Focusing on common bladder, lung and breast cancers, three UCSF oncologists describe how antibody drug conjugates (ADCs) are changing the treatment landscape, especially for refractory cases. Each specialist explains when they consider certain ADCs and breaks down recent trials to reveal keys to using these innovative products, covering the data on progression-free survival, which patient groups show benefits and common toxicities. Hear about the plethora of clinical trials underway and what they may signify for standard protocols.
So welcome to Advances in oncology, the Revolution of Antibody drug Conjugates one of our cancer center live webinars. I'm Hope Brio, a breast medical oncologist at U CS F. Um And I am excited also to introduce my co moderator and the developer of this series Laura Curcio. Laura. Good evening, everyone and welcome. Thank you for attending. We have a really exciting lineup tonight and um it includes Hope Roo as one of our speakers. So I'm really excited. Um Please also look, look at the end and we'll share our upcoming webinars that are coming up for the rest of the year and um enjoy the evening. Thanks. So, our presenters today are some of our esteemed faculty who've generously donated their time uh to educate our community and answer questions. Uh So we have aim Kuskin, who's an Associate Professor of Clinical Medicine in the Division of Hematology Oncology and Matt Guben who's a professor in Thoracic medical oncology also are under division of hematology oncology. And of course, I've introduced myself uh for the first time. I'm actually speaker in the cancer center uh live program as opposed to moderating only. So, uh we, our agenda is here. We're in our welcome time which will go off to our talks very quickly. Uh Badim will talk about ad CS in urothelial carcinoma, present and future, quite an interesting area with a lot of uh challenges I think. And uh then uh Matt will talk about AD CS and non small cell lung cancer and I'll talk about some of the new directions and uh treatment of breast cancer with AD CS. Now, at the bottom of your screen or at the top of your screen, depending on how it uh works for you, you'll see the chat. I'm not seeing the Q and A button that we usually have. So, uh what you will do is let's see if I can find there. It is Q and A. OK. So there's a Q and A and it might be under uh more for you. There's a little three dots to the right with more. And uh if you um click that you can put a question in and the speaker when they're done talking or during the program can actually answer that. Uh that question that you have in. Um if you have trouble accessing the Q and A, you can always put it into the chat, but the Q and A is a little bit easier uh to use for a question and answer period. Uh And of course, we'll have the opportunity to talk a little bit uh between ourselves as well to address your questions, but put in your thoughts, comments, questions, anything you want into the Q and A button again, if it's not immediately on your screen, look under more. It says Q and A and you can put anything into that um at any time. So uh we will uh go ahead and get started. But I first just want to uh mention our cancer center services referral center, which is a single point of access for adult cancer services. Um And the uh has a specific phone number easily accessible and you'll get a fax in 24 hours uh confirming the receipt of your referral request. Uh And the clinic staff will go back and schedule an appointment and get records. Uh It's open actually for talking to live people between eight and six pm, five days a week. But again, if you send something uh electronically, people will get back to you in the first working day. And MD link also works, which is just U CS F health.org/md link. Um You can get CME credit if you signed up for CME credit, the survey link will be in the chat feature. Uh and you can copy and paste that link into a new window. You can also scan the QR code and we will show it to you again. It must be completed by the end of the day, next week, October 2nd in order to uh be functional for you. So, uh and then uh we'll talk a little bit more about other programs as we go on this uh through the, through this. So I am going to go on and uh stop sharing and Vadim Kuskin will start his presentation at this time. OK. Uh Hopefully everyone can, can see my screen. Um Great. OK, excellent. Um So, yeah, I'm, I'm really, I just wanted to say thank you, first of all, for the opportunity to um uh speak today on this topic. That's, that's very important to me. I really appreciate the, the invitation and um you know, the opportunity to, to share some of this um this data in our recent experiences with antibody drug conjugates and ureth cancer. Um I'm Vadim Koshkin, I'm an associate professor here at uh U CS F. I'm in geo oncology and I focus specifically in bladder cancer. Um Here are my disclosures and um you know, many talks like this, we, we start with a slide that, that uh in, in bladder cancer that looks like this or something along these lines, which really just highlights the significant development in this disease space just over the past um really 10 years or so because really up until around 2016 or so, we really just had um chemotherapy available to treat these patients with advanced ureth cancer. But really, since 2016, um we've had quite a few approvals as uh as as you can see on this slide. Um initially starting in 2016. There, we entered the immunotherapy era with approval of multiple um uh immune checkpoint inhibitors, starting with, with a Talab and uh finishing out with pembrolizumab in 2017. Um in 2019, then we actually entered the targeted therapy era in ureth cancer in earnest um with initially approval of Uritin, which actually is not an antibody drug conjugate, but a um a Tracy kinase inhibitor. Uh And then with Informa Doin in 2019, that was the first um A DC approval in urothelial cancer. Since then. Al almost yearly. There has been uh there have been additional developments punctuated by in 2023. Just about a year ago, the approval of Informa Doin and pembrolizumab uh for patients with metastatic urea cancer, which was really a very big, big step for for this field. And so I'll, I'll go over some of these data. Now, right now, there are three antibody drug conjugates uh that are uh that have FDA approval in ureth cancer. And this includes in for Doin which I uh mentioned as the first um A DC approved in this uh uh for this disease. It's a uh nect in four targeting drug. It actually is only approved for ethel cancer. So many actually outside of geo oncology are not as familiar with this drug. Um And the, the chemotherapy payload for this um A DC is M MA E so like a, a Taxane type uh uh compound. Um There's also cuss a GOV Tin which actually has other approvals including breast cancer. It targets uh trope two and uh has a toy Sua one chemotherapy uh payload. And then most recently and this is the most recent approval in ureth of cancer just earlier this year in April is trastuzumab dere tin uh which is a her two targeting antibody drug conjugates also with a Topo Samara inhibitor. So this brings us to uh the current landscape, the current treatment landscape in urothelial cancer. Um And this slide is, is quite a bit busier than it looked just a few years ago, certainly much busier than it looked 10 years ago. Um So in the first line setting, this combination of important mevo doin and pembrolizumab is really uh uh the uh one of the pivotal regimens that we really offer for um this disease at this point, at least in the United States. But outside the United States, there are um uh there's still use for platinum based chemotherapy followed by a Valium, a switch maintenance that was um the most recent standard of care here in the US as well before approval of inform and Pembroke. Um And actually, recently, there was also an approval of combination of chemotherapy and immunotherapy and that was the first time this happened in ureth cancer and that was with a combination of CISplatin, Gymy and Nivolumab, but only for CISplatin eligible patients beyond first line as subsequent therapy Uh We also have quite a few options and here is where we have uh a few of these uh ad CS approved as monotherapy including again for an unselected patient population. Both so, CEU Zab and Fortum are approved as monotherapy and then for patients with high her two expression for Suzume Derek Dean is approved as well. And so I'll go over some of this data. Now informa ado was first approved as monotherapy or achieved full approval in ethel cancer uh uh with EV 301 study. So this was a large phase three global trial uh that included patients uh with metastatic disease who are treatment refractory. They had progressed on uh prior platinum based chemotherapy and a prior immune checkpoint inhibitor as well. And these patients were randomized to receive either in for a doin or what would have been the standard of care at the time, which is uh basically third line chemotherapy for these patients with uh mostly taxane. So dosa paclitaxel or uh INFL in Europe. Um and this trial uh really met all its end points with uh an impressive advantage shown for and for the meva doin. So uh there was uh significantly higher response rates for ev relative to third line chemotherapy. So 41% versus 18% and an advantage in progression free survival as well with an impressive hazard ratio of 0.62. And importantly, most important of all, of course, an advantage in median overall survival. So four and for a in this third line setting, median OS was 13 months, which is um uh much better than we had seen basically with prior therapies. Uh and this is relative to about nine months for chemotherapy and again, with it has a ratio of 0.7 uh as this trial was ongoing in Fort IAB. And, and once it read out, actually in Fortum was already being investigated, actually, in combination with pembrolizumab in an earlier treatment setting. So, uh for treatment naive patients um in the metastatic setting, um uh who were randomized as part of this EV 302 study to receive in for Eva doin and pembrolizumab versus again, what was