Welcome to the ISLAC webinar, Emerging ADCs and Their Role in Advanced Lung Cancer Treatment. I am Antoinette Wozniak, I am the Chief Scientific Officer for the Lung Cancer Research Foundation and an Adjunct Professor of Medicine at the University of Pittsburgh. I will be your presentation moderator today. We will start this activity with some brief housekeeping items. This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education. The International Association for the Study of Lung Cancer is accredited by the ACCME to provide continuing medical education for physicians. The International Association for the Study of Lung Cancer designates the live format for this educational activity for a maximum of one AMA PRA credit one category one credits. Physicians should only claim credit commiserate with the extent of their participation in this activity. All faculty planners and reviewers for the webinar today have disclosed their conflicts of interest. This information is provided on the following two slides. Okay, we'll get started. Our first presenter is Dr. Daniel Tan. Dr. Tan is the Head of the Division of Clinical Trials and Epidemiological Sciences at the National Cancer Center Singapore. He's also Director of the Experimental Therapeutics Unit and a Senior Clinician in the Genome Institute of Singapore. He is an Associate Professor at Duke University, which collaborates with the National University of Singapore. Dr. Tan will discuss ADCs, their structure, mechanism of action, and future development. Dr. Tan. Thank you very much, Dr. Wozniak, for this kind introduction. And it's a real pleasure to have the opportunity to speak on this topic and kick off this three lectures on ADCs. So I'll spend the first part talking about the structure, mechanism of action, as well as some of the drug development opportunities on the horizon. So to kick us off, I think we are increasingly hearing about antibody drug conjugates. And in terms of structure, they are quite simply an antibody that we attach onto a cytotoxic drug via a linker. And in theory, because of the ability to now increase the dose of cytotoxic drug on an antibody, you could increase the minimum effective dose. And conversely, because again, if we manage to have this payload linked onto the antibody in circulation, you could actually increase the maximum tolerability. And this, in theory, should increase the therapeutic index. But however, as you can see, while some of these concepts have been validated preclinically, I think the clinical experience perhaps is yet to be validated, and certainly at least with this generation of payloads and linkers that we've seen. If we go on to the brief timeline for ADC development, it really very much kickstarted only after the ability to produce monoclonal antibodies, and again, the further advance was when we managed to humanize some of these antibodies as shown, you know, to reduce immunogenicity. And that really resulted in subsequent development of the first ADCs targeting CD33 and a subsequent slew of ADCs that were increasingly approved in a range of different cancer types. And today, there are 12 FDA-approved ADCs and more than 400 in development. This just gives you a snapshot of some of the FDA-approved ADCs. You can see across a range of different cancer types, some of the different targets, and also a range of different payloads here, largely targeting microtubules or topoisomerase inhibitors. Now, if we look into some of the key considerations and the component of an ADC, you can see some critical aspects include, of course, the antibodies and the selectivity of the antibody, as well as the precise drug or the payload, as that is the thing that elicits cytotoxicity. And when we look into the linker, it's actually worth mentioning that there are two components to this. One is the linker with the antibody, and that's governed by bioconjugation methods, and that in some ways determines the drug-antibody ratio, which can affect ADCs, the molecule stability. And then there's the linker-drug attachment. And in this subject, you would have heard that some are cleavable, non-cleavable. Some are particularly cleaved in response to a certain pH and certain conditions at the tumor. And I think this, again, can be a critical aspect that determines efficacy of a particular ADC. Now, if we now look into the ADCs in development in non-small cell lung cancer, I think the point in this slide is, again, we do see a range of targets that have been gone into development, a range of different linkers, as well as different payloads. Again, as I mentioned earlier, topoisomerase, as well as microtubule inhibitors, predominate this current generation of ADCs. And of note, some of these ADCs are in selected populations, while others are in all-coma population. And if we now focus on individual considerations in terms of the choice of target, starting with the choice of target, I think there are important antigen properties that are worth looking out for, that is homogeneous expression levels in the tumor. And in order to achieve that therapeutic index, low or no expression in healthy tissue, as well as selectivity of the specific epitopes. So there are, for example, specific glycosylation residues that may allow greater selectivity. Antibody properties in terms of affinity and avidity will also need to be considered, as well as the extent to which they are humanized in order to reduce this home immunogenicity. And finally, again, the half-life in circulation can also be a consideration. Other aspects include whether, in addition to being able to bind to the target, there is a certain oncogenic dependency on the target. And in this instance, HER3 sometimes could be one of them, where you have dimerization across with HER2 and path activation. So part of the therapeutic effect is disruption of that, of the receptor. And also other factors include internalization, trafficking of the payload, as well as, of course, the chemosensitivity of the drug. Now, all of this target biology is also critical in consideration of what we would then be able to select optimally, you know, the patients that may benefit the most through using robust predictive biomarkers. And these ideally should be specific and quantifiable. And this, in a way, should reflect both the antigen target and perhaps, if feasible, even