Chapters Transcript Video Metastatic Disease: ADCs and Bispecific Antibodies So, thanks for having me at what I'll dub as Philly Lung. Is that OK to, to call this Philly Lung? I don't know if there's another, uh, uh, conference. So, these are my disclosures. Uh, so today I just want to briefly talk about some of the mechanism of actions of antibody drug conjugates, some of which we've already covered, as well as by specifics, but really my focus is to review data in the frontline settings. This is really early kind of data from, you know, phase one, B studies, really in the non-actionable genomic alteration metastatic population. And just wanted to, to review some current enrolling studies as well. I, I'll try to be quick. I don't know if my timer started actually. I think it's still stuck at 10. So, so I guess, I guess I have a free, free reign. All right, so introducing the main characters, we've already talked about a lot of these Dato DXD Rovagasammi, which is the bio-specific, uh, digit PD1 inhibitor, and then, you know, Doctor, uh, Homos and Haas have kind of brought up Ivanesimab, but we'll, we'll, we'll dig a little deeper. So Rovagasamig, I, I tried to include a little pronunciation key for you there because, um, definitely a mouthful. But you know, as Haas kind of alluded to, there, there's been some nice kind of pre-clinical uh X vivo data looking at kind of interferon gamma release assays with rovagasammi versus kind of PD1 plus digit combinations, Pembro alone, digit alone. Um, it, it seems like, you know, at least pre-clinically that there's maybe some suggestion that this bio-specific is kind of, um, you know, activating the immune system a little bit better than the anti antibodies, you know, by themselves when given, you know, together. Sorry, uh, so we got our first kind of look at how this, uh, drug performs in Artemidi one, you know, Part A and B, very minimal clinical activity. This is in a check, uh, point, you know, resistant population. We saw a response rate of 6%, but more recently we've seen some data, uh, on. The treatment naive patients and, and this was uh, you know, an early study enrolling patients with uh who had to have been PDL1 positive, you know, interestingly, patients could have received, uh, chemotherapy for metastatic disease, so maybe not quite our kind of traditional population. But really focusing on safety, this seemed to be a very tolerable medication, you know, there is a less than, you know, 4%, uh, about discontinuation rate for treatment-related adverse events. There are no grade 3 or 4 toxicities seen. So really, you know, looks very kind of clean. In terms of, uh, uh, side effects, we had some initial kind of data presented at World Lung, you know, the TPS 50% or higher, looked very favorable, 60% response rates seemed to hold up, you know, most recently at ESO when looking at the PDL1 50% or higher. Really, it seems to be pretty active in that population. The duration of responses not yet met, but looking at this, this has kind of led to two, you know, phase 3 studies that are ongoing comparing. The keynote 407 and keynote 189 regimens versus ropogastimi and chemo in the squamous, non-squamous kind of respective populations that are PDO1 positive. So, very interesting to see if, if this combination approach will, will help improve kind of more long term outcomes. Kind of shifting gears here, you know, we'll talk a little bit about Dato DXD, the Tropian Longo 2 study. This is a multi-cohort, so it kind of makes you a little dizzy when you look at it, but really it's Dato DXD at two different doses, 4 and 6, Pembro, and then some patients got carbo and cisplatin as a part of a triplet. These cohorts were not meant to be like compared in terms of efficacy and things like that, but we're still gonna do that. So, we saw a little bit of data at ASCO, you know, the doublet kind of producing a response rate, uh, north of 50% at 54.8%, um, you know, PFS of 11. The triplet, you know, looked similar. PFS 55%, you know, I'm sorry, uh, overall response rate 55%. PFS about 7 months. Really, this is some early data, you know, the triplets seem to have more high risk patients with brain mets may not have been, um, you know, very balanced, but interestingly we're starting to look at some, uh, biomarkers, you know, to, to Hassa's point, who should we be giving these molecules to there's some suggestion on the right that maybe the TOP 2 NMR positive patients had a little bit higher PFS. These are all very small numbers. But I, I wanted to zoom in a little bit on safety, you know, and, and one thing that stood out to me, uh, is the ILD rates, right? And we looked at adjudicated ILD and pneumonitis, and, you know, all grade was about 25%, so about 1 in 4 patients would have had ILD on this. Study, uh, approximately and you know grade 3 still very low at 5 and 2, but I must say grade 2, pneumonitis is, it's, it's still something that catches our attention in clinic and, and is something that, you know, is very serious, um, if not intervened on, so we didn't get that quite breakdown. It's also worth noting that the discontinuation rate here was pretty high, you know, we're looking at Dato DXD was discontinued in 30 patients for a treatment emergent adverse event, um, so that, that's something to, to, to note and we'll talk about that as we go through. So the question becomes, what if you put these drugs together, right? Let's put Dado DXD, let's put robogatami