standard of care at the time, which is a uh platinum based chemotherapy doublet. So, uh CISplatin Gym Cytopan for CISplatin eligible patients or carboplatin uh um Gym Cytopan for those who are CISplatin ineligible. Um And again, here, this combination of EVM pembrolizumab showed really um uh impressive benefit relative to this standard of care chemotherapy, which at that point had been standard of care for uh 2 to 3 decades in urothelial cancer. So much higher response rates we saw with EV and pembrolizumab with about two thirds of patients responding as opposed to about 44% with chemotherapy. Um most patients had clinical benefit with this regimen as well. So really only about 9% of patients had primary progressive disease who started this regimen and then uh basically progressed. Um and also complete response rates of 29%. So almost a third of patients with AC R which again, much higher than the sort of 10 to 15% of patients we see with complete responses with chemotherapy. And really numbers that we, we hadn't seen before with this disease. Uh progression free survival for EVP was 12.5 months, has a ratio of under 0.5 and overall survival, median overall survival was 31.5 months. Again. Uh uh We hadn't really seen numbers like this for this disease before. For um uh just, just to give a baseline for um uh upfront platinum based chemotherapy, usually median OS of about 15 to 16 months is expected. So this basically more than doubled it. And uh this trial when it was presented at um Asmo last year actually received a, a standing ovation which which really showcases how, how dramatic um the dramatic benefit of this, of this combination and uh the outcome scene and these outcomes were really seen across um all substances of patients really across the board. Uh patients uh uh had more favorable outcomes receiving EVP versus uh platinum based chemo. Um This was also regardless of CISplatin eligibility, uh which I highlight here and I go over this a little bit more um on the next slide where again, uh regardless of whether patients got CISplatin Gym, Cyto or Carboplatinum Cyto in the control arm, those patients who were, who were, you know, eligible for each respective therapy and got informed of a dope and pembrolizumab did much better. So, um whereas previously, we really were separating patients in the front line setting into those who were CISplatin eligible versus CISplatin and eligible. Now, to some extent, that distinction is, is not as critical because um in forum e doin and pembrolizumab is beneficial across all these groups. Uh It is also notable at the same time that this data came out at asthma last year. Again, there was another trial that also read out as positive in urothelial cancer and ordinarily, this trial uh would have also overturned or would have overturned standard of care uh for metastatic ureth cancer that again has been around for 20 to 30 years, which is the um platinum doublet for front line patients. This was a checkmate 901 study which combined CISplatin Gym Cytopan and Nivolumab. Uh And compared it to CISplatin GM Cytopan in only CISplatin eligible patients. And this data was actually presented um right after ev 302, it also led to the approval of this regimen. And of course, we can't help but compare how the two different trials, how, how, how these two combinations measure up even though we are comparing across trials. And so with checkmate 901, even though this is a somewhat of a different patient population, but the the numbers we see are just not as impressive as with V and pem bro. So median overall survival while better with combining the volume of relative to chemotherapy. Um not as dramatically better as with V pembroke as shown here, same for um the hazard ratio for progression free survival and same with the response rates. Again here we uh uh still see, you know, relatively higher response rates and with chemotherapy alone but not that, you know, almost 70% of patients including 30% complete responses that we see with uh EV and pembroke combination with EV 302, looking at the toxicity of this regimen as well. It's quite different from chemotherapy. Really. The main um uh the major side effects that we sort of look at and worry about are um especially early on our skin toxicities which both pembroke and inform can cause um uh that uh occurs quite frequently within the first two cycles usually. Uh And then as a later side effect that we worry about that's commonly uh peripheral neuropathy and that develops in many patients who are on this combination long enough and particularly who are on in for doin long enough because it's really, it's, it's a side effect of the, the chemotherapy payload of EV, which is um M MA E A again, a tax like um compound. Um So many patients do develop neuropathy, it does end up being for many uh uh the toxicity that leads to dose reductions and often even do this uh uh discontinuation of treatment actually. But we don't see our cytopenia like what we see with chemotherapy at the bottom of the, of the slide here with EVM Pembroke, that's those are usually relatively mild and not like what we see with uh uh the platinum doublet. Next I switch gears a little bit to talk about some of the other um uh antibody drug conjugates and uh starting first with SOSUS A gov T can. Uh So this is a troop two targeting drug again, it's approved in other malignancies as well uh in breast cancer, in particular. And I know doctor Rel knows quite a bit about this drug um in ethel cancer, this was approved based on, well, a actually I it received an accelerated approval, not yet a full approval based on a um non randomized phase two study of multiple cohorts and that was trophy UO one. I'll focus just on cohort one, which was a population of patients who had progressed on prior platinum based chemotherapy um and an immune checkpoint inhibitor. So in other words, very similar population to EV 301. The first trial with inform me doin that I highlighted um these patients receive sosus gov T can uh response rates to SOSU zab in this third line setting were about 28%. So not, not as impressive as the uh 40% response rates we see with EV in the same setting and the median uh PFS and OS were also a bit shorter than what we see with EV. Um But this was enough to get this drug accelerated approval um with a confirmatory phase three trial pending and that was trope uh uh that was uh tropics uh 04. Uh This trial again included the same population patients progressing on a prior um platinum based uh uh chemotherapy and an immune checkpoint inhibitor and randomized to receive either CSU aab or again, what would have been standard of care at the time, uh which is third line chemotherapy. Um We haven't seen actually the full results of this trial yet, but there was a press release over the summer indicating that actually it did not meet its primary end points. It was a negative study, meaning souza did not out outperform this third line chemotherapy, which in urea cancer is actually not a not a particularly high bar. I would argue. Um as a result of this, this drug is still approved, we can still use it but its role in urea cancer has been placed somewhat in doubt. Uh The toxicity of this drug is very different from um in forum and uh which is of course beneficial. If you're kind of sequencing these drugs, you don't see uh neuropathy, you don't see skin toxicity. Um What you do see a lot are cytopenias and, and loose stools. And so that's uh and this is data from again, the uh the phase two study. Next I talk about um her two expression and then targeting in ureth cancer as well. So in urea cancer, this has actually long been um probably underappreciated. This disease space is significantly behind, of course, breast cancer and then gastric cancer where this these drugs have been approved now for some time. Um But we're, we're starting to appreciate more and more that um actually a high proportion of patients with metastatic and advanced cancer do have at least some degree of her two expression based on most recent um literature. We estimate that about 15% of patients are high express uh defined as having her two IHC three plus or two plus and fish positive. Um And about another third to 40% of patients are uh low express. So don't quite meet that threshold but have some degree of her two expression. So altogether, probably over 50% of patients with um metastatic urea cancer have some degree of her two expression as as a result can benefit from her two targeted therapy based based on data I will show um shortly um There are several antibody drug conjugates with pretty advanced data in this space for ureth cancer, trastuzumab Derek Deakin is actually now approved. It's uh uh it's an A DC consisting of uh uh trastuzumab, of course, uh which is well, a well known antibody against her two which is linked to octopi isama one payload. And then there's also the SAB VO doin which is a different anti her two antibody uh which has an M MA E payload. So actually, exactly like in for, I'll focus on trastuzumab first because of course, that's a drug that does have approval in this uh um uh for advanced urothelial cancer. So it actually has a pan tumor approval across um several different malignancies. Um in addition to of course, breast cancer and also uh uh G I or gastric cancers where it actually is more established. But this study was um Destiny Pan Tumor two which was a uh basket study of multiple different tumors, multiple different baskets including uh Gyong tumors and also a bladder cohort of about 41 patients. All these patients were treatment refractory and received uh Truma Derek Stickin as monotherapy. Uh They all have uh they all had at least IHC two plus uh her two expression um in the, in the overall cohort 41 patients, the uh investigator assessed response rate was about 40% but it was certainly enriched in patients with higher expression. So IC three plus uh where it was 56% and the FDA approval, this pan tumor approval was actually four patients with IHC three plus um tumors even though actually, if you look at the data, despite the lower response rates with IHC two plus the median PFS and median OS look pretty