chemosensitivity biomarkers. Now, talking about A. linkus, the next component, it does increasingly, it is increasingly recognized as playing a key role in ADC efficacy. And the characteristics can substantially impact the therapeutic index and hence efficacy and pharmacokinetics. And in this, it does, in a way, maintain that balance between the monoclonal antibody, as well as the cell-killing ability of the cytotoxic drug, as well as maintaining, hopefully, a reduced systemic toxicity as it's bound onto the drug. For this, you know, it tries to maintain high plasma stability in circulation to prevent premature drug release. And ideally, drug release in the right circumstances to maximize therapeutic effect. And so, I show you on the right here some classification systems between cleavable and non-cleavable. And with the cleavable linkers, you can, again, as I mentioned, specific conditions like pH or certain presence of certain enzymatic conditions can actually contribute to that release of drug at the site of tumor. Now, another important concept is this drug-antibody ratio. And I alluded to this earlier that, to some extent, this is a property that's contingent on how well, how the drug is bound to the antibody and the number of drug molecules that can be attached to this antibody. When you have a low drug-antibody ratio, it reduces the potency, in a sense. But if you have too many molecules based on using current linker technology, you can also lead to some disadvantages. For example, instability of the ADC, hence increased systemic effect, and alter, augment the pharmacokinetic properties of the molecule. So, there has been a lot of effort in terms of trying to further engineer more precisely the drug-to-antibody ratio. And again, this is partly due to, again, how these ADCs were made previously, just stochastic linking between using lysine residues. And you can see, you may end up binding to various sites on the antibody. And then, the next iteration was using the cysteine interchange disulfide bonds that gave a lot more precision in terms of specific conjugation sites, and with a DAR of three to eight molecules. And the future, probably it's moving towards more engineered drug-antibody sites that we can bind these drugs onto the antibody. Hopefully, in the bid to have more predictable PK and ADC stability as a result. Now, in terms of payloads, they are the chemotherapy agent that ultimately exerts the cytotoxic effects on tumor cells. Commonly, as I mentioned, microtubule binding agents and alkylating agents and topoisomerase, as you can see in this pie chart on the right, do account for majority of the ADCs in development. But again, there are a range of different payloads in development shown in the figure, and certainly more diverse payloads are anticipated, including non-chemotherapy payloads, such as immune-stimulating agents. Now, just to hone in on the mechanism, talk a bit about mechanism of action of ADCs, I mentioned about the importance of tight drug binding while they're in circulation, and then at the site of the tumor, these ADCs then diffuse to the target cells, and the first hit really is the initial binding of the antibody, depending whether it does have some immune effector function conferred there, or there are specific disruption of the receptor dimerization and resulting in the therapeutic effect. But then subsequently, then the ADCs become internalized, processed by sometimes endocytosis mechanisms, and again, endocytosis of these payloads is again an important, increasingly important recognized area. And then the payload eventually is released in the cell, resulting in cell death, and potentially there is the chance for bystander effect as well, especially with membrane permeable payloads when they get released. So ultimately, I think with each ADC, there is a bit of a balance of how it maintains the binding in circulation versus how it's deployed at the site of the tumor, and this balance ultimately could determine how successful we are in developing, or how efficacious the extent of toxicity we observe in the current ADCs. So just briefly on some of the current drug development efforts and perspectives on the horizon, again, I think we'll cover some of the efficacy data that we've seen in lung cancer, but I think optimizing patient selection is going to be increasingly important, and balancing out and being able to manage some of the side effects that occur, rational combinations to enhance efficacy and overcome resistance will need to be looked at. Again, in terms of patient selection, if we look across even a drug like trisuzumab durextican targeting HER2, we do see different biomarker classes even being used across different cancers, in breast cancer, HER2 expression, gastric, you have fish in HER2, and lung cancer, we use HER2 mutations, but again, the thresholds also do seem to be varying in different cancer types as to the extent of efficacy. Again, highlighting some of the differences, perhaps in how each individual cancer may traffic and have the effect of the drug may be different in the context of different cancers. It could also reflect some of the efficacy of the specific chemotherapeutic agents in the different tumor type settings. Now, when we talk about resistance, there are a range of possibilities. Again, this is a relatively new field, so what we do and what are anticipated include things like antigen, reduced expression on the cell surface, perhaps resistance to specific payloads, in which case there may be a role for cycling through even ADCs with similar targets with different payloads, and vice versa, using the same target with a different, or using a different target with the same payload, depending on the mechanism of resistance. And as I mentioned earlier, given the mechanism of action, there could be other kind of ways that the cancer cell may subvert the effectiveness, including things like alteration of lysosome processing, trafficking of each of these, the payload trafficking into the tumor, and all of these that may be a rationale to explore the use of small molecules to modulate some of these processes. In terms of combinations, again, we have been, we have seen exploration of existing stance of care combined with these ADCs, including chemotherapy, immunotherapy, as well as anti-VEGF combinations. In this instance, I think there