together, let's see how it performs in the treatment naive population. That's what the rope and Longo 4 specifically cohort 5, tried to look at. These patients could have been squamous, non-squamous. They're, they, they could have had, uh, greater than 50% or less than 50%, and those were kind of looked at separately. But importantly, they didn't, they couldn't have an actual genomic alteration. So let's take a little bit of dive again into safety, right? So about 1 in 5 patients would have discontinued study drug due to a treatment emergent adverse event. All of them would have discontinued Dato DXD while a few of them would have continued on Rovagasammi alone. We saw that kind of the adjudicated ILD rate was about 12.5%, grade 3 was 5%, so it looked a little bit better than some of the combinations with chemo in terms of just absolute numbers of ILD, of course these are different patient populations, different trials, etc. And of course we see a little bit high rates of, you know, stomatitis or kind of on target trope 2 related, you know, side effects. How about efficacy? We saw, you know, again, this, this north of 50% response rate, 57.5%, duration of response and PFS are still immature, but you could see, you know, from the waterfall plot. There's some depth here in terms of response, right? And there's quite a few patients that are still ongoing, so very curious to see what more kind of time delivers to us to show us, you know, are we going to see some higher PFSs and DORs uh in this population with these combinations. But close on its tail, you know, we saw some phase two data from ESO of accetuzumab gobetecan, you know, the tigid and PDL1 antibody combinations, as well as this, you know, dynamite combination of SACTMT or saccetuzumab. Toromotecan and pembrolizumab, you know, response rate very impressive, 70, about 70%, but really what's even more impressive is these very low interstitial lung disease, uh, and pneumonitis kind of, um, you know, treatment emerging adverse events. Definitely something that caught my attention. We need to see if that holds up with more time. Lastly, I want to talk a little bit about Ivanesimab. You know, we've seen this study already presented, Harmony 2, in terms of really delving into safety. We're seeing with these bi-specific VEGF combinations, we're kind of predictably seeing some of the VEGF type side effects. So you can see on the bottom right, you know, hypertension, proteinuria, and really hemorrhage, right? So hemorrhage, you know, we're, we're seeing about a 14% in vanesimab, 11% in Pembroke, so, so kind of early signs of maybe there's not, you know, so much of that issue. We already saw this, uh, you know, instead of a pumpkin, I put a little Volvo there, so PFS of 0.5. Unfortunately the OS didn't seem to hold up, but more recently we, we saw some data ESMO and Harmony 6, particularly in the squamous population. So this study was squams. They had to have, um, you know, any PDL one expression, you know, uh, we're getting Ivanesimab versus, uh, you know, chemotherapy versus chemo versus, uh, tizillizumab, which is anti-PD1. But let's drill into safety here. And interestingly, uh, There is some data about major blood vessel encasement, cavitation, history of hemoptysis, ultra central or central kind of tumor location. And you know there's quite a bit of patients on this study, 20% had major blood vessel encasement, which is a lot of times an exclusion criteria for enrolling onto these types of trials. We saw that a hemorrhage rate, all grade was about 20%. We don't know if that's only from, you know, the tumor or if somebody had a really bad nosebleed, and grade 3 seemed to be pretty low. Obviously we'd be very interested to see what the hemoptysis rates are on this, you know, as more time goes on, but this to me was a very promising, you know, at least safety finding. You know, we saw some improvements in overall response, of course, we saw the PFS benefit. Let's see if it holds up with OS and how does it stack up to kind of other PD1, PDL1 VEGF inhibitors? You know, this is very early data also in the frontline setting, you know, a China-based study of uh combinations of carbotaxol, carbopem, you know, based on histology, very high response rates, particularly in the squamous cell population, 84%. Um, let's see if this holds up. You know, the authors kind of looked at VEGF toxicity based on historic chemo Bev versus, you know, this drug and chemo. Looked, you know, about the same, so I mean, let's see if the, the dialogue of, you know, VEGF and squamous cell, let's see if that's gonna be changed in the future. I'm very excited about these combinations of, uh, the PDO-1 VEGF by specifics with TRP 2 ADCs as well as some of the B7H3 ADCs have looked very promising. So, you know, in conclusion, there's a lot of open questions, right? So in my mind, I, I think I have like the 50 2010 rule, 50% response rate, 20% uh discontinuation rate due to uh treatment related adverse events, and 10% ILD to me is like something that. I think is very meaningful. It makes us hope to the future. We're not sure if this is just improving PFS and ORR but won't approve OS, and we got to dig into the PDO on negatives, the squamouses, and really see what difference is that making. But, um, thank you for your attention and, uh. I think I that that that's that's it I I. Thank you. Created by Related Presenters Neel Belani, MD Medical Oncologist, Virginia Cancer Specialists