similar. Um though granted of course, these are fairly small cohorts. Um The adverse events associated with trastuzumab are more similar. Uh I would say to some of the adverse events with um uh CSU Zume Go T and so, uh and again, these are more payload dependent um with the topo summaries, one payload, you expect more cytopenias, which we see with this drug. But another um side effect we do see with this drug which is not frequent, but something we do need to pay attention to is actually pneumonitis. And uh there were almost about 10% of patients in this study that had some degree of pneumonitis and there were even some treatment related deaths. So um certainly something to, to pay attention to when, when giving this drug. So now I I step back to, again, back to the treatment landscape um to review some of the, some of the data, you know, that was just highlighted um again in the, in the first line therapy uh or f uh in the first line setting um in, for Eva doin and pembrolizumab is the major a DC combination that we will use in el cancer and in the United States. Nowadays, most patients will probably will be getting this combination as opposed to um chemo based regimens. Although um around the world, uh many patients uh it will be some time before. Of course, this is this is adopted more widely. Um and then the other antibodies are conjugates we mostly use in the subsequent treatment setting or right now, we actually exclusively use in the subsequent treatment setting. Um And we have limited data of, of how to really sequence these various agents that are uh uh treatment option after, you know, prior progression on in forum medo and pembrolizumab or even on prior um chemotherapy. And again, some of these ad CS are available for all comers. So like in Fort IAB, a single agent, assuming they haven't had inform before. So Szab um uh whereas trastuzumab Derek dein is approved for uh is, is available and will benefit only a selected patient population, those with IHC three plus tumors. I also want to talk about um some of the future antibody drug conjugates and development. Um focusing again on the CDO and I mentioned earlier, this drug uh initially was developed in China, although it's now in global studies and there are uh uh several studies um from China highlighting uh again, the benefits. Uh and I mean pretty robust activity of this drug as single agent. This is especially the case again in patients with higher her two expressions. So I see 23 plus or two plus here in this pretty sizable cohort of over 100 patients response rate is about 50%. But even in patients with lower her two expressions. So IHC one plus um it's a little hard to see here, but we, we see response rates of about 40% actually. Uh and importantly, this drug does seem to have synergy when combined with an immune checkpoint inhibitor. So they're analogous to the inform Avo doin and pembrolizumab combination that I was highlighting earlier. Um This was also uh a clinical trial done in China, uh where patients were treated with this combination and uh response rates were pretty robust that 75% more, more. So even in patients with high her two expression median overall survival, um uh lo from long term follow up from this study, this data was just presented at um asthma as well, was 33 months. So really actually pretty similar to what we see with in for me doin and pembrolizumab combination. So for a selected patient population, this uh your combination of uh her two targeting A DC and an immune checkpoint inhibitor uh may be an option going forward and it's right now being investigated both in phase two and phase three clinical trials. Um And we, we have the phase two open here, U CS F and we'll have phase three as well. Finally, um these antibody drug conjugates, I think increasingly will be moving into other treatment settings as well, including in the preoperative setting for uh ethel cancer. This is a different patient population. So these are patients with localized bladder cancer, not metastatic. So the these are patients we're trying to cure. And uh the approach here to cure them is really with a radical cystectomy, a big surgery to remove the bladder. Um for those patients who are also eligible for platinum based chemotherapy. Uh I should say cis plan based chemotherapy, which is about half of the population. We give them neoadjuvant cis plant-based chemo and then those patients who still have high risk disease at the time of surgery. So bas basically still bulky tumors are no po lymph node positive disease at the time of surgery. Then we also give adjuvant Neval app. This standard of care also is about to change based on actually data that was just presented at Asthma from the Niagara study. So this trial um actually combined standard of care cyp plan based chemotherapy with Derval A followed by radical cystectomy and then adjuvant devali and showed a benefit of this approach to previous standard, which is clan based chemotherapy. So for the time being, this probably will be the new standard of care. But I think a few of the antibody uh drug conjugate trials in particular within for doin that are that are coming may supplant that still um there is data with um actually new adjuvant and for doin as well, a single agent. And there we see response rates of about in the mid thirties analogous to chemotherapy. And now there are several large phase three trials which include this combination of informed epidote and pembrolizumab relative to again, the previous standard of care chemotherapy in this period, operative setting. And I think a trial like Keynote B 15 here um very well could introduce an standard of care in a preoperative setting, which would also be in for me doin and pembrolizumab. This um combination that we saw yield very impressive results in uh the metastatic setting. There are other trials as well, in particular for CISplatin and eligible patients where the standard of care right now is no systemic therapy, they just get surgery. Um And uh these trials like keynote 905, again, randomize these patients uh against um uh uh PMB and EV. And then there's also a Vol Volga study which combines EV with Devali NAB and Tremel IAB or Devali NAB alone. Um And um I anticipate that a lot of these trials actually may uh um uh result in uh um well may alter our standard of care as well. So finally, my take home points, um antibodies or conjugates and combinations have really played a pretty pivotal role in the recent um significant advances in the treatment of advanced ureth cancer. If there is uh one point, someone should remember from this talk is that uh in forum of a doin and pembrolizumab, this particular combination represents a new standard of care in metastatic ureth cancer. I think it will be moving into probably earlier treatment settings as well, although that's not yet standard of care. Um We have other antibody drug conjugates approved in this setting as well, which have also helped to uh really revolutionize our care of um patients with this disease. And that includes the student A gov T and then um now her two targeted drugs um as well. And then, as I alluded to earlier, I think these drugs will eventually be entering earlier treatment settings in ureth cancer as well, meaning that more patients will be getting them and then it will of course influence our um uh subsequent approach um uh to treating these patients in a metastatic setting as well. Um So with that, I thank you for your attention and look forward to the, to the next talks and the discussion. Thanks so much. That was great, really well, very well done. And I think that the sequencing of your data was really nicely done. So why don't you go ahead and stop sharing so that Matt can go ahead and share? And I think that what's really was interesting was one that different ad CS work for urothelial cancer compared to say breast cancer where, you know, we have our different approaches and the nect in four was quite toxic. It's actually really interesting. Uh And I wonder if people with urothelial cancer get more neutropenia problems with sasu up because we've been able to kind of manage this altogether and breast cancer. So it's really interesting to me because, you know, obviously nect and four expression plays a role, but um we don't understand this well. And then I think what's also exciting is this move towards neoadjuvant therapy to try and reduce the extent of surgery and um and the disability that, that can place on patients. So really well done. Um Please to the audience put your questions into Q and A and I know Fatima will be happy to answer them and uh we'll keep track of it. Uh Any thoughts or comments and Matt you're on uh you're not. No. Are you on mute? There we go. Can you see my slides? OK. We can't see your slides, but we can now hear you right. How about, let's see. How about now? Now? It's perfect. All right, everybody. Thanks for sharing your dinner hour with us a precious time, but an exciting topic. Um I'm in charge over the next 15 or 20 minutes to talk about the status of antibody drug conjugates specifically and non small cell lung cancer. Uh Here are my disclosures and of course I will be discussing unfortunately, lung cancer, a lot of non yet FDA approved treatment indications, but a lot of exciting work in progress. So what I wanted to do today is really kind of give um five stories. There are obviously dozens of ad CS in development and non small cell lung cancer, but I want to share kind of AAA sampler of five stories. Two of them are in broad or agnostic targets really the troop two story and C A camp five and then three stories that have specific targets that are unique and need to be measured. These being her two, her three and met. And what I think you'll find over the course of my talk is that I'm not going to use the word revolution. I think there's more of a movement. There's some exciting successes here. There are some failures and some promising data for the future, but we haven't quite revolutionized, revolutionized the non small cell line cancer therapy yet, you know this modality. So I'll start with Trump two. already introduced by Dr Kokin. We'll hear more