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My name is Josh Sabari. I'm a thoracic medical oncologist at NYU Langone Health Perlmutter Cancer Center in New York. Really excited to discuss evolving paradigms in lung cancer, clinical integration of PD1 and PDL1 VEGF bi-specific monoclonal antibodies. These are my disclosures. In the discussion today, we're gonna define by specific antibodies, a really hot and exciting area in lung cancer, as well as all solid tumors. We'll talk about the background, the innovation, the mechanism of action of these agents. We'll also talk about the development strategy in lung cancer. And I wanna Spotlight or highlight two novel therapies here, Ivanesimab, a PD1 VEGF monoclonal antibody, as well as pumidomi, a PDL1 VEGFA, uh, monoclonal antibody or bi-specific antibody in this setting. And then we'll end, uh, with some conclusions. So for the objective one of the discussion, we're gonna talk about the mechanism of action shift, and you'll sort of get where I'm going. We're moving from single monoclonal antibodies to more bi-specific. Why? We know that bi-specific antibodies may improve specificity as well as reduce the Rates of, um, you know, resistance and recurrence of disease. So we'll look at PD1 and PDL1, VEGF by specific antibody therapies. How do they differ from conventional therapy and how may they improve patient outcomes? We'll look at exciting data presented recently at ASCO 2026. So we know that monoclonal antibodies were designed to recognize one epitope or antigen. Here you can see a monoclonal antibody uh with two arms targeting that same antigen. We'll say antigen A binding site. When we think about bi-specific antibodies, we're, we're constructing, we're engineering these antibodies to be able to target multiple epitopes. Here we're looking at two. And the idea being that we may be able to improve specificity, and we may be able to target multiple different, you know, sort of redundancies or, or inconsistencies or liabilities in the tumor as well in, as in our immune system. So when I think about a bi-specific antibody, again, it's targeting two different epitopes or antigens, and these really range in size. Size from small proteins to large IgG-like molecules with additional domains, and you can imagine for a bi-specific antibody, you know, the, the, the sky is the limit. We can really build upon this platform for thinking about different strategies. Today, we're gonna focus on PD1, VEGF, but you can think about different constructs that can exist and they're being developed in the clinic now. Now, it's important to think about the physical linkage of two binding specificities that can create a dependency both across time and across space. And I think it's a little bit out there, but we know that binding events temporarily can occur sequentially, and we know that spatially, they can occur simultaneously. And this can lead to, again, enhanced activity of these agents in The clinical practice setting. And we have a few of these already FDA approved for use in solid tumor oncology. So Amiantumab and EGFR and met bi-specific antibody, FDA approved for the management of EGFR mutant non-small cell lung cancer. We recently saw the approval of tarlatumab, a CD3, uh, DLL-3 bi-specific, uh, um, uh, monoclonal antibody. B-specific antibody. And, you know, tarlatumab being unique in that it's targeting CD3, uh, which is expressed on T cells. So this is a bite or a bi-specific T cell engager. And also recently, we saw the approval of xenoctuzumab, a HER2, HER3 bi-specific antibody, uh, FDA approved an NRG1 fusion-positive metastatic non-small cell lung cancer. So, a lot of work has gone into developing these bio-specific antibodies. And if you look at the literature, early literature from the 1960s first mentions this idea of, you know, sort of scientifically fiction. Could we create antibodies that target more than one thing. And a lot of work has been done, both targeting FC portion of the receptor, uh, um, to try to better understand and how to, you know, sort of manipulate these. Constructs to better achieve our outcome, which is targeting uh tumor cells and also targeting the tumor microenvironment. So again, the first bi-specific monoclonal antibody that was approved in lung cancer dates back to about 2021, uh, 2022 now with Amivanumab, uh, in EGFR mutant metastatic non-small cell lung cancer, and we've seen so many more, uh, developed over the last, uh, couple of years. So, what is the mechanism of action here? Well, we know that there's a multi-modality mechanism of action. So there's