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I'm Edward Garin, and I will be, uh, in this segment addressing the limitations of current, uh, standard of care. And we will be focusing on non-small cell lung cancer. Before we begin, these are our disclosures. We will start with a polling question. Um, in this polling question, we have a 64 year old patient, uh, who has metastatic non-squamous, non-small cell lung cancer. The patient is Uh, discussing treatment options. And to explain why the oncology field is moving towards therapies that simultaneously target the immune system and tumor angiogenesis, uh, you as the practitioner, uh, referenced foundational trial data that combined, uh, PDL-1 inhibitor, uh, uh, an antibody along with an antibody directed against, uh, VEGF alongside standard chemotherapy. Um, based on the clinical data evaluating a PDL-1 inhibitor plus a VEGF inhibitor and chemotherapy, Um, in this case, it was, uh, otezallizumab, bevacizumab, carboplatin, and paclitaxel versus, uh, just a VEGF, uh, inhibitor and chemotherapy, uh, in this case, bevacizumab and carboplatin and paclitaxel. Uh, what was the hazard ratio for progression-free survival in the intention to treat population? Uh, the choices here are A, uh, has a ratio of less than 0.4, B, uh, has a ratio of, uh, 0.6 to 6.9. Uh, C, a hazard ratio of 0.7 to 0.8, or D, a hazard ratio of 0.8 or more. OK. We'll now go on to sort of the historic benchmarks. And um really, there's been a tremendous amount of progress over the last several years in the management of non-small cell lung cancer. And, um, we'll be speaking more about, uh, precision oncology later in, uh, in this presentation. Uh, but, uh, at least in the, the early 2000s, uh, really the only tools we had available to us were chemotherapy approaches. And what you can see here is that Uh, when multiple different chemotherapy approaches were evaluated, one versus the other, there really was very little difference. Um, there were some toxicity differences, but in terms of effectiveness, uh, what we saw was really the same. There also, and, and this is still actually a standard today, docetaxel was approved. Um, uh, uh, about 25 years ago, um, based on, uh, approval, uh, for improvements over, uh, best supportive care. And you can see the overall metrics here, um, which in many respects are somewhat disappointing. Pointing. At the time, the response rate was, uh, was about 7%, uh, with the median, uh, overall survival of 7 months. Uh, docetaxel does remain a standard of care. Um, interestingly, probably based on some improvements in things like supportive medications, um, we do have somewhat better outcomes with, uh, docetaxel. But, um, still, uh, our options in previously treated patients is limited. I would argue that for uh patients without driver mutations, uh, really the major advance in uh recent years has been, uh, the availability of immunotherapy. And, um, immunotherapy, it was originally approved in previously treated patients. Um, but that data really has now become largely irrelevant, as most people, certainly in the United States would receive a PD1 or PDL1 inhibitor, um, in the frontline setting. Now, there are multiple different, uh, agents that are approved. So I will not be going through the data on each, uh, but we'll be tending to go through sort of the first data set approved. Um, in an individual setting. And for, uh, patients in a frontline setting, the original approval was for monotherapy with pembrolizumab in patients with uh PDL1 expression in at least half of their tumor cells. Um, and you can see here with progression-free survival on the left, um, showing, uh, really tremendous benefits for this population of pembrolizumab over chemotherapy. And on the right, you can see the overall survival benefit, uh, again, showing very impressive hazard ratios. Uh, this, you know, certainly is exciting data. And over time, we have, uh, seen that, that these benefits, uh, are in many cases, uh, maintained. There is at this point, similar data in this upfront setting for patients who received, uh, emiblimab, uh, an alternate PD1 inhibitor, or the PDL1 inhibitor, otezlalizumab. One of the things that I think is particularly exciting, uh, about this class of agents is that there appear to be some patients that have true durable responses. And you can see, um, here is published data, um, from a five-year follow-up. There's now over 10-year follow-up on these patients from the original pembrolizumab study. You can see, uh, on the left here, um, is overall survival in treatment naive patients, um, which is really, I think today, the more relevant population than on the right, the, the previously treated patients. And you can see that, um, that really a, a good percentage of the patients Um, are alive 5 years after the initiation of therapy. Um, you can see that for the entire population, it's over 15% and nearly 30% for the population who had PDL1 in at least 50% of their tumor cells. As you are aware, there is now also data for chemotherapy. Um, and what you see here is data from the keynote 189 study showing progression-free survival above and overall survival when pembrolizumab is added to, uh, to chemotherapy. Um, the red is placebo, showing the chemotherapy alone. Um, there now is similar data along with chemotherapy for, uh, for cemiblimab, uh, as well. And as you can see here, um, even in these aggressive therapies, um, you can see those who have, uh, less than 1% PDL1 expression. Appear to have at least some numeric benefit, but it is not as great as, uh, as the other patients. And what you can also see is that the great majority of these patients have progressed, um, really even at, at a year. Um, and I think that, that, that is quite telling when one looks at the, uh, the overall survival on the right. Um, you can see still, um, benefits across the board. But outside of these patients with high PDL one expression, which are at the bottom, um, you know, most of these patients, uh, see a marginal benefit, um, really underscoring the importance, um, really in all patients of having additional options, um, that would, would improve. Obviously, there is a group who does very well, but we don't know upfront who those people always are. Um, here, you can see similar data. I won't go through the breakdown based on PDL one expression, but similar data on the left progression-free survival of the right and the overall survival, um, for squamous cell carcinoma, the prior data that I showed was for non-squamous disease. And again, you can see the addition of pembrolizumab, um, it does show an improvement, uh, over chemotherapy alone. Um, there are some other approaches that people have looked at. And one, Um, has been adding antiangiogenic therapy. Um, this is, uh, a data set that as we have started to see data coming back from by specific Uh, drugs that are targeting both, uh, PD1 or PDL1 along with, uh, VEGF or VEGF receptor. You can see that, uh, this has become, uh, sort of something that people have looked at more in this study. Um, otezallizumab, uh, along with bevacizumab, carboplatin, and paclitaxel was compared to the same regimen without uh otezlalizumab. Otezlalizumab, of course, is a PDL1 inhibitor. And what you can see here is that uh the, there was a, a, a hazard ratio between 0.6 and 0.65 for um the addition of otezallizumab to bevacizumab, carboplatin, and, uh, paclitaxel. Uh, I'm not going to go too in-depth into um CTA4 inhibition. Uh, this is a somewhat controversial, uh, topic in, in the management of non-small cell lung cancer. Um, this is from the Checkmate 227 study. This is the schema for this study. And, um, as part of this study, patients were randomized based on PDL1 expression greater than or less than 1%, uh, to different arms, one of which in each arm, included, uh, a combination of devolumab along with ipilimumab. Um, this study did show, uh, good outcomes in those patients. Although it is hard to know how it would compare to, for instance, uh, the pembrolizumab chemotherapy, particularly in patients, uh, who were PDL1 positive. There are also regimens.