will be some attention paid to some of the overlapping toxicities, for example, pneumonitis, and certainly we will look forward to some of this data that hopefully will be, will emerge in the coming years. So, this concludes my talk, and just to take a message here, I think antibody drug conjugates are certainly here, and will increasingly feature in our therapeutic toolbox. The key challenges now include optimizing patient selection. I think we've seen some proof of concept clinical efficacy that Dr. Levy will cover in the next talk, and I think that one of the key is going to be able to then be experienced and familiar with some matchment of some of the toxicities as well. And again, I showed the schematic here, highlighting some of the limitations with the current ADCs. Perhaps in the clinic, we're not necessarily seeing that that will increase and widening of the therapeutic index, but indeed, at least we do see enhanced efficacy. So, with the same kind of dose, chemotherapy dose, and this therapeutic index, however, may be improved further through rational drug development efforts, including using newer linker technologies, perhaps combining with alternate payloads, mentioned there, including possibly even targeted therapies. And again, I think some of the future efforts are going to be focused on rational combinations for which more data is anticipated. So, with that, thank you very much for your attention. We'll be happy to take questions later, and for now, I'll hand the time back to Dr. Wozniak. Thank you, Dr. Tan, for that excellent presentation. Our next presenter is Dr. Benjamin Levy. Dr. Levy is an Associate Professor at Johns Hopkins School of Medicine and is the Clinical Director at the Johns Hopkins Sydney Chemo Cancer Center in the National Capital Region in the United States. Dr. Levy will address the use of antibody drug conjugates in lung cancer. Ben? Thanks, Toni, and thanks, Dan, for kind of creating a foundation, making my talk a little easier, giving a lot of the rationale of why we're starting to leverage these drugs in our clinic. And I think Dr. Tan did a nice job here, elegantly going over the three components of an antibody drug conjugate, the monoclonal antibody, the linker, and the payload, and all the nuances and intricacies that are going into this. And we've come such a long way in synthetic biochemistry to develop these drugs. And, you know, for the drugs I'm going to be talking about, you know, all of these antibody drug conjugates, most, if not all, have settled on an IgG1 molecule. The differences between these drugs will be which target that IgG1 goes after, the payload, obviously, and the linker, because all of these are a little different. And all of them have, obviously, different activity, depending on which setting you're looking at, different targets, as I've discussed, as well as different toxicities. So we're not short on targets right now. I mean, the sky's the limit. And what I've come to, what I think we've all started to witness is this antibody drug conjugate blitz, where we've got all these novel technologies and, again, advancements in synthetic biochemistry to really harness these drugs, put the three components together, allow them to, as Dr. Tan talked about, target an antigen, be endocytosed, release the payload. But there are other ways these drugs may work as well. I'm going to go over most of these compounds here. I just want to say one thing before we start, which is that, and I know we have some pathologists on the call, whether immunohistochemistry or protein expression is truly predictive of response or is the right target for these drugs is unclear. The story looks simple schematically, but whether or not protein expression really predicts efficacy of these antibody drug conjugates, we're not really sure. So we really only have a nascent understanding of how these drugs work. That's okay. We'll figure it out as we begin to leverage these drugs more and more in clinical trials, as well as in the approved space. So we'll start, of course, with trastuzumab durex decan. It is an antibody drug conjugate that has, once again, an IgG1 monoclonal antibody targeted to HER2, a topoisomerase 1 inhibitor payload, as well as a tetrapeptide-based cleavable linker. Cleavable linkers, as Dr. Tan mentioned, a little bit more flexible in their ability to allow detachment of the payload from the monoclonal antibody. It's important to talk about this one first because it is FDA approved in non-small cell lung cancer, specifically for HER2 exon 20 mutations. The trial that got this drug approved by the FDA was the Destiny Lung 2 study, not the study published in the New England Journal of Medicine, which was the phase one experience. This is the Destiny Lung 2 study. This was looking at patients with metastatic non-small cell lung cancer harboring a HER2 mutation who had received at least one prior line of treatment, randomized 2-to-1 to 5.4 mg per kg Q3 weeks or 6.4 mg per kg Q3 weeks. The reason that they did this was in the publication, the earlier study that was published in the New England Journal of Medicine that used 6.4, there did seem to be a high rate of ILD. They wanted to see if a lower dose could one, achieve the same efficacy and two, be better tolerated as it relates to interstitial lung disease. The objective response in the 5.4 mg per kg was 53%, a little bit higher than we saw in the 6.4 mg per kg, which was at 42%. We saw meaningful objective response at the 5.4 mg per kg. We saw a disease control rate of 90%. We saw a duration of response in the 5.4 mg per kg dose that hadn't been reached. I think importantly, what we saw is, remember, from the Destiny Lung 1, that was the one published in the New England Journal of Medicine, we saw a interstitial lung disease pneumonitis rate of around a quarter of patients. This is the slide from Destiny Lung 1. Fast forward to Destiny Lung 2, the adjudicated drug-related ILD, we can see in the 5.4 mg per kg that the adjudicated ILD was only 6%. The bottom line here is, number one, 5.4 mg per kg of trastuzumab drug CKAM is approved as a second-line drug for HER2 exon 20 mutations, not HER2 overexpression, not HER2 amplification, but HER2 exon insertion 20 mutations. Remember to look at your NGS report. This is important because this is the first FDA approved ADC in non-small cell