In this new edition of the Cancer Center Live Series, three UCSF specialists present exciting updates on difficult-to-treat gastrointestinal malignancies, including pancreatic cancer, peritoneal metastases and advanced biliary tract cancers.
Discover:
· Why germline testing is important and how to navigate new chemo options for metastatic pancreatic cancer, such as NALIRIFOX – recently approved as a first-line treatment – as well as targeted therapies, such as PARP inhibitors
· Why peritoneal metastasis can progress with frightening speed, the promise of CRS/HIPEC (cytoreductive surgery + hyperthermic intraperitoneal chemotherapy) for increasing survival, and which colon cancer patients might benefit from CRS/HIPEC
· How the last few years have seen rising rates of biliary tract cancers but also newly approved chemo protocols and immunotherapy options for certain patient groups, with benefits such as lengthening response time
Bonus: A look at current clinical trials on these challenging cancers
Thanks so much. And uh really the Cancer center live series is the brainchild of Laura who's really worked hard with Joy O sent to make sure that these educational events occur. Uh And we do four events per year. We'll tell you more about the next one in a moment. Uh We have fabulous faculty members from our G I oncology program who are on today. Andrew Coe, who's professor and associate chief for and of the Division of Hematology Oncology and really carried us through the pandemic as the leader of our division. Uh So, uh we're really thrilled to have him here. Uh Mohammed Adam, who's assistant professor in residence in the Division of Surgical Oncology, who will tell us more about some of the new surgical techniques. And Katie Kelly, who's professor of Clinical Medicine and co-director of Clinical Research in our Division of Hematology Oncology and has taken on the big role of chairing our Data and Safety Monitoring committee and has run this uh extremely well. So we're excited to hear from all three, our agenda is here. Uh We're at the welcome part and then we're gonna hear from Andrew Coe about pancreatic cancer in 2024. Are we finally moving beyond just chemotherapy? So, an area which has changed dramatically over the last 10 years in particular and then we'll hear about cyto reductive surgery and high p for peritoneal malignancies. A really interesting new area from Doctor Adam. And then it updates in advanced biliary tract cancers, expanding roles for immunotherapy and targeted therapies from Katie Kelly who led and published one of the most important studies in this area in the last year. Uh So, and then we'll close and give you uh a link for ac me, a link to today's recorded session which you heard about uh from Laura will be sent to all attendees within four weeks. Uh So just before we get started, I want to briefly tell you about cancer services referral center which serves as a single point of access for adult cancer services. And this tells you a little bit about how to refer a patient to U CS F. Uh You can fax it or you can actually uh work uh within the uh internet service. There's a telephone number uh and one point of contact so that you don't have to rely on the facts necessarily. So, um the telephone number is shown here, it's easily accessible and somebody answers the phone between eight and six P eight AM and 6 p.m. Monday through Friday. Uh We're of course happy to see your uh patients. And MD link is a great thing to remember because it's just U CS F health.org/md link. And that gets you to the uh internet session. Uh We have upcoming sessions just to tell you about. On March 28th, we have our collaboration with John Muir Health. Uh And we're going to be talking uh about advances in hepatobiliary and pancreatic disease in that group uh session. And there's a few uh a registration link there. And then uh we're excited about our next uh cancer Center live series on April 17th where we'll talk about advances in new techniques in radiation oncology. And we have, we'll have four speakers talking about different areas and then CME uh credit will occur afterwards. A survey link will be posted at the end. So you have to stay on to get CME credit and you'll copy and paste the link into a new window. Uh So you have to complete this by the end of the day on March 6th to receive CME credit. So I'll go back now to the agenda and I introduce Andrew Coe to start our next session. Thanks so much, Doctor Rogo, Doctor Crecio for the opportunity to speak and for all those participating in this early evening hour. I'm gonna share my screen right now and you can let me know when we are good to go. We can see it looks perfect. Thanks. Well, I've had the privilege. Uh My name is Andrew Co. I've had the privilege of being at U CS F now for more than a couple of decades and part of a really terrific uh G I uh oncology team um with some really wonderful colleagues for leaders in their field. And my area of focus for much of my career has been on uh pancreatic cancer and I I title my talk pancreatic cancer in 2024. Are we finally moving beyond just chemotherapy? So for starters, I'm gonna say chemotherapy remains a mainstay of treatments and that's not going away. But I hope by the end of our this talk to be able to convince you that as particularly for certain uh uh niches of our patient population, we do have uh an increasing number of um uh targeted uh options. This is just my uh uh disclosures primarily in the form of support for clinical trials paid directly to U CS F. Not to myself learning objective wise, I'd like, I would like to review the la the latest data regarding optimal selection of chemotherapy. So, cytotoxic therapy for patients with metastatic pancreas cancer, which as I said, uh still remains the mainstay of treatment. But I do want to focus a lot of attention on uh understanding how molecular findings um especially as we're now routinely doing both uh somatic and germline testing on uh our patients can inform the use of targeted and even occasionally immune based therapies uh for patients both in standard practice as well as uh looking ahead to uh clinical trial opportunities I like to start by way of a case presentation fairly typical in terms of uh adrenaline in seventies presenting with abdominal pain and progressive fatigue. You see on this Coronal image of AC T scan, the presence of a pancreatic body mass with multiple hepatic lesions and retro peral adenopathy. He retains an AAA pretty good performance status and biopsy. One of these liver lesions demonstrates invasive adenocarcinoma consistent with the pancreas primary. Um As now we do routinely uh next gen sequencing uh reveals pathogenic mutations in Kras. And here specific genotyping, notably, a G 12 C A mutation is important to highlight as well as a number of other, a fairly common um genes that are mutated in pancreas cancer. The tumor is micro cite stable with a low tumor mutational burden. So the question is, how do these results, how can we use these results um to inform either uh current or future uh treatment decision making. I'm guessing the audience is pretty well aware of the, the two pivotal studies um historically that have defined our use of chemotherapy for patients with newly diagnosed metastatic pancreas cancer. One is this regimen called firino. So we've really, I think graduated to using more of a modified version of fal fino. But this original French study now more than a decade old uh shows the superior superiority of Falin over gemcitabine for fit patients with metastatic disease. Um And this was a very important study because this was the first study that sort of showed immediate survival in this patient population approaching one year contemporary data. In fact, if you look at uh uh current studies and series shows that with fox, we're actually hitting a median survival of upwards of 14 months based on some series. And then the other combination regimen of used commonly is gemcitabine plus NAB paclitaxel or abraxane, which compared to Gemcitabine, again, perhaps not quite as impressive as the fox data but was clearly superior to gemcitabine alone in terms of median survival and other very clinically relevant um outcome parameters. And again, if you look at contemporary uh series, the this combination was associated with the median survival from metastatic uh disease of close to one year. The inevitable cross study comparison uh table that I show here just highlights the point that Gymy mean that paclitaxel was a much larger study across a wider swath of patients in different geographic regions, including older folks up into their mid eighties and with a a performance status uh down to a KP of 70. So it is a little bit more of a Generali uh regimen that can be cut across a lot of uh uh different demographics and, and um poor performance status patients. But for the longest time that this sort of the big Matzo ball was uh would there ever be a head, direct, head head comparison between ferox and gem nap pack with Taxol to see which one comes out on top and lo and behold it this past year's ESMO Congress. Um, a Japanese Cooper group study called The Generate Trial. Looked at this very question. It was a three arm study. Um, with a third arm that I'm not gonna really talk about. Uh consisting of S one and oral flu fluorine used in Asian countries quite a bit. Uh S plus I rock, but the, the two comparator arms of greatest interest were Furin or modified Furin versus gem nap papo Taxol. Again, for a purely metastatic patient population with the overall survival and cutting to the chase if you look at these Kaplan Meyer survival curse, what you see, I'll say somewhat, surprisingly. First of all is just how well these patients did but really seeing if anything numerically a a and improved median survival with the patients receiving gem nap paclitaxel compared to Mo modified Purox. So 17 versus 14 months and the study was actually powered to look for an improvement in uh the in the pal regimen. And because they saw the flip, this study actually uh closed early to a cruel because it was clear that Purox was not going to turn out to be better than gem, that pelota or if anything seemed to be a bit inferior. Um And similarly, there was certainly no improvements um with modified Purox in terms of uh progression free survival. And this table shows sort of the other outcome measures including very similar response rates and below 30% for both. And uh I'll say kind of uh not surprising uh toxicity profiles. So as I note this trial was actually terminated for F for futility. After this preplanned, interim analysis showed that pyra was not going to be better. And the investigators actually concluded that gym nap plot should represent the first line standard of care for metastatic pancreas cancer. Now, that kind of flies in the face of what I think myself and a lot of my colleagues who see a lot of patients with pancreatic cancer um do in practice with sort of the feeling that modified purox if anything is is sort of the the the real gold standard for fit patients and then maybe even adding further to the confusion. Um is this phase three international Napoli three trial um which just recently received FDA approval for the front line treatment of metastatic pancreas cancer. And this is basically using a, I'll call it a Fox adjacent regimen because it's very similar Furin. But with the substitution of nano liposomal irian, which as we uh no is used, is approved for the second line setting for metastatic pancreas cancer after gem based treatment. But basically using NA nano liposomal iron can in place of Furin a so called regimen called NALL Fox. And so a Napoli three trial compared Nay Fox to gem nap P tax with over all survival being the primary endpoint. And this study was a positive study because now, Larry Fox was superior to gem nap. Paclitaxel has a ratio not particularly impressive 0.83 with a difference in median survival of 11.1 versus 9.2 months and improvement in media pfs as well. Now, I think what's a lot of us when we saw these data set is, hm. Well, now Larry Fox in this study, median survival 11.1 months. That original French trial of F Fear Knox, 11.1 months, you couldn't get more identical results if you if you tried. Um And so it really raised the important question of, well, is, is Nell Fox, is it really a a step above F Knox? And should we be now using taking patients who we normally would treat fal Knox and give them Nary Fox instead? So this is how I kind of put it all together. Uh in terms of our selection of chemotherapy for patients Napoli three, as I just showed you now, letter Fox is better than GEM NP with tax. But now letter Fox seems basically equivalent to Faus. On the other hand, you have this Japanese study that I showed you where Gem Nakli axel seems to be better than Pina or at the very least equal. So where does that leave us? So a few thoughts, one cost considerations, we know that the the cost of NA leary is a lot higher than free iron Tehan. I will say also in the Naar Fox, the dose of oxide plan was slightly lower than we typically give in the Furin uh regimen. I think an outstanding question that has to do with whether the the very robust results seen in this Japanese study is Generali well beyond just the Japanese patient population. And then what I'll say, fun is can any sort of predictive biomarkers or genetic signatures allow for more rational decision making? I don't know the answer to that because we don't have really good biomarker data for in either of these studies. What I will say and what um is is commonly known is that at least for the subset of patients who have homologous recombination deficient pancreas cancer. So that may be 10 15% of patients who have a somatic or germline Bracco or Pal B two or even some other um sort of a non core hr D pathway mutations that these patients tend to respond much better to platinum based therapies. And at some point during the course of treatment should receive some form of platinum based chemotherapy such as Fox or or Mallary Fox. And this is just one set of data uh amongst many now that show clearly the benefit of platinum based therapies for hr D associated pancreas cancer Fox Neller fox would obviously be suitable for this subset of patients. But I will say that a regimen such as even gems and CISplatin may be of have similar efficacy. And this is one phase two study. It was a randomized phase two study of gem cyb and CISplatin with or without the parp inhibitor bli. And the point wasn't sort of the benefit of the lid, which there wasn't really a lot of added benefit. But if you just look at all patients in both arms who got gem cy amine and CIS plan, you see from this waterfall plot that upwards of 70% had a very striking. In fact, the vast majority had at least some response, clearly demonstrating the responsiveness of this uh BRCA and probably two mutated cohort of patients to platinum based chemotherapy, whether it be CISplatin um or potentially oxaliplatin. And this actually forms the basis of a newly opened Cooper Group uh study. Uh myself and one of my junior uh colleagues who work with us at U CS F, Dr Erica Singh are leading this alliance trial looking specifically at a strategy in patients with BRCA or probably two mutated pancreas cancer who have already received ferox of then continuing on with a different platinum agent, specifically CISplatin in combination with gem and nap paclitaxel versus sort of standard gem nap paclitaxel in the second line setting. So I I would encourage if you uh any of you have patients in your um a practice who have a known somatic or germline uh BRAC or probably two mutation um have gotten fur knock uh and are still well enough to get continue with some uh second line treatment. This is a study that's intended to address this very question. Now, all this being said, you can tell that the point for right now is that compared to a lot of um uh my colleagues taking care of folks with breast or lung or other types of cancers where we're really, where they're really able to give more nuanced um and targeted treatments based on molecular subsets in in pancreas cancer. By and large, we're deciding between these different chemotherapy regimens based mostly on clinical criteria, age performance status comorbidities. Um But what I wanna focus my attention in the next few minutes is just that there really is no evidence beyond just sort of this hr D subpopulation um of some molecular and genetic subtypes of pancreas cancer that may help guide selection of therapy to summarize precision oncology for pancreas cancer. Um We're at least starting to move in this direction. First of all, this is just a reminder that all patients should get germline testing, irrespective of whether they have a provocative family history of cancer or not as well. If you're going to be treating your patients with pancreas cancer, you absolutely should consider um doing um next gen sequencing like their profiling on these um on patients ideally from a tumor sample or e even with uh panels using blood based uh CT DNA. And we know that that does matter, even though only a