patients' bone marrow is kind of beat up, and you don't have this heme toxicity here. You can't have nosebleeds in 30%, and nausea in 27%. Mervituximab, negligible heme tox, similar, but you can have diarrhea and you can have nausea in 46 and 31%, low grade, but common. And then similarly with Upafetamab, here you can see some thrombocytopenia, and so you have to be aware from that. It's pretty quick, like week two, and transient, but it happens, and so you have to watch for that. You can also see AST elevations, which again are transient, not associated with High's Law, but there, and you have to watch to make sure someone's not progressing, and nausea in 50%. And so nausea, vomiting, fatigue, even though these are differentiated and targeted, they're still very common, and so you have to remember to use standard premedications and send patients home with rescue medications so that they can stay on these important medications with good efficacy and tolerability. So in conclusion, I think antibody drug conjugates, hopefully you all agree with us, are an emerging therapy, targeted therapy for ovarian, endometrial, and for targeted, and the non-targeted thus far for cervical, because we don't have to test for tissue factor. These are very attractive because of the differentiated toxicity profiles, but the toxicity profiles are nuanced, you have to understand each one and the nuances of each one so you can recognize and mitigate early on so that patients can stay on effective therapies without having undue side effects, and have good quality of life. And with that, I thank you for your attention. Thank you. Thank you, Dr. Moore. So we covered a lot, efficacy, covered the class, how it works, efficacy in certain areas with certain drugs, and then we need to cover toxicities. So basically all the stuff you need to know how to use these drugs. So I'm gonna go through a couple cases and then get some commentary. And so again, be prepared to vote. So here's the first case I'll present. So a 75-year-old patient presents with recurrent platinum-resistant ovarian cancer. She is interested in discussing participating in a clinical trial with Mervituximab, but is concerned about ocular toxicity. A friend told her that the medication will make her go blind. Which of the following most accurately describes the clinical experience with ocular toxicity seen in the pivotal trials with this agent? So A, the friend is right, it will cause blindness. Now I'm gonna give you a hint, that's not the right answer. Visual changes largely occur due to hardening of the lens, which just causes a refraction effect. C is the principal effect is combination of keratopathy and blurred vision and predictable in onset. D is while visual disturbances are largely reversible, it usually takes months to resolve. And then E, ocular toxicity was frequent cause of treatment discontinuation for Mervituximab in the studies. So go ahead and vote. Excellent. All right, is there any of these answers that, you better not say A. Are there any answers here that you think or you have heard or that you're concerned about? Anybody? Okay. Mostly looks like you all agree with that. Okay. Or else you're super shy. Or you're having post-prandial, not complete insomnia. Okay, let me go on to the next question here. Okay, so that was the right answer. Okay. So this patient, five weeks after starting therapy, she reports having some difficulty driving at night, particularly in reading traffic signs in low light. She gets an ophthalmological exam and demonstrates no cordial injury. So this was graded as a grade two. So the question is, based on what Dr. Moore just presented, what is the appropriate next step? A, discontinue therapy. B, hold dosing until resolved, then reduce the dose in the next cycle. C, hold the dose to recovery to grade one, then restart the next cycle at the same dose, unless it was more than two week delay, or don't hold the dose and dose reduce the next cycle. Okay. You know, it takes some, I will tell you, it takes, um, and you'll, we'll learn this because you're all smart. It just takes some practice, uh, to, to sort of get this, get, get your groove down with eye toxicity with these, uh, agents. So you know, the first time you have a grade two, which is just a little bit symptomatic and, and usually they come in like cycle two day 15, like that's usually when they come in, it's usually resolved by the time they're supposed to get cycle three or pretty close to that, like a week later. So that's a grade two that's quickly resolved and you can just restart at the same dose and keep cruising. And a lot of times it never happens again, but if it does happen again, or if it takes quite a bit to come down from grade two, back down to asymptomatic, like more than two or three weeks, then we, you know, on study, we would discuss it with the medical monitor, but usually we would dose reduce in that case. So, um, so it sort of comes down to how bad a grade two it is and how long it takes to recover. It hasn't happened before is to determining whether or not you keep them on the same dose or dose reduced. And you just get, I think, a feel for it as, um, as you treat more and more patients, uh, with this agent. So, uh, it's not hard, but