from Dr R go. But um I'd like to start, obviously, we know that Trump two is over expressed in multiple cancers. And there are really at least in the lung cancer research space two drugs at the forefront in terms of broad uh trial efforts. And I'm gonna focus most on the second line though there's a lot of other efforts as well. Data poom A XT can, data BXT and C you have go T can are the ones that I will allude to um tropia. L 01 was the phase three trial that really tried to test a ODXD against our long standing and uh no love lost second line therapy of dosa Taxol and basically took patients with advanced disease, either with or without actionable genomic alterations. Notably, without, they could have had one or two prior lines and with, and this did include EGFR ALC all the like all the ones that we treated, targeted therapies, they had to have had the targeted therapy line and the platinum based chemo line patients randomized 1 to 1 to either dod XD on a Q three week basis or dose of Taxol standard dosing and the dual primary end points for PFS and OS. So when we saw the result at emo last year, this was the top line data, this was a positive trial. If you look at the primary endpoint of progression free survival in all comers in this advanced non small cell lung cancer patient population, you had a real but modest benefit over crappy dose of Taxol. It has a ratio of 0.75 and about uh you know, 0.7 months there. But the really interesting story and what I don't think anyone even at the development team expected was that a very important biomarker was histology. And if you split these out, this wasn't, this was a stratification point, but this was not a powered primary endpoint non squamous patients had acid ratio of 0.63. Their benefit purple over pink squamous reversed the story and squamous patients had detriment with dod XD compared to dose of Taxol. And this is what I explained by preclinical data with respect to show to expression. This wasn't actually seen in the early phase trials, but this is the result we got and this is leading to some interesting discussions with the FDA that I think they are still going for the non famous indication, but that was not the intent of Tria lo one to be fair. Overall survival was presented a couple of weeks ago at World L by Dr Sands. Kind of shows a similar story non squamous on the left with a, a pretty good trend toward overall survival. And then again, a really a trend toward detriment uh with respect to squamous cation. It's really interesting. Um whenever we talk about these Asians, Doctor Kash can allude to this. Um Doctor Russ put in a lot of work in terms of toxicities of AD CS. But for dod XD, because it probably will become part of our Armamentarium and lung cancer, it's important to know we know dosa and we know what cytopenia is. We know kind of what to look out for there. But I think it's important to keep these three things in mind when we're at least starting to, to prescribe this drug. First of all, the rate of stomatitis and mucositis is real. This is, this is more than twice as frequent, the data data DXT setting and a good 6% of people on the study had grade three or higher. So it really requires proactive maintenance, ocular events, never the comfort uh setting of, of medical oncologists, most of them low grade, most of them dry eye and increased lacrim information. But again, something that we have to be prepared to proactively counsel our patients about. And then of course, a recurring theme in this talk will be drug related ILD and it's tough lung cancer. You can have what looks like pneumonitis due to uh tumor progression and lymphangitic fashion. So that adjudication is an important component to this. And it's important to note that in the dod XD arm, there were seven great five IL DS though four out of the seven cases were disease progression um by investigators. So it's a real entity. It warrants follow up. It warrants kind of careful attention. But um again, not necessarily a deal breaker with respect to the use of this drug. Again, no one likes dosa Taxol, we'll take incremental benefits. But um it, it, this was an interesting finding. Now again, I presented this as a broad target because the idea was that troop two is fairly universally over expressed to non small cell lung cancer that we wouldn't really need an extra biomarker. Now. Well, maybe histology is an important one, but there was an interesting paper given by Gino at World Lung a couple of weeks ago where they have this normalized membrane ratio measured by quantitative continuous scoring. It does require some upfront work to package the slides. But basically A I looks at these full slides presumably in a central fashion and calculates this NMR value for every tumor cell, you know methods. Aside, the key thing was that this was a discriminating feature. You could kind of quantify in a pretty good way that this was a predictive biomarker for benefit. If patients positive and Mr Status, the discussant who was a pathologist from Yale kind of talked about the challenges of implementing this, but this might again in, in a drug that's not the most exciting banker and over our standard of care, this may be a path forward if it's realizable to try to figure out the patients who are bound to have better benefit or to move on to some other options if they don't. So not ready for prime time, but kind of of interest. Now alluded to the fact that patients with actional genomic alterations were allowed. We're very happy to see this because in the immunotherapy space, we don't get to put EGFR and ALC uh tumors on these, on these trials. But this is kind of an alternative for a chemo arm and these patients were involved in troop tropia L 01, but tropia mo five was a distinct look at just these patients, patients who had one of these um seven genomic alterations we've already had. Um uh at least a line of targeted therapy is appropriate. They already had set of toxic Asian containing therapies here. The primary point was just overall response rate. This is this is just kind of a phase two single arm what we saw in these patients who are pretty heavily treated, they're at least third line and in the case of al and EGFR, more like 4th and 5th line beyond, we are seeing some reasonable overall response rates 34% with EGFR 49% across all the mutations. So again, single arm but but important to think that this is an option for these patients though, as I'll point out in my, in some subsequent stories here, I think there may be some more compelling options when we have, for example, her three, a motivation to use that in an EGFR patient. So broadly speaking, what we found, I think the surprise takeaway at EMA last year, there was clear PFS benefit in non squamous disease, largely hadden, no carcinoma, but Squam had detriment os seems to be in, in favor for the non Squam. We have to watch for the distinct toxic cities like ILD like stomatitis. Um And uh but we also want to keep this in mind for patients with a gas. And also to point out that there is some work being done to say maybe we shouldn't use this in a blanket way, but maybe there is a realizable predictive biomarker we could use for these patients. Now, of course, this isn't the only choke to agents. Um certainly in breast and, and neuroth we have sat, you know, t and playing a role. So this uh space non small cell lung cancer was, was viewed with great anticipation and ultimately led to the evoke 01 phase three trial again, it's thought to be a pretty easy trial, try to beat this crappy second line chemotherapy. Um We've used for ages, unfortunately, as for this year, we learned that the OS primary endpoint was not met has a ratio of 0.83. Interestingly, unlike uh the data DXD data, there wasn't much difference between non slave and slain. So kind of interesting where the structure of the of the molecule, the payload, there must be some other factor at play. Another kind of and I caught a broad target though it did require expression. My point in saying a broad target is that they weren't looking for anything specific about known biology of the cell accepts. Does it express C AC five? This was promising an early phase trials again, should be easy. We find expressing cells, let's beat dosa PFS endpoint, not M OS endpoint, not met. Now, these drugs and others including dod XD, there are immunotherapy combinations in the first line. There are even some as Doctor Koshkin uh mentioned some neoadjuvant efforts, but clearly these aren't um they aren't automatically gonna win. So I think we really have to think about how we use them in what sequence. And if there are biomarkers that help us enrich how to use these in a smart way when again, there are competing options. And of course, these aren't the only ones. This was a nice slide from Esma this year, Dr Bean. So talking about AD CS broadly, there's a lot of quote unquote agnostic targets beyond Trobe two, you see B seven H three, integra and beta six, B seven H four others. Nin four, you know, playing neuroth lung cancer is among the, the the diseases being studied, we have to stay tuned and see if any of these hit. So again, negative phase three, second line trial for Sassy uh for two of michi and then we're waiting for some first time combo data, a lot more targets to come in agnostic or broad targets. But now let's move to the specific targets. I think there are some really exciting success stories that have already been announced or that are in the making in this space that I think have a lot of potential in the non small cell lung cancer area. The first of course, is her too and I won't belabor this because Doctor Koch did a good job of it. Dr R go of course is is, is is certainly gonna mention this, but we do have an indication um in non small cell lung cancer, destiny lung. 01, this is the new England paper a few years ago. This was open label phase 291 patients prior had prior treatment. Not notably, I want to point out if you ever pull that article, it was 6.4 mix per kig though the approved dose because of toxicity is actually 5.4. So we're like uh breast dosing, what we saw was a AAA response rate, 55%. Um