lung cancer. We know at the 5.4 mg per kg dose that the ILD rate is quite low and is something that we can monitor carefully, and I know we'll talk about toxicity in the next section. Moving on to pituitumab drugs CKAM, this is a HER3 antibody drug conjugate. Once again, an IgG1 monoclonal antibody targeting HER3, a protein that's overexpressed in non-small cell lung cancer, a cleavable tetrapeptide-based linker, and then, once again, a toporhizal 1-inhibitor payload. This compound was originally exploited in a phase 1 study looking at multiple doses, but what was reported on was the 5.6 mg per kg dose specifically in patients with adenocarcinoma with an EGFR mutation who'd had prior EGFR TKI and platinum-based treatment or chemotherapy. If we looked at patients who had, this is the table one of any study, looking at patient and tumor characteristics. Again, the most important is looking at 5.6 mg per kg dose, the 57 patients. All of these patients had received a prior TKI. Most of these patients had received a prior platinum doublet. Again, these were all patients who had an EGFR mutation. These were patients who got TKI, chemotherapy, maybe another drug, and then went on to receive pituitary map directs decant. The objective response here, if we look at those patients who had had prior TKI plus or minus platinum-based chemotherapy or who had had prior TKI and platinum chemotherapy, the objective response rate was roughly 40%. This is exciting. This drug was given at an average line of therapy in this study of three or four to elicit an objective response rate of 40% in patients who are highly pretreated where EGFR mutated with an unmet need is pretty remarkable. I'm excited about this drug. I look forward to seeing where it heads. I have not used this drug in my clinic yet, but nevertheless, to me, eliciting a response rate of 40% at an average line of therapy or three or four, my take is if you move this drug up into the first line or second line, you're going to see a higher objective response rate only for the biological rationale that there's more heterogeneity, the longer line of treatments you get, and you may have an opportunity to elicit real cell kill at an earlier line of therapy. My own scientific postulate there. This drug elicited response rates no matter what the EGFR TKI resistance pattern is. Importantly, HER3 expression did not predict response to this drug. We'll see this same theme in the TROP2 experience as well. It begs the question, is overexpression or is protein expression the real biomarker here? I'll put my nickel down and say probably not. I think we'll see later on, but I'm not convinced that overexpression or protein expression is what truly predicts response to these drugs. Once again, we have a nascent understanding of how these drugs truly work. We need more preclinical work. Perhaps we do the clinical work first and work backwards and figure out who are those patients who actually responded. This is how a lot of drug development has gone. In terms of toxicities, we are seeing AEs with this drug that are manageable, cytopenias, fatigue, anemia. We are seeing, again, I haven't used this drug. My understanding, talking to those who have, is that it's fairly well-tolerated and can be given. There are dose decrements and dose reductions and dose interruptions that had to be used in this trial. Nevertheless, a drug that I think will play into our clinics very soon, maybe next year or so. There are ongoing studies with protrudibab drugs, decan, and a niche of EGFR mutation. We're combining it with osomertinib in the frontline. We'll have to see if the toxicity can be mitigated. We'll have to see if this elicits meaningful response rates. We may have to compare this combination to FLORA2, which we'll get results on very soon, with chemo plus TKI. It's getting confusing, it's getting complicated, but that's generating a lot of enthusiasm and it's generating a lot of options for our patients. Moving on to TROP2. TROP2 expression is seen on a lot of lung cancer. It's ubiquitously expressed on many cancers and not expressed on normal host tissue, so it's an ideal target. The first TROP2 ADC was sesatuzumab guaviticin. Once again, a monoclonal antibody that binds to TROP2, a hydrolyzable linker, and a cytotoxic payload, which is a toperoisomerase 1 inhibitor, SN38. This compound was looked at in the lung cancer field a long time ago, which seems like a long time ago, four or five years ago, which is an eternity in lung cancer because so many changes have occurred. We see that there was a cohort of 54 patients looking at two different doses of sesatuzumab guaviticin, 8 milligrams and 10 milligrams. This was in a highly pre-treated group of patients, unselected for TROP2, and the objective response rate was 16%. That's not terribly encouraging. Nevertheless, this drug appropriately is being brought back to be evaluated. We see AEs in this trial. Once again, GI and cytopenias, GI toxicities and cytopenias were seen. We didn't see stomatitis. Once again, TROP2 expression did not seem to make a difference in predicting efficacy. On to the next TROP2 ADC, datapodumab drugs, TCAN, once again, an HG1 molecule targeting monoclonal antibodies, sorry, targeting TROP2, a topoisomerase inhibitor payload, a tetrapeptide-based cleavable linker, has a DAR, as Dr. Chan talked about, the importance of DAR of four. The first study to look at this was a first in human phase one study looking at 50, 50, and 80 patients respectively in a four, six, and eight milligram, kilogram dose, and looking at maximum tolerated dose safety and tolerability, and this is the data we saw from the original presentation. This was an objective response rate at the four, six, and eight milligram dose of the objective response rate was 23%, 21%, and 25% respectively. We see the spider plots here on the right. These are highly pre-TRO group of patients. They are unselected for TROP2. This has been subsequently updated and published in the Journal of Clinical Oncology, JCO. The objective response rate of the six mg per kg, which is the dose that's going to be moved forward in all studies, went up to about 26, 27%. So, this is an older slide from the original presentation at Royal Lung, and again, the presentation, the publication in JCO shows a higher response rate in that six mg per kg. That's what's going