many ways that these bi-specific antibodies are targeting. Uh, they can be bridging cells, uh, to the affector cell. Uh, we can see sort of receptor directly inhibiting. We can also see receptor activation if it's occurring in cysts. And then also, you can see sort of direct inhibition and downstream signaling prevention. Um, another thing that can occur is if you're engaging immune cells. Here I'm showing the ADCC or antibody-dependent cellular cytotoxicity. You can see this is a bite looking at a T cell, CD3 engaging, and on the tumor cell here, potentially engaging. CLL 3, you can see that you can actually get immune activation. And this occurs actually with all our uh bi-specific monoclonal antibodies, including PD1 uh and uh PDL1 VEGF bi-specific antibodies in the clinical practice setting. So what is the mechanism of action specifically now looking at a PD1 VEGF by specific? Well, again, we know a lot about VEGF inhibition, vascular endothelial growth factor. We know that tumors can secrete VEGFA and that promotes neovascularization, leading to growth and invasion and metastasis. Multiple therapeutic modalities have been developed to target um VEEGF, and we know that by inhibiting VEGF, we can Starve tumor cells by blocking tumors, nutrient and oxygen supply. So there are monoclonal antibodies such as bevacizumab, for example, or ramisumumab, both FDA approved and non-small cell lung cancer that have shown progression-free survival as well as overall survival benefit. We also have multikinase inhibitors um that target VEGF that are approved outside of lung cancer but being developed as well in the lung cancer setting. I don't have to explain to you PD1 or PDL1. You all know well, uh, that there's an explosion of immune checkpoint inhibitors approved. We know that PD1 is expressed on immune cells, T cells in particular, uh, and it's an inhibitory receptor. Whereas PDL1 is expressed on tumor cells and really acts as the ligand, and this system of binding prevents autoimmunity and allows for immune evasion. Uh, so preventing the immune system. From recognizing and attacking things that it shouldn't be attacking. And here, uh, tumor cells, which we would hope the immune system would potentially, uh, recognize as foreign. So by, by co-opting this system, by using a checkpoint inhibitor, PD1 or PDL1 inhibitor, we can activate, uh, um, this, uh, system to allow uh T cell activation and, uh, autoimmunity, which is again, uh, something that we are co-opting in this population. Now, why do we need them to be specifically a bi-specific, right? Why can't we just use a PD1 or PDL1 inhibitor with a VEGF inhibitor simultaneously? Well, we know that the presence of VEGF increases PD1 and PDL1 binding avidity. By 17, 18-fold in some studies. And we also know that the presence of PD1 and PDL1 increases VEGF binding avidity. So these, these uh binding actually will improve specificity of these agents in this setting. So there's been an explosion of data. Here, we'll start with Ivanesimab, uh, a PD1, uh, VEGF, a bi-specific antibody. We saw data from the Harmony A trial, uh, which was done, uh, in EGFR mutant non-small cell lung cancer in the second line. There is also a Harmony study, which is the global study of this, uh, looking at Ivanesimab plus chemotherapy versus chemotherapy alone. And we did see a preliminary improvement in over Overall survival as well as progression-free survival. This is currently sitting with the FDA for approval. Harmony Two was also done in China. This is in the first-line driver mutation negative space in non-small cell lung cancer. And we studied Ivanesimab here versus pembrolizumab in those patients with PDL1 greater than 1%. We looked at both non-small cell squam as well as non-squam. And one can argue that pembrolizumab is a Single agent is the wrong control arm for patients with PDL1 less than 50%. Median progression-free survival was positive, 11 months versus about 6 months, and median overall survival not yet reached. More recently, we saw data at ASCO 2026 on the Harmony Six trial, which looked at first-line squamous patients receiving Ivanesimab plus chemo versus tisillizumab, a PDI1. Inhibitor plus chemotherapy. Very nicely designed trial, again, done in China only here. Positive for progression-free survival, but was also very impressive, positive for median overall survival, 28 months for the treatment arm versus 24 months for the control arm. Again, this is China-only data. They did not enroll patients greater than 75 years, and they excluded patients with particular risk factors like hemoptysis, for example.