And so that was reassuring the PFS 8.2 months. And um and uh of course, we again have to talk about pneumonitis. This is something the breast teams have really looked at and we have to think about this. It was 26% on this trial, which did lead to some thought thoughts about how to mitigate it, how to identify it. But also whether that lower dose may be useful. And that hasn't been the ex to date and that becomes important because having been shown in a second line and beyond setting, you know what the next destination is a first line and there is an accruing destiny lung 04 trial at the 5.4 dose. The hope is in treatment naive patients, we're going to get a longer pfs, well, longer time to exposure, longer exposure to drug, more risk for pneumonitis. So really important to be watching these patients like a hawk and to be acting early on asymptomatic pneumonitis that you find at time of staging. Now, there's an interesting story, but these are her two mutated patients who got the label and those were the most exciting findings. But when you look, there's not a 1 to 1 correspondence between her two mutations and her two expression or amplification. And and if you look on the bottom, there's a huge range in these, her two muted patients that whether they have zero expression, one plus two plus three plus. So these are, these are overlapping Venn diagrams but not the same population. So DLO one also had her two over expressing cohorts. And these are the, the, the waterfalls for these patients and these aren't bad, these aren't shabby either. They're not quite as impressive as the her two mutation uh patients. But these are reasonable. And so as you know, and as a Kashin just mentioned, these were one of the cohorts of patients that led to the FDA approval for her two over expressing specifically IHC three plus because their, their response rate was was reasonable for a second line or beyond therapy. Now IC three plus about 5% of our non small cell lung cancer patients um and kind of unclear whether that hurts you over expression is dynamic and the thought is maybe that it's more likely to be over expressed in subsequent lines. So is there a motivation for repeat biopsy which we do all the time in actional genomic alterations? Not so much in non genotype about patients? Now, moving from her two to her three, this is the story of Partricia B. Derek's T can. Now her three remember is kind of in that her family. Her one is EGFR which we know in love and non small cell lung cancer. Her three is the orphan receptor that doesn't dimer, but it is over expressed in a large proportion of non small cell lung cancers and virtually all of patients with EGFR mutations and specifically implicated in the TK I resistance setting that we are at a loss of what to do for. So I'm pretty sure my direct TN is uh again, a topo suma is linked to antibody to her three phase one data were pretty compelling, heavily pretreated patients, 39% response rate. This led to the phase two, her Thea Lungo one trial. So this is at least third line or beyond primary end point overall response rate 29%. And with CNS benefit as well. PFS sits there 5.5 months, but we'll take it again compared to dosa Taxol or subsequent line chemotherapies. This is a nice therapy that we've to be able to inject at some point in that treatment sequence, even as the EGFR treatment sequence becomes more complicated. And notably, I should mention toxicity. Interestingly, you know, even though we're talking about the EGFR um patient population, when you look at that set of toxicities, we really are seeing more things that are chemo associated, right? And so it's really more payload toxicity, not really her family um toxicity like uh you know, the rash and diarrhea that we are are mostly accustomed with, with our EGFR agents. And of course, what we're excited to see is the phase three study, they went straight to phase three. This is a second line um uh phase three after TK I resistance randomized, not against dos attack but against platinum double chemo. So putting their money where their mouth is primary end point PFS. And about five or six days ago, we got the press release as is true lung cancer all the time, press release before data, but we do have a positive trial. So I'm very excited to see this reporting out. Padua came and went. They did not get approved but not for data but for some uh manufacturing contracting issues. So the hope is that at their next Padua, we're going to see an approval. I don't have any insight in data, but this does look promising and then finally to round it out and, and to bring this to a close, I think another compelling story is Met. Met of course, has a story history and non small cell lung cancer when I was a fellow approximately 50 years ago, uh Met Mab was really the talk of the town because Met was known to be over expressed in a lot of tumors, much excitement and then failed barely in the phase three. So we're trying again in a different way. Tali V is AC Met targeting a DC with an M MA E payload. And the phase two luminosity trial reported out last year was promising and it does show kind of in a promising way the gradient that you kind of expect where C met high patients had a response rate 35%. These are patients after second line therapy and seme intermediate about 23% with a very respectable duration response. And this has led um I should also say that we are talking about toxicity, anything hitting met. Um because this is a space where we have met inhibitors, right? For our, for our met mutations, we have a Met bic antibody in, in, in in use. The toxicities are really notable. Neuropathy is a fairly high grade toxicity edema which is a very ne oriented. And then the pneumonitis here a 3% grade three rate. And then from an ophthalmologic point of view, blurry vision and keratitis were relatively common. We are eagerly awaiting the phase three trial where in the second line after platinum public chemotherapy, hoping to beat a dose of Taxol in a uh met high selected patient population fingers crossed. So again, I think that even though we are looking at very possibly a data DXD approval, at least for the non squamous population for some modest benefit over a dose of Taxol. But we'll take it, I think some of the really exciting action in the non small cell lung space continues truly to be different versions of what's in effect targeted therapy, right? Her two AD CS for her two mutations and now a AAA subset of patients with her two over expression in her three, even though it's not a her three target, it's really an EGFR kind of family target but very promising data after TK I, after chemo, very promising. And then in the Mets space which we've been really challenged with over the years, I think a compelling A DC. And of course, these are just three examples and there are many other drugs for these targets and more to come. But I think again, maybe short of a revolution, we have a movement and we're used to lung cancer being on the forefront of targeted therapy, immunotherapy. We're all behind you all in uh in AD CS. But I think there's a really promising there, there both in the broad targets and in the specific targets. And with that, um I'll, I'll take my slides down and welcome any questions in the chat. That was a fabulous, really uh very interesting data. And it's also intriguing to me that, you know, where do you put these different AD CS? There's a whole bunch of AD CS that have uh durex Toan uh payloads, the three of them now. And uh I actually even took out the Patria Di Toan her 3D XD slide from mine because we only have phase two data. And there was a little bit of data presented at ESMO just recently that, you know, it looks good. But what are you going to do with so many Dire Toan? We don't know, you know about changing the payload, changing the target. So complicated. And um also sequencing is really an interesting question too because that's also potential in lung cancer, right. Um But we're starting to ask it's too early to have really good, good data. But I think to speculate that maybe there's a role for sequencing when there's a different payload or again, maybe a complimentary target. I think sequencing is going to be the name of the game going forward as it is already with our targeted therapies where we have to, when do you plug in chemo? When do you plug in non TK I targeted therapies. It's again, it's, it's, it's great to have these choices, but I don't think we have a lot of data driving those decisions yet. At least. No, it is really interesting. And I, I wonder with lung cancer, I don't mean to like suggest that you could poke people with lung cancer more than breast cancer. But I just like, you know, I wonder, like, because you have higher nodes and things like that, like, could you get tumor to have a better idea about the mechanisms of resistance and breast cancer? It's been so complicated because even in when they did, uh three patients had autopsies, fresh autopsies at Mass General. And uh the what was fascinating was looking at a trope to a DC that they had responded to and then had disease progression. And then the what they found was that there were toposar mutations and trope two alterations in different organs in the same patient. That's fascinating. I haven't seen those data. That's really the heterogeneity clearly. Uh I guess she says that Mark Schuman has his hand raised, uh says uh joy, which of course I can't see. Um And uh I don't know if you can unmute and speak because usually what people do is put it in. But I guess you can try, Mark. Can you hear me? Yes, we can. OK. So uh thinking about combination AD CS uh naively, I would think using two different types of AD CS uh like for any of these cancers might be uh synergistic might be more effective. So that's one question. The other is um to what extent is the research on identifying other targets in lung cancer? For AD CS? I think like like other tumor types, I showed that one slide where there are a lot of targets that are about to be broadly expressed. So they're going to be targets. You just have to choose your, the design of your A DC. But I think there's a lot of interest in kind of honing more lung cancer specific targets. Again, her three is a great example. I know it has applicability in breast potentially too, but it, it's very compelling how that might work in an EGFR setting. So there's, there's a lot of work, it's mostly kind of early phase one and drug development. But II I think that that's where the promise lies and not the revolution. But the movement toward, and then it's just about drug discovery. But I think it's, it's interesting even with Trump two again, what, what do we know about the expression? How, how important is that to the success? And, and I think that's where that, that the data world l was kind of interesting to see the pathologist try to set out a little better. Um But again, struggling with how do you get enough tissue, what do you send the tissue for the positive tissue? So, not a kind of a nonanswer mark, I admit, but there's a lot of work in that space is what I'd say. And I think that um there's a big issue with combinations of combined toxicity. Uh And uh unfortunately, even when there's no overlapping toxicities, you really can take uh what is chemo with a better targeted potential and make it really toxic? So I think, you know, this is a, a question in various patients, although um I'll show you some data with immunotherapy. And uh we saw that before too. Uh immunotherapy and AD CS have a lot of preclinical data to support them as do as does the combination of Parp inhibitors in a DC. So a lot of intriguing areas for a combination, we're studying a novel uh camp though T can um nanoparticle uh with a P inhibitor in I spy. So a lot of really fascinating areas to explore. But again, we had a lot of the same payload. So we'll see. Um, if there aren't other questions, I think we'll go on to. But, you know, put questions into Q and A because we have our speakers and everybody can contribute and I'd be interested in your thoughts after we uh go on and do this section here. So, um of our speakers actually because they have a lot of different perspective, which I think can be really helpful. So, let's see here. Hopefully, I can find my button to make it into a slideshow. OK. All right. So, uh we're gonna talk about uh now breast cancer where it is really a revolution. I think I like what Matt suggested. Um It's really completely changed our treatment for breast cancer and uh it will continue to do so as we move these agents earlier in the metastatic setting and into the early stage and post neoadjuvant setting, my disclosures. Um So the key here and you've been hearing about it from the last two speakers is such a nice introduction and also a review of what's going on which, you know, we really don't cross paths much. Uh But we cross ad CS. So that's really interesting. And um the, you know, we started doing studies with TDM one, the first A DC for her two positive breast cancer, you know, a very long time ago. And uh we looked at whether or not that worked in uh tumors that had a little bit of her two but weren't classically her two positive by assoc cap guidelines. And it didn't work. Now, how have we revolutionized these AD CS to make them much more effective? Uh There are a number of different ways as you can see our most effective A DC trust tab Drugan has the same target. So there wasn't an improvement of the target. We now have a biosimilar trust tab, it really was improving two different things. So one is the linker technology and the second is the payload. Uh So the linker technology is much better now and it allows tumor specific uh uh release of the digestion of the linker and release of the payload. Um And so you can see these are all Cleve linkers and it allows uh a much better access to the tumor cell uh for this payload. In addition, the new uh payloads that have been looked at one don't have as much cumulative toxicity, although we have Bodoin still being studied in Decitabine as you heard about and another antimicrobial agent. Uh in another experimental, her two A DC A Rx 788. Um and those drugs may have differential toxicities that are cumulative such as neuropathy and keratitis. Actually, we're seeing this new eye toxicity that's quite interesting and are working on understanding that uh developing it as well. But the payloads generally, the tumor has not seen before. So topoisomerase one inhibitors unfortunately are the main payloads that we've studied, but in breast cancer, there's not resistance to topoisomerase inhibitors because they're not part of our Standard Armamentarium. And then the other part, which is probably extremely important is that they are membrane probable. So they're hydrophilic as opposed to being hydrophobic uh like the M Tansen derivative of mm Tansen and TDM one. So what that has been thought to result in is this bystander effect. Um and the bystander effect is a cartoon. We don't really know exactly how this works. Um There is some preclinical data suggesting that you get nearby destruction of tumor cells that don't express the target because you've leaked the uh payload out into the local tumor environment. But what's been fascinating about TDXD is that it works even if there's extremely rare expression of her too. And so we don't totally understand how this bystander effect worked, but we clearly can kill tumor cells that don't express the target. Well, with these new AD CS, we thought that having a high drug to antibody ratio. So having a lot of toxin per antibody was going make a big difference. But it turns out that the newer AD CS with these improved linkers and toxins, they work even when the drug to antibody ratio is relatively low. So it's not just the dar although that may contribute to tox specific toxicities. So what data do we have? So TDXD is certainly the most successful and the most effective A DC that we currently have in breast cancer across her two expression. Uh So, uh the first studies in her two positive disease based on remarkable efficacy in phase one studies, uh looked at patients who had metastatic, her two positive classic, her two positive breast cancer and compared TDXD to our most effective and only A DC at the time. TDM one here, we saw a remarkable progression free survival benefit. I mean, just huge, I mean, we just don't see those kinds of things going from about seven months, you know, to well over 20 months. Um and uh hazard ratio of 0.3 and also an improvement in overall survival seen just at the beginning with the hazard ratio of 0.73 at the first presentation of the data, which we now uh become sort of used to seeing with these AD CS with the exception of now, I'll show you in a moment. Um And this is the most updated data actually that was just presented um at uh as O and published in nature medicine. Uh So in these patients, it's classic, her two positive disease, 50% hr positive 15% baseline brain mats, mostly visceral disease. Um they'd received a median of two lines of prior therapy. And even though a third of the patients who got TDM one crossed over to receive TDXD, we still saw that PFS and overall survival benefit, which was amazing toxicity matt mentioned it's really important interstitial lung disease was seen in almost 17% but no one died, which is unique to Destiny. Breast 03. It's the only breast cancer trial where no one died from ILD. And we'll talk about it more. The most common toxicity of TDXD across all studies is nausea and we worked very hard actually to control nausea with the use of OLANZapine, the antipsychotic as a way to control this long delayed nausea that we see sometimes very little bone marrow suppression. I had a patient on the very first phase one's trial for four years. You wouldn't even know she was getting chemotherapy. So it's remarkable how little you see another study which of course, had a lower number but came after destiny breast 03 and of course, doesn't have a lot of pertinence to the US population. Now is giving TDXD in the third line or greater setting against treatment of physician choice with a cape Cine combination with her two targeted therapy also showed an improvement in PFS and OS and similar toxicity with a 0.5% mortality from interstitial lung disease. But of course, now we want to treat in the second line with TDXD and we'll move earlier soon. Now, one of the big questions is what to do with brain meds and her two positive disease because very common, even though you treat effectively brain meds sort of escape our treatment. And it's thought that the big antibody trustee ma can't cross the blood brain barrier. But there again, we didn't really understand what we were talking about. So it does and the TDXD does. And we don't really understand why it may be that the brain barriers already has some destruction based on having brain mets. Uh But the current prevention studies will help us understand this. We've seen that uh there is efficacy in brain mets previously treated untreated in both the randomized phase three trials and in phase two trials and efficacy in leptomeningeal disease, which is remarkable with long survivals. This study was presented for the first time at ESMO just last week, destiny breast 12. And this looked at patients who had baseline brain metastases. And there was another cohort that had no baseline brain metastases. The primary endpoint in the brain METS group was PFS. They had patients who were previously treated and stable and those with active brain METS not treated who didn't need immediate treatment. And what they saw was a remarkable progression free survival as you can see here. So a median progression free survival at 12 months is quite remarkable. And the overall response rate, 52% and 55% in those with active brain meds. And then they looked at the CNS progression free survival was also was remarkable. And the CNS response rate, you know, 72 62% depending on active brain METS are previously treated so dramatically, a positive study. And I think really uh defines the role of TDXD in patients with brain metastases from her two positive disease. And now we're looking at TDXD in more detail in patients who do not have her two positive disease but have brain metastases. The adverse events were very similar. They didn't see um the we don't see cardiac toxicity really to speak of, but they saw a lot of toxicity in terms of ILD. And that's why I'm showing this slide because nothing new in terms of toxicity. But what you can see is that there was a 2.3% grade five toxicity in patients with brain meds. That's huge compared to what we've seen in other studies, which is about 1% or less turned out. They went back and looked at these patients, they were on steroids and they were not given P JP prophylaxis. So 44 out of the six died of what appeared to be Pneumocystis pneumonia in the end. So we were all tweeting about the fact that breast oncologists need a repeat education in uh using uh P JP prophylaxis, which is now quite easy because we have not only uh Bactrim, you know, sulfa. Uh but we also have a tova for patients who have sulfa allergies. So you don't have to deal with Dapsone. So anyway, this is a big education uh part because these patients who are on steroids um and are are at higher risk for pulmonary complications on TDXD. Um So The approach has changed based on all of this data to the therapy for metastatic her two positive breast cancer for active CNS disease. The triplet called her to climb with the oral Tracy kinase inhibitor to cat nib resume and cape cy amine was our standard. But based on this data and the other contributing data. Rezum Di Direct Toan is at least an equal uh choice of therapy in patients with active CNS disease in the second line setting. Um and T catnip tras tab cap cytopan should be non cross resistant and could be used in sequencing. You don't get the diarrhea with TDXD and hand foot syndrome, but you do have the risk of ILD and a little more nausea and then we sequence with all the other agents that are available to us. However, this whole process may change. So our schema may change in the relatively near future. So Destiny breast 09 is likely to present data next year. This trial is challenging the cleopatra like approach of a taane resume per tab is first line therapy and substituting the taxane with TDXD, either with Pertuzumab or Pertuzumab placebo as first line therapy. I don't think any of us would believe that this could not be positive given the data we've seen so far and we expect that we'll be using TDXD as our standard first line therapy in the not too distant future for metastatic her two positive breast cancer. Now, what happens. If you've been on TDXD, you don't want to stay on them for 10 years. Like we leave, you know, we drop the taxane and continue the antibodies. Now, often for 10 years, we're looking at when we should stop these antibodies for the small proportion of patients who are cured of metastatic, her two positive breast cancer. So what do we do with TDXD? It's hard to get that drug forever. So they, we were actually doing a study with our colleagues in Spain. Uh looking at giving TDXD as induction with best response, dropping TDXD and continuing so-called HP as maintenance therapy called the demeter trial. So that will be interesting as well. So what do we do with the patients who don't have her two positive disease? Well, in our phase one trial, we saw very nice data in patients who had her two low metastatic breast cancer. So these are one plus or two plus by IHC without evidence of gene amplification. So destiny, breast 04 is a trial. Our first in person meeting after the start of the pandemic where they also got a standing ovation, uh really very cool results. So these patients had received a median of one line of prior chemotherapy for hormone receptor positive breast cancer and had centrally confirmed her too low disease. Uh The disease was endocrine refractory. So they progressed on endocrine therapy. They were randomized to TDXD or treatment of physician choice, which was in more than 50% of patients alin they saw was remarkable improvement in overall survival um as well as progression free survival in these updated data. Uh really striking results in a patient population. With this, you know, upfront almost a more than six month improvement in overall survival, which was really exciting. And then they had enrolled a small cohort 58 patients with hormone receptor negative, her two low disease, 40 TDXD 18 treatment of physician choice. And in that tiny population which was just exploratory, they also saw a dramatic improvement going almost a 10 month improvement in overall survival and a huge improvement in progression free survival. So that, that, that led the FDA to approve TDXD in patients with her two low metastatic disease and regardless of whether it was hormone receptor positive or negative. So full approval based on uh 4018 patients pretty impressive uh data. So uh in subgroup analysis, there were no subgroups that didn't benefit from treatment and the toxicity was quite similar in this patient population. So, no difference. Uh Again, this 1% about risk of death from interstitial lung disease. And the largest discontinuation rate was for ILD pneumonitis at 8%. Um So, lastly, before we talk more about the uh pneumonitis is the most recent data that was presented at Osco this year. Um and Destiny Breast 06. So they are taking a lesson from our breast cancer San Antonio meetings where we can turn around and add in new data we added in new data three days after a press release last year. So in this case, this was a very late Abstract Destiny Breast 06, but it was long awaited. And so they had a special session made just for DB 06. So the whole idea here is that about two thirds of patients with hr positive disease, hormone receptor positive have her you low disease. Uh but another about 1/5 to a quarter have ultra low. So that means not one plus or two plus without gene amplification, designed to identify her two positive disease, but less than one plus but not zero. So faint, incomplete membrane staining in up to 10% of tumor cells to be one plus has to be greater than 10%. And then there's a small population who will truly be zero. Most of those patients have basal like nasty triple negative disease. So dey breast 06 randomized patients who had either her two low disease or ultra low disease centrally confirmed to receive TDXD or treatment of physician choice difference from DB 06. We got the ultra low and these patients had no prior chemotherapy, they had to have endocrine refractory disease but no prior chemo, they all had hormone receptor positive disease. So no triple negative breast cancer. That's her too low. 713 her too low. 100 and 53 ultra low So it was an exploratory group medium follow up was about a year and a half. And these ultra low patients didn't look any different in terms of demographics or tumor characteristics to hurt you low. And they, most of them had received a CD K 46 inhibitor, which is really important. And 60% of patients received cape Cytopan in the control arm, they saw was an improvement in progression free survival in her you low disease and an early suggestion of overall survival benefit. Now, this is not in any way statistically significant. And 1/5 of the patients in the T PC group have already crossed over to receive TDXD, which may be very important and may limit our ability to look at survival. We need to understand sequencing in these patients and we don't what about the 153 ultra low patients? They also had a very similar improvement in progression free survival and this suggestion of an overall survival trend. Although again, crossover occurs in this patient population will be much less because it's not approved in ultra low disease. So fascinating data and really exciting has already changed the thinking about how we should treat patients. One of the questions was how was concordant were central and local results. But it actually the concordance was pretty good for her two low 78% of the scam samples that were zero locally. Uh Some of them actually had a quarter of them, her two low disease that were still struggling a little bit with local testing and then the ultra low, nobody commented on because it wasn't real endpoint for the local groups, but 40% were ultra low. So it has led all of us to go back to our pathologists and ask them to say 0 to 1 plus which our pathologists have kindly uh, elected to do so. Our really sick patients, we can give TDXD in the first line setting. Again, the same kind of toxicities with a 0.7% grade five of mortality. But these were patients who were older and some who got treatment even after they had grade one ILT and weren't given steroids early. So I do think that we can counter this. So are we gonna give K TT DXC to everybody has their first line chemo probably not only 3% of patients had bone metastases as their only site of uh disease. So it was really a high risk population. Um So what we would do is say bone soft tissue dominant, you know, lung disease free interval, we probably still give Capecitabine. They can travel, they don't lose their hair and they don't have a risk of ILD. Uh But for patients who have high volume visceral disease and short response to endocrine therapy are losing the estrogen receptor. TDXD is an option in the first line setting and we're learning more about ultra low disease. Although I've already treated a couple of patients with ultra low disease in clinic who had rapidly progressive hepatic metastases and liver dysfunction. So, this is really a big change in our treatment. Uh course for patients with hormone receptor positive disease. What do we do about the risk of uh ILD? So it's a big deal. You don't wanna kill your patient with their treatment, particularly not early in their course of metastatic disease, not any time. But um the this was a pooled analysis of nine TDXD studies that found that 87% occurred in the 1st 12 months. And risk factors included being from Japan, which increases your risk of ILD from all sorts of drugs including CDK 46 inhibitors and then renal insufficiency, moderate severe decrease was a big risk factor. As you can see down in about four lines down here. Um elderly patients more heavily pretreated and higher dose. So the recommendations here are to hold for asymptomatic ground glass opacities. We treat with a half milligram per kilogram of steroids re scan in three weeks. And in almost all patients, I can retreat for grade two symptomatic ILD. We recommend complete discontinuation of TDXD. The only issue comes up if you think they really had like COVID or asthma or something like that. And one of the patients I had on DB 04, I did retreat and I thought she had grade one, but the adjudication committee decided she had grade two. She eventually had what I called grade two and stopped. She did very well. She didn't have any progression from there, but it can be quite complicated evaluating these patients. You just don't want to miss it and have somebody rapidly progress to a more mortal event. We actually looked at patients who were recalled after grade one ILD and data presented at Esma breast this year and found that uh you could be retreated and some patients even had recurrent grade one and were retreated again. Uh And then a third of the patients were retreated for more than six months and a little under 20% for more than 12 months. So, if you have grade one ILD, you can retreat after resolution of the ground glass opacities and get significant clinical benefit. So we'll just finish up with a few other um ad CS used for breast cancer. So, unlike what we heard about the results of Sasa Gobi and SG in other cancers, we've seen very nice efficacy particularly in triple negative breast cancer in the ascent phase three trial, where patients who were heavily pretreated, median of three lines of prior chemotherapy for metastatic disease. And yet SASA have resulted in an improvement in PFS and a remarkable improvement in overall survival in this very hard to treat subset of breast cancer with a poor survival. The toxicity is indeed neutropenia and we've learned to use growth factors preventively in higher risk patients and also to use the long acting growth factor peg Phil grast them after day eight, which helps a lot diarrhea can be an issue about 10% grade three. And I'll show you some of the risk factors that now we can evaluate in uh at U CS F by the use of pharmacogenomics to try and uh better dose our patients. Um So we also studied uh saco Gove and in patients with hr positive her two negative disease, very heavily pretreated. 90% had visceral meds and media of three lines of prior chemotherapy. We also saw an improvement in PFS and a significant improvement in overall survival. Uh And actually what was interesting was three times as many patients at 12 months were free from progression who received SASAE then received our prior best chemo Irian in the late line setting. So what do I mean about toxicity? Well, uh the payload for Ace Mago AEC can is a gatto one inhibitor uh SN 38 which is the active metabolite of irinotecan. Um And we know that irinotecan toxicity is increased in poor metabolizers and metabolism is through UGT one A one. So we looked at star 28 homozygous who are poor metabolizers of uh Irene T can in both ascent and tropic. So too. And what we found was that in this 10, about 10% of the population that they had significantly more, grade three diarrhea, a little bit more neutropenia. But we can manage that a little bit more febrile neutropenia as well. But the big difference was diarrhea. So that's brought up an interesting trial design in our alliance uh Cooper group to think about starting low in patients who have poor metabolizing phenotypes. And we've used this now, I actually check pharmacogenomics at UCSF to see whether or not patients have heterozygos or homozygos. And there are other poor metabolizing phenotypes that are seen in different racial and ethnic groups that are of great interest. I've had a couple of heterozygos and one patient actually needed octreotide despite dose reduction to manage her diarrhea and we have a new trope two A DC data poom. A direct can you heard about in troop on breast O? One patients who received a median of one line of prior chemo and hr positive disease received do DXD or T PC, again, mostly Arabian in the T PC group. And what they saw was improvement in progression free survival and time to subsequent therapy. Quite impressive and nice. The drug is given every three weeks as opposed to day one and day eight like Sasi zab. So there was great interest in that. There was a lot less dose reductions and interruptions compared to the standard chemo. Uh but the most common toxicity is nausea like all the Durex Toan AD CS, there's some alopecia and then stomatitis is a unique toxicity of TDXD probably because of efficient delivery of Durex Toan to the mucosa and it's unclear why it happens with TDXD. It doesn't happen with Sasu Zuma. You do not get diarrhea from data DXD, but you can get ocular surface events, but they're low grade, mostly uh dry eye as opposed to an interfering with vision. They see drug related ILD, but it's a low grade, only 3.3% all grade, no grade five events. There was one patient but had a complication with the viral syndrome but does appear to be less than TDXD. So we've been waiting to see the overall survival and hot off the press. September 23rd Monday, we saw this press release that showed that tropia breast 01 did not meet its survival end point. This was a dual primary endpoint compared to PFS. Now, why would that be, could it be that data is not quite as good as the others? I think we've seen the trope two ad CS are not as effective as the her two A DC. But this is probably in my guess due to crossover to other A DCs and depending on where you were enrolled, you could get TDXD, you could get Satu Zab if you were on the control arm. And in fact, my patient, one of my patients on Trion breast, one who was on standard of care went on to receive TDXD had pneumonitis and then got Sasu Zuma for eight months. So all of my patients on the control arm received a subsequent A DC. So it would be very interesting to see this data when it is presented and it brings up a question about approval and what we can do with our new AD CS even that are highly effective because we can use other ones sequentially. The combination of AD CS plus checkpoint inhibitors is of great interest data. And DVA Sassou and Teli has shown very high response rates in triple negative breast cancer. In the first line metastatic setting, uh really impressive, almost 80%. And there are a lot of trials looking at these combinations in triple negative disease, in hormone receptor positive disease and in patients who have not achieved a pathologic complete response after neoadjuvant therapy for triple negative breast cancer. Um these are all the different studies and I'm more than happy to share these slides if you're interested. And then the last kid on the block is Sasi map, Dr T can sac TMT. So this is another trope two A DC. It also has a novel to 01 inhibitor A bellow T can derivative and it was developed in China. So this trial was done all in China. The opti trop breast study, triple negative breast cancer in the first line setting. And uh they had uh sorry for, for triple negative breast cancer with prior chemotherapy regimens very similar to ascent. So up to two, prior chemotherapy regimens showed an improvement in progression free and overall survival with a suggestion of a better outcome in high trope, two expression, very good response rates as well. And they talk toxicity that crosses data and sasae. So some stomatitis, some neutropenia. So we'll see what happens because this drug now is being been licensed by Merck and is being studied in multiple trials, hormone receptor positive disease in the first line setting. And we're starting a triple negative trial in PDL one negative metastatic disease. Lots of new AD CS uh including AD CS with an immune payload and eriBULin payload drug. We're currently studying in a phase one B expansion trial, um combinations with checkpoint inhibitors. Um And then uh multiple new approaches to developing AD CS. As I was mentioning earlier, we have a trial looking at sequencing Saum gov T can and a vim with other therapies including a mec inhibitor funded by the breast cancer Research Foundation through our consortium called T BC 0 47 in patients with triple negative metastatic breast cancer. There are sequencing studies looking at data and TDXD and Hr positive Triple negative disease, a registry study by our own Laura Hubbert within our uh consortium looking at Sasi Zab and TDXD and then a series study looking at SASA after TDXD all ongoing in the US. So, really exciting area. You've heard some exciting new data in three different cancers. Um in breast cancer, we've established efficacy of TDXD across all of the subsets including subsets. We didn't even know we had her two low and ultra low disease. We're now moving the AD CS into the early stage setting. There are multiple neoadjuvant trials and we reported from our I spy two trials. Remarkable I could see with without a poom directs to Canada in the neoadjuvant setting, allowing a number of patients to get much shorter treatment and go to surgery earlier with immune marker, positive high risk early stage disease. Lots of questions, toxicity management is critical and we'll look to the future to try and understand how we should be sequencing these agents as we move forward. So with that, I'll thank you and we'll do questions. We have some time to discuss this a little bit before the end of our session here. I don't see any questions in the chat but feel free and I just wanna highlight our Cancer Center live series. Next events we have best of the year November 13th, which is a collaboration between U CS F and John Muir Health focusing on common cancer updates with direct application of clinical practice. We'll cover breast cancer, lung cancer, gu cancers and G I cancers because we're missing some of them. We're gonna do updates in other cancers. We don't want to leave anybody out uh in uh February. And then we'll look at special topics in surgery. So many new changes in uh surgery with a robotic uh techniques and a lot of really uh exciting new approaches. Both in surgery and reconstruction, uh, we'll see in the future. So with that, I will close and stop sharing and hope that we have a little discussion, uh, available.