to move forward. Look at the spider plots here. Some of these are durable. Some of these are meaningful. Some of these are ongoing. I've had a lot of experience with this drug, and I would say that, you know, this is a drug that will probably make it into our clinic as an FDA-approved drug in the next six to 12 months. You know, you got to talk about efficacy as well as tolerability. I always ask the question, is the juice worth the squeeze? Does the drug have meaningful activity, but are the toxicities being able to be mitigated? One of the things that came up with this drug and comes up over again is the stomatitis. This is a side effect that we're not really used to dealing with in lung cancer, and we saw high rates of stomatitis here. Most of them are grade one or two. That's important, but it is there, and we need to learn how to mitigate it. Happy to answer questions at the very end. We see GI toxicities, fatigue, again, cytopenias, but that stomatitis comes front and center for us, and we need to be mindful of it. Again, most are grade one or two, but we need to understand how to mitigate that moving forward. The Tropion Lung 2 study, I think, is important to talk about because it is the first ever study looking at an antibody drug conjugate as first line, either in combination with immunotherapy or in combination with immunotherapy plus platinum. This was a complicated design. I don't have enough time to go over this all. It was six cohorts looking at either four milligrams or six milligrams of datapodimab druxecan, either in combination with Pembro or in combination with Pembro plus platinum. There were patients who were pretreated, and there were patients who were treatment naive. Once again, the first experience we have looking at ADCs in the front line in combination with immunotherapy or in combination with immunotherapy plus platinum. I'm just going to move forward here to the first line experience. There were 34 patients in the datapodimab druxecan plus Pembro. There were 53 patients in the datapodimab plus Pembro plus platinum in the first line. If we look at the objective response rate from the doublet, the objective response rate was 50 percent. We look at the triplet arm, the objective response rate was around 57 percent. We see that these responses were, again, durable. The disease control rate was quite high, 91 percent in each arm. The duration of response has not been reached. And we look at the first line setting here on the right, the 84 patients who either got doublet or triplet in the first line. This is a pretty encouraging waterfall plot. And we'll have to see how this plays out. We look at the spider plots here. Again, the doublet therapy first line subgroup, triplet therapy first line subgroup, we're looking at spider plots that show meaningful and durable responses with treatment that's ongoing and was independent of PD-L1. So important to note this. Once again, is the juice worth the squeeze? Can we use these drugs in a meaningful way in combination with one another without too much toxicity? And we saw here that once again, the stomatitis is there. You can see from the tornado plot, most of this is grade one or two, but some of the 8 percent and 4 percent in the doublet and triplet arm were grade three or four. And seeing the cytopenias and the GI toxicities, there were other adverse events of special interest. There were ILDs reported, but they're low, 3 percent in each arm. And then ocular surface toxicities, which clinically manifest mostly as dry eyes. There are ongoing studies, and I'm going to just briefly go over this and then move to the last two ADCs that are in development briefly. These are the ongoing studies in the phase three or two setting that are going to probably solidify, clarify, and establish where these companions may end up in the non-small cell lung cancer treatment continuum. Last two ADCs I want to briefly go over, talisotuzumab and dotan. It's an anti-CMET antibody linked to MMAE cytotoxin. And this is, once again, CMET overexpression is very important, not only in EGFR mutant lung cancer, but EGFR wild type. This was a complicated design, so bear with me. This was looking at single agent talisotuzumab and dotan and CMET positive non-small cell lung cancer. There were essentially three cohorts. There was a non-squamous EGFR mutant cohort, there was a non-squamous EGFR wild cohort, and then there was a squamous cohort. So essentially three cohorts. And within the mutant and non-mutant cohort in the non-squames, they divided it up by CMET high and CMET intermediate. The bottom line here is it seems like there was really good activity in the CMET high EGFR wild type group. And again, this is kind of counterintuitive. This is one of the few studies we have where IHC may predict response to this drug. Interestingly, if you look at the CMET high in the EGFR mutant patient population, the objective response rate was only 18%. We're seeing clinical observations that don't have a lot of scientific rationale, and that's the way it goes sometimes. We'll have to see how these drugs sort of bear out and more of these observations translationally and at the level of the tumor microenvironment, at the level of the genetic alterations that are on earth, to see who these drugs work for and who they don't. Last ADC I want to talk about, to some minima of Tansyne. This is a CKAM5, ADC CKAM5, I call it the OG. CKAM5 is CEA, it's the original CEA that we measure in colorectal cancer. It is overexpressed in lung cancer as well, so it makes a lot of sense to try to target this protein. So this is a humanized antibody, it has a cytotoxic agent that's a DM4, this is a microtubule inhibitor, and then it's got a cleavable linker. Very little data on this drug so far. There have been iterations or have been publications of this. This is the original experience looking at single agent, to some minima of ritansine, and non-squamous, non-small cell lung cancer, and enriching for CKAM5 overexpression. And dividing that is either high expression or moderate expression. I don't have time to go over how they did this IHC. The bottom line is the objective response in the high expressors was 20%, and in the moderate expressors it was only 7%. Suggests that maybe an enrichment strategy by IHC for CKAM may predict response. This is a small number of patients, but