it just takes some time and a lot of people don't have a lot of experience with these medicines. We just happen to put a lot of patients on it, so it'll just take some time and reaching out and getting help and having a good partner with either optometrists or ophthalmologists to help kind of guide you. It's a really good advice. When we start using this drug, we did not know how to manage the side effect, but we perform a learning curve in the management and we work together with our ophthalmologist and ocular expert, and now it's really easy to manage. And I fully agree with you. The first occurrence, we simply wait and when resolved, we restarted the same doses. I mean, I think it's quite important to identify very early in the patient's course these ocular events because if you are able to identify and then you refer the patient to the ophthalmologist, I mean, you can proceed with this action. Otherwise, the patient needs to have the drug stopped for a longer time, and eventually you need to reduce the dose. So as Keta said, this is a learning curve, and then you need to be very aware about the potential side effects related with the drug. You know, as this drug goes out into the wild, you know, you're going to see all kinds of different usages of it and different variances. What's the best communication tool, I guess, both to patients and providers that we can provide, you know, ahead of time to, you know, help them get through kind of the learning curve? Because you all have all administered this drug many times, so I think it might be helpful for those who have not used it. So that's a great question, and I think I can point to a couple of things. The first is that we were worried about this when we launched Forward One, you know, because it had been open, there were over 100, like 200 patients treated by all at phase one sites mainly in the U.S., and then we launched Forward One globally, so we were really worried about how trialists across the globe would manage this, and they did great. You know, it really was just, it wasn't, and I don't want to say it's not an issue, but it wasn't an issue for the trial. We had 1% of patients discontinue because, you know, you guys are smart and learned how to do it really quick, and we had the ability to partner with eye specialists in all over the globe to help patients. So I think one thing just to say is that we've already, at least at trial centers, launched it well, and that's a nice signal for moving forward successfully. I think the other thing that I think would point to, and I just will call out, and thank you Immunogen, but I will call out Cigen. They did a nice job rolling out to Zotamab, which has a different eye toxicity, but some of the same mitigation strategies in terms of eye exams and eye drops, and so the patient-facing documents are pretty exceptional for how to use that medicine, and the establishing networks to eye doctors for those that didn't participate in the trial, like at my site we didn't participate in that trial. So there's kind of a halo effect, I think, already in place, like you already have physicians using an ADC that has some eye toxicity and guide cancers with examples of really nice patient-facing and physician-facing checkboxes. So I mean, I think that they've done a nice job setting the roadmap for how to do it well, and I think that Immunogen will likely build on that, and the other companies will build on that from there that have these similar drugs. But in my opinion, the foundation's laid for us to do this very safely for our patients. Okay, great. Kat? I fully agree. I just want to add my experience. Patients are usually scared about what they do not know. So if we spend time in explaining this kind of symptom and reassuring them they solve, they are very no consequence. If we explain the importance to use premedication, to use eye drops, it's easy to manage. And the second advice I really want to suggest is to work with a dedicated ophthalmologist, because these side effects are new for the oncologist, but also for the ophthalmologist. So if you identify in your network of colleagues a dedicated physician, it will be easier to manage in a multidisciplinarity board. And if I may, for sure that education is a key part in the development to incorporate this drug in the daily practice. But when you inform the patient, in my experience, it's quite important to convey that the side effects are fully recovered, that will not be permanent, because when you explain any kind of eye adverse event, the patients are really concerned about that. So I think the key point is, you know, it will be mild, grade one or two in the majority of cases, and for sure you will be fully recovered following the procedures and the management that we will recommend you. So I presented that case, that first option, kind of in jest, you know, that the friend told her it would cause blindness, but actually that came from a real case, a patient of mine who basically said, oh, I heard that causes blindness. So it's out there. So if you've never given it, you should know that your patient's expectations are that they've heard the worst of the worst from somebody who obviously, you know, doesn't have any experience, but heard it from