this may start to weave a story. This has now been published, and there's updates looking at different iterations of this in combination with chemotherapy. We need to learn about toxicities of these drugs. There is corneal AEs that we see. I don't have time to go over this. Dr. Zer will probably go over these corneal AEs that are seen. Last ADC I lied to, there's one more, DS7300. This is an ADC that is targeting B7H3, which is overexpressed in a wide range of cancers. Once again, an IgG1 monoclonal antibody targeting B7H3, a Duruxtecan payload, and a cleavable tetrapeptide linker. This was looked at in both a dose escalation and expansion study, specifically in an extensive stage small cell lung cancer. If we look at the waterfall plot from the small cell lung cancer subset, this waterfall plot looks encouraging for this ADC. Once again, we're a highly pre-treated group of patients. This is encouraging. This is moving forward. We see the spider plot there. There are always, again, AEs that we need to be mindful of when we're giving these drugs. We're still learning the toxicities of these drugs, nausea, anemia. There were infusion-related reactions from this compound. We need to learn how to mitigate these. Summary, multiple antibody drug conjugates are making their way. Trastuzumab drug secant is approved for HER2 exon 20 insertion mutation, non-small cell lung cancer. TROPE ADCs are getting there. MET and CKAM5 ADCs are emerging. D7 7300, maybe looking good in small cell. The future is bright. We need to better define biomarkers. We need to better define what space they're going to go into, and we need to better define how to mitigate toxicity. Thanks so much. Alana, how about I turn it over to you? Hi, everybody. My name is Alana Zer. I'm a medical oncologist at the Rambam Healthcare Campus in Israel. I'm very happy to be here. Last but not least, we will discuss toxicity. As you heard, ADCs are designed to achieve high specificity and low toxicity, but they can still cause debilitating and potentially fatal adverse events. Over the next 10 minutes, we will briefly discuss the mechanisms of these toxicities, some specific toxicities of ADCs that are relevant in lung cancer, and how to manage it, maybe even how to prevent them. ADCs toxicities can be mediated through any of the components of the drug, antibody, linker, or payload. When we look at the antibody component, it can contribute to the toxicity profile through the introduction of on-target, off-tumor toxicity. For example, we know that blocking HER2 can result in cardiac toxicity or blocking MET can result in edema, etc. The antibody can also affect immune-related toxicities by engagement of the FC receptors on immune cells. Next, the linker. The linker can also affect toxicity. Less stable linkers, mostly cleavable linkers, are expected to lead to increased chemotherapy-related toxicity because of higher concentration of released payload outside tumor cells. But this is not really one-to-one since more stable linkers sometimes are associated with increased incidence of unexpected toxicities such as ocular toxicities, and maybe we will have time to discuss it later in the panel. The majority of ADC toxicity is thought to be derived from the payloads, the actual chemotherapy. Now, normal cells that are commonly affected include cells that line the GI tract with, as you heard, stomatitis, GI toxicity, diarrhea, hair follicles, so we see some hair loss, and myeloid cells causing myelosuppression. Now, the type of toxicity is related to the type of the payload, and the severity is also affected by the DAR, the drug-to-antibody ratio, what was previously explained by my colleagues. Meta-analysis have shown that specific payloads are associated with specific toxicities. For example, the MMAE, which is a microtubule inhibitor payload, which is found, for example, in TelisoV, a MET targeting ADC, can cause cytopenia and peripheral neuropathy because it's a microtubule inhibitor, while SN38, which is a topoisomer, has one inhibitor payload. We have it in Sosituzumab, Govitecan, is associated more with diarrhea, as SN33 usually do. Let's look at some specific toxicity associated with antibody drug conjugates. It is important to know that we will touch single-agent ADCs toxicities, and that there are ongoing trials now, as was presented previously, that are looking at combinations of ADCs with chemotherapy, with immunotherapy, with targeted therapies. And naturally, with this combination, we expect more toxicities and different toxicities, but we do not have time to go through that. So despite the fancy names, most of the time we are dealing with chemotherapy toxicity. And the most common AEs, as we know, are hematological and GI toxicities. Now, there are variations according to the drug, as you see here, with the frequencies of all gray toxicity of the main ADCs that we use in clinical trials today in lung cancer. And the management of them is not very different than what we are usually doing with standard chemotherapy toxicity. The NCCN has already incorporated some of the ADCs in their hematogenic score and in their treatment guidelines. And we also use the same guidelines to manage diarrhea or naturopenic fever, as you can see here. Now, I would like to turn, actually, to more unique toxicities of ADC. And first is the pulmonary toxicity, as Ben previously described. Now, ADCs that have a Daruxetacan payload in them are associated with pneumonitis and ILD more than other ADCs. And in fact, Tdxd or Enhertu was associated with 3% mortality rate from pneumonitis, both in destiny breast one and in destiny lung one, which is a lot. Now, the pathogenesis of ADC-related pneumonitis is not fully understood. But the mechanisms that are proposed include both bystander effect, which means that the high affinity of the target antibody for tumor cells might lead to increased exposure of normal lung tissue to the payload, but also local inflammation, where the antibody can bind and activate immune cells and immune mediators leading to an inflammatory process. Pooled analysis of drug-related ILD or pneumonitis from trastuzumab Daruxetacan or Tdxd in all monotherapy studies has identified several risk factors for pneumonitis. And these include impaired baseline renal function, lower baseline oxygen saturation, as well as the presence of pulmonary comorbidities such as COPD, asthma, pulmonary fibrosis, radiation pneumonitis. There is also some correlation with Asian origin and increased toxicity. And finally, a higher dose of Tdxd is associated with a higher risk for pneumonitis. And as you heard before, this has had an effect on the final dose that we're using. Another thing worth noting is that pneumonitis is a cumulative toxicity. While it can appear even after a single dose, it is more likely to appear as treatment continues, as you can see on the left. So we should basically be suspecting it anytime during the treatment. Now, mortality from pneumonitis has decreased after the first few trials with Tdxd. And apparently there is a learning curve coming from our breast colleagues on how to manage ADC-related ILD and even specific guidelines. First, the guidelines refer to patients and providers' education, what to do before you start treatment, how to educate the patient about the possibility of pneumonitis. Then the guidelines suggest proactive monitoring during treatment. This includes direct questioning in clinic, scheduled high-resolution CT of the thorax, even when we don't need the CT scan for response evaluation, and pulmonary function test and O2 saturation monitoring during treatment. When we do suspect pneumonitis or ILD, the workup is very similar to what we do when we suspect immune-related pneumonitis. And once ILD or pneumonitis are diagnosed, they are managed according to severity. And the treatment guidelines, again, are quite similar to what we do with immune-related pneumonitis, only here it's slightly more rigorous. So they suggest to start or consider a low dose of steroids at 0.5 milligram per kilogram, even at grade one pneumonitis. And they suggested grade two pneumonitis or more to permanently discontinue Tdxd and HER2. Now turning to ocular toxicity, ADCs can affect the ocular surface, meaning the cornea or the conjunctiva. And it can cause dry eye symptoms, but also keratitis and very, very rarely corneal ulcers. Now relevant payloads are mostly the DM4 payload, which is used at the CCAM5-ADC-2-SAR. Ben is pronouncing this much better than me, so I'll use abbreviations. But it can also happen with DATO-DXD, the TROP2-targeting ADC, and with TELUSO-V, as you've seen. It is unclear why the eye is particularly sensitive to these toxicities with these payloads, but it may be related to accumulation of the drug within the epithelial cell of the cornea, which is why the ophthalmologists sometimes see non-inflammatory deposits at the periphery of the cornea. It seems that these events are reversible. They're usually not severe, and they do not require permanent treatment discontinuation, but they do require sometimes dose delay or dose reduction. The median time to recovery after discontinuation is only two weeks. And there are some conflicting data about the need or the use or the efficacy of prophylaxis with artificial tears and steroids, since with the lung cancer ADC, we don't see such a high rate of keratitis and ocular toxicity. There is no clear recommendation to use prophylaxis. When treatment is needed, when toxicity occurs, then usually topical ophthalmology corticosteroids do the work, but definitely you should send your patients for an eye consult as well. Now, of course, ADCs that contain microtubule inhibitors payload are associated with peripheral neuropathy. These payloads include the MMAE in Telisov-E, the DM4 in the CCAM5-targeting 2-SAR antibody, and rarely we would see neuropathy with DM1, which I think is barely used today, TDM1 in HER2-positive lung cancer. Rodelvy also has a little bit occurrence of peripheral neuropathy, but it's quite rare. Now, ADC-induced peripheral neuropathy is generally mild. Rarely we see grade three or more, as you can see in this table. Most patients improve with discontinuation or dose reduction, but residual neuropathy appears to remain as we see with standard chemotherapy-induced peripheral neuropathy. Long-term peripheral neuropathy outcomes really are unknown today, but as I said, there are some early data suggesting that there is incomplete recovery. And this will have significant impact, I think, when we start considering introducing these therapies into the adjuvant setting because of the potential for irreversible toxicity. And last, we will briefly discuss strategies to prevent toxicities. Now, the most logical and easy path to take is to change the dosing or to deal with the dosing first, a dose cap. A dose cap of 125 milligram was adopted in patients with TCC, treated with Enfortumab, after several fatal adverse events occurred in patients who were obese, who were more than 100 kilograms of weight. Another way is to change the duration of treatment, which is significant, especially when we talk about neuropathy or accumulating toxicity. We can maybe discontinue treatment earlier. Another method that is tested is using the same cumulative dose of the drug, but with a lower peak plasma concentration, a lower Cmax, and doing so by using dose splitting. This was done in ALL successfully, and it is being tested in other tumors too. And finally, we can also test lower doses in a randomized manner, as was done in Destinyland 2, maybe a lower dose is as effective or even more effective. Another strategy that is investigated is pharmacogenomics. Just like with Irinopticin, we know that patients who are treated with an SN33 payload antibody drug conjugate are more sensitive when they have a UGT1A1 polymorphism, and they're at a higher risk for toxicity, so maybe potentially in the future, the patients can be screened for this polymorphism and the dose can be adjusted to it. Future strategies to reduce toxicity include new development and drug design. And this include, for example, a probudy instead of an antibody, which is an antibody masked by protease cleavable peptides that they enable selective activation within the TME. And many efforts are also done to improve the linker stability, although, as we said, we don't know if it's actually going to result in better toxicity profile. And there are novel payloads that are being developed, not only Topo2 inhibitors, but also payloads that are TKIs and more. So to conclude, as my colleague says, antibody drug conjugates are a new promising class of drugs in lung cancer, and their use is increasing. And despite their ideally targeted mechanism, most ADCs confer frequent and sometimes life-threatening toxicities. There are multiple and independent factors that are associated with these toxicities. It can be the target, the antibody, the linker, the payload, patient genetics, and more. And we expect future combination to appear, which will make management of these side effects even more complicated. So awareness to these adverse events and to their management is crucial, and pretreatment and on-treatment monitoring is key. And with that, I would like to thank you for listening and go back to my colleagues in the panel. I'm going to go ahead and ask really two questions here. The first to Dan. Dan, you talked a lot a bit about, you know, the structure. You elegantly went over this. You know, cleavable versus non-cleavable linkers. Where are we heading with this? You talked about some futures of cleavable linkers or non-cleavable. Where are we heading? What's the benefit, or where do most of these contemporary ADCs sit with these linkers? Yeah, no, thanks for that, Ben. You know, I think at the moment with the current slew of linkers, you know, they are, again, exploiting features in the microenvironment increasingly. There, again, are technologies that maybe even allow more precise deployment of these payloads. And again, you know, I can't say that I am a linker expert in this instance, but I think overall, there are certainly efforts to, again, you know, as I said, refine the ability to then more precisely control when the payload is released with regards to, again, mutating in circulation. I guess the other thing I would say is that it's not always just about the linker. And I do think that, you know, even the drug antibody ratio and how the number of drug molecules link on to the half-life of the antibody, all those actually contribute to the overall stability of the ADC. So again, I think it's really about having, striking that right balance and having that optimal ADC that we deploy. And that's something that's probably pretty difficult to predict beforehand. Yeah, so much, so much, a lot of complexity with these drugs and how to develop them. Never before has biochemistry been so important in the field of therapeutics and oncology and how these are developed in the lab and what is the basic chemical structure. Alana, you had a nice overview of adverse events with these drugs. And there was a question that came in specifically about ILD. And, you know, is there ever going to be a point where we look at these drugs in combination with radiation? You know, we have to keep in mind that we had the same issue with PD-1 drugs and PD-L1 drugs when they first developed. We said, there's no way we're gonna use these together. There was all kinds of issues in the U.S. about even the specific design of using Dervalumab post-concurrent chemoradiation given the overlapping toxicity. Your thoughts on whether we can safely combine these with radiation at some point or even as consolidation or beforehand, do we have any signals there of how to move forward with this in maybe the locally advanced setting? The only thing we know now is that in patients who've had radiation pneumonitis, there is a higher risk of ADC-related pneumonitis from this meta-analysis that was published. I would be very cautious in combination and maybe a first step would be to combine ADCs that are less associated with pneumonitis. ADCs that do not have the Ruxdecan payload with radiation in a clinical trial and see what the results are. Because as you said, those drugs are effective. Eventually they will go into clinical trials in stage three and we'll have more and more patients who have been irradiated or are currently irradiated. And it's an important question. Right. Ben, I do have one question for you for which I really, I honestly do not know the answer because I don't think I have enough experience. What about CNS activity? I mean, we're treating patients with lung cancer. This is super important. And I haven't seen anything published. Yeah, there's not a lot. I think that, great question. First of all, I get asked this question all the time, what's going on with the activity of these drugs in the CNS? Do they have activity? Do they not? And how do you use it? And I kind of draw a blank. It's interesting is that if you look at the approval of a drug like trastuzumab, Ruxdecan in breast cancer, you see this drug has incredible activity for leptomeningeal disease and breast cancer. And I was able to, for better or for worse, cover the breast cancer service a few months ago. And I saw this and I was blown away because is the blood brain barrier that different in breast cancer than it is in lung cancer? These drugs work differently. So it's there. The potential is there. Have I seen it in lung cancer? Yes, I've seen it. Is it as profound as what I've seen or what I've heard or what I've read in the breast cancer literature? No. I think like all these other drugs, biologically, they're just too big to get into the brain, but we know that's not the case. We know that's not the case with immunotherapy. We have early data on that. So Dan, I don't know if you have any thoughts. It's such a great question, what your experience is, or if you want to harness your PhD here, any preclinical data on this. I think it's going to be really anecdotal and it's quite surprising and remarkable. I mean, I guess sometimes we think of the cerebral metastasis as having maybe an arterial supply and you could anticipate that you could see drug effect there but for leptomeningeal disease to respond as well as you've described is truly quite remarkable. And certainly I think we definitely need to examine this space more closely, particularly given the therapeutic area with EGFR, immune and lung cancer, postosometinib, that's certainly going to be an area that we look at this activity with great interest. Another unmet need and an unanswered question of lung cancer that I think will be addressed with ADCs in the next six to 12 months. I want to, first of all, thank all the presenters for an excellent webinar. I want to thank everyone for joining us today. Thank you again.

webinar

antibody-drug conjugates

ADCs

lung cancer treatment

cytotoxic drug

linker

therapeutic index

clinical validation

FDA-approved ADCs

development opportunities