somebody who heard it from somebody who probably heard it from somebody. And it was on Fox News. No, I'm just kidding. It's a political statement. So I'm just kidding. So this patient, so we did that, and so this patient really did great. She returned, and it was nearly resolved, and so the question here is about surveillance. So we always see these, you know, we present these cases, you have a toxicity, we kind of fix it, it goes away, and we never think about it again, but this is obviously something we need to continue to monitor. So the question here is, if this patient had resolution in an easy, you know, for the first cycle, just as we had outlined, what is the recommended frequency of subsequent eye exams? So is it, we don't have to worry about it because we've stopped therapy. Should we do it every other cycle, every, excuse me, every cycle, every other cycle, or only wait until the symptoms are? Some of this, I ask this question because, you know, when people have a toxicity that they're not familiar with, they usually are hypervigilant, making sure that the patient's actually safe. That's why I ask this question. See, the more discussion I had, people were saying, oh, wait a minute, then maybe I'll change my answer. Okay. So I'll go on to the answer here. So it's every other cycle. You guys, yeah, go ahead and comment. I was joking with Dana because when we performed the trial, we were scared about this new kind of side effect. So after the patient experienced grade two or, in one case, grade three ocular toxicity, we used to visit the patient by ophthalmology every cycle. When I received FDA inspection, the inspector told me, too much. Every other cycle, it was enough. You had a violation for doing too careful monitoring. Yeah. That's classic, yeah. So I know we focused a lot of discussion on marivituximab because that's kind of what we wanted to get an interest in. I know it's available only on research. So obviously, a lot of this experience would have come from clinical, following the clinical trial protocol, unless you didn't. But that's all good. So I think as these things, again, as they get out into the public, hopefully soon, some of this will come back up again. So I encourage you to revisit this lecture because it will be made available on the education portal so you can kind of listen to how we've navigated some of these adverse events. One thing I wanted to ask you guys, oh, I know, in the audience. So you heard from Keta, she said to make sure you have a strong working relationship with your ophthalmologist. In the United States, we have a lot of optometrists that are eye professionals that aren't physicians. So Katie, I wondered, since you're drinking, I wondered if you could tell us, what do you think about sending them to Walmart or Target to have an eye exam versus sending them to a physician to do a fully dedicated ophthalmological exam? So I think it's optometrists in the U.S. are actually quite qualified to do these exams to an extent, and the same is true for Tazotamab, where you're assessing for conjunctivitis. They can do a slit, you can do a slit lamp, which I say isn't hard, even though I've never done one, but apparently it's not hard. So you just have to do a slit lamp. I think the key thing will be that, and Dr. LaRusso brought this up, that many of them, if any, will have ever seen corneal microcysts because they don't exist in nature other than this really rare genetic disorder. So basically no one's ever seen it unless they're at some specialty center. And so you have to, if you're going to use like a Walmart or whatever optometrist, which is fine actually, it's cheaper for the patient, you just have to send them out with some information that has been provided in the clinical trials, and I assume will come out when the medicine is available commercially, that you can send with your patient to the optometrist or ophthalmologist saying this is what we're looking for, this is what causes it, and this is sort of how the information we need to know from a grading standpoint. And then they relax. But if you just send them and the patient's like, I have blurry vision, and then they look and there's all these little microcysts, they get very concerned that they're on something that could be permanently damaging their eye. So they're fully capable is my short answer. My long answer is that there just has to be a small bit of effort initially to sending them with information so that they know what the patient's on and what the expectations are and what they could see, so they can communicate back with us effectively and not cause anxiety on the part of the patient, because I've too had, early, early on, it's been years now, but patients that came back saying the ophthalmologist told them that they were going to go blind and this drug was going to permanently damage their eye, and I'm like, no, no. But they're genuinely worried because they don't see these microcysts in life normally. Yeah. Yeah. You know, I think, you know, if you think about, you know, back in the day when we started using Lifesumdox Rubicin, we had people get echocardiograms like they were on Adriamycin. And when we started people on immune checkpoint inhibitors, you know, that we had an army of people that we had to consult with for every adverse event they had, and we got better at it. Like, just like you say, we're, you know, you guys are smart. You figure out, you take your clinical experience and you go forward with it, and it's something that comes with. But this is a drug that's coming in, you know, it's only limitedly available for Sodamab, and we hope we'll have Merfotexamab soon. So it's just something that's going to be rolling out through, you know, throughout the world, hopefully for therapy, and so getting that experience, I think, will be really helpful. Okay, let me go on to the last case. And I remind you, there's some mics out there, I can't see everybody, but there's some mics on either side of the room. So if you have questions, just bring them on. Otherwise, I'm just going to make up these questions. No. Just kidding. I put my friends on the spot. Okay, we have another patient, 73 years old, who, no relevant family history, no relevant surgical history. It was first diagnosed in 2012. She had high-grade serous ovarian cancer. She was BRCA wild-type in the tumor. She had a treatment with optimal cytoreduction, stage 3C, and then was treated with PacCarbo and Bev for six cycles, and then was on Bev maintenance, and she went into her first remission, which lasted almost five years. So then she presented with a rising CON25, had a PET scan that showed adenopathy, both above and below the diaphragm, and then was treated with Pegleted Lifestyle with Doxorubicin and Carboplatin as her first regimen. She had a response to that and was placed on a PARP inhibitor, like you've not heard anything about that at this meeting. She started that in 2018, ultimately had a progression with, again, adenopathy, elevated CON25, been on it for two years, went on to a third line of therapy, so it had been two years since her platinum, went back on PacCarbo, Carboplatin, Liposomal Doxorubicin, and Bevacizumab. Anna, was this on a trial, or did you just give her as per the protocol? Just for reference, it's a clinical practice. Clinical practice, okay, so they were treated as far as the OVAR-221 protocol, but this was treated as a standard of care. She got six cycles of that, had another response with a declining CA125. So long history, you know, again, now almost eight years since diagnosis, and then was put on a clinical trial for platinum-sensitive high folate receptor alpha expression, the PICOLO trial, which you heard about. And so the question I'm going to raise to you is that she calls the office with a two-week history of cough and mild shortness of breath while climbing stairs. So what is the next appropriate step? A, ignore her symptoms and tell her to get a treadmill. Man, you guys are, I got to get the energy up here. That's not the right answer, but I know Mike Pearl back there is going to say A. All right, reassure her that this is expected and let her know, have her let you know if it gets worse. C, have her come to clinic for evaluation, check her for COVID, vitals, exam, and if it's all normal, reassure her and tell her to come back next infusion. Or D, have her come to clinic for evaluation, assess her respiratory status, check her O2 saturation, and get some imaging. Go ahead and vote. We have a very talented audience. I think we'll make sure that this goes out to all the other ISSs, because nobody's as good as you guys. Okay. I'll move on here. So that, of course, is the right answer there. So her imaging shows some mild patchy changes. Her O2 sat was normal, vitals and the rest of her exam is normal. So you expect non-infectious pneumonitis, grade two. What's the next step? Discontinue therapy. Hold the therapy until it's resolved and dose reduced for the next cycle. Hold the dose till recovery to grade one and then restart the next cycle at the same dose unless it's held for more than two weeks. Or D, don't hold the dose, but reduce it on the next cycle. So same answers as the first one. Oh, there we go. Now we got something. This one might lead to a little more controversy. So this is good. Okay, let's see if we get any more answers. Hi, guys. Since you guys just showed up, we're going to restart the whole program over. Did you get something to eat? Okay. All right, let's go on here. So the answer to this is C, which is to hold the dose to grade one, restart on the next cycle the same dose unless held more than two weeks. So you guys, comments? Yeah. So this is, and I didn't have enough time to really go into the nuances, but this is really where you have to pay attention to pneumonitis and you have to understand each particular drug. So unlike neutropenia and other things where there's sort of a very clear and consistent intervention with pneumonitis, it varies. So I gave you the example and I think the people that answered A heard me when I said with trastuzumab durextacan with symptomatic pneumonitis, the recommendations, at least on the most recent mitigation strategies, are to stop because they had deaths. And so that's correct for that agent. For mervituximab, we actually saw pneumonitis grade one. I actually don't remember the rate, but it wasn't rare. So we would see it on the CT scan, ground glass opacities, but the patients felt fine and they were never symptomatic and we just didn't hold dose and we kept treating and there really was, I think, maybe only one or two symptomatic. I'd have to double check, but it was a very minimal, no deaths and no grade three. So with that particular drug, while I'm not saying you can be blase about it and just ignore it, here you do have the opportunity to sort of hold, this is symptomatic, so I would have held, I might have started steroids, brought it back down to resolved or grade one and then I would have restarted either at the same dose or a dose spot. Again, it depends on how severe the CT looks and how symptomatic she was. This is sort of the art, I think, of medicine, but you can restart here and then if it happens again, I would probably discontinue. So this drug, pneumonitis, you can see mervituximab, but it's very rarely symptomatic and you really rarely have to modify, whereas trastuzumab, duroxetacan, it's a very different story and then I think we'll see what happens with lupafetamab where the dose optimization may have eliminated much of it and so we still have, I think we just don't really know the mitigation for that one other than we have to pay attention to it. So it's very much drug dependent, but not ignorable, it's what I would say. Okay, any other? Sorry, I fully agree with you, Katie, you know, I mean the frequency of pneumonitis with mervituximab is quite low. Nevertheless, we need to be aware about this option and if the patients complain about any kind of respiratory symptom, we need to rule out that the patient is not suffering from pneumonitis because if we are able to identify early, either radiological or clinically, I mean, we can proceed in that way and the patient can continue under treatment. If we are not able to identify, to detect, then the patient, you know, can develop a grade three or even greater and then we will be in trouble. It's quite a similar comment. In most parts of cases, this radiological picture are identified when a patient perform a CT scan for tumor evaluation, so are completely asymptomatic. But it is absolutely important if patient refer any symptom, she immediately has to come to the hospital to evaluate the pulmonary situation. This is important. High resolution CT scan is the best. Yeah, I purposely put this case in to highlight something that I think all of the speakers have mentioned. So one, it's not something we ignore. Two, it is absolutely drug dependent, right? So it's a different, different drugs have different adverse events and getting experience with the drug that you're using rather than just the class, you know, it's the same thing as saying, well, the whole class does this or the whole class does that. We saw the differences on the ophthalmological adverse events, although the kind of the severity of that is actually more consistent than potentially you might see from pneumonitis that would come from immune checkpoint inhibitor versus something that might come from gemcitabine, which might come different from an ADC and even within the class of the ADCs would be different. So kind of the motivation here is really to provide you a spectrum of how these adverse events can show as you gain more and more experience with the drugs as they roll out into this class to be mindful of the drug specific adverse events just like we are with all the other agents we do that we treat patients with. We got about a minute left. Does anybody have any questions from the audience or comments that they, from their own experiences or anything I didn't cover very well? Doug, did I do anything wrong? Okay, I got the thumbs up from him. That's important. Okay, any final words from you guys? This has been a great session. And I just wanna highlight again that this session will be available through the portal and it's gonna be a good one to go back and review. I know I often listen to these guys many times talk over and over again to make sure I understand the nuances and the fine points of what we're dealing with. I would like to say that this patient had a great response with MIRVE into the picolotrial after first cycle. I mean, she got a partial response with a reduction of 50% in the target relation. Yes. So it was fantastic. Yeah, it's super exciting to see that. Now, this patient now 10 years from diagnosis, right? I mean, she has absolutely regular normal life. Wow, there you go. Last short comment. These are really the most interesting class of agent that we are using in this moment. In all the disease, in all the gynecological cancer, in setting a patient to have already received PARP, already received BAP, this is in my already receiving immunotherapy, this is the most interesting class of agent we are using. Oh, fantastic. Well, with that, I wanna thank you all for joining us for this session. Great, thank all my three speakers for their wonderful presentation. And... Thank you. And I also wanna thank you, Minjin, for supporting the session. It's just been fantastic. So have a great rest of the meeting.

ocular toxicities

pulmonary toxicities

antibody-drug conjugates

gynecological cancers

conjunctivitis

keratopathy

regular eye exams

mitigation strategies

pulmonary toxicity

non-infectious pneumonitis

respiratory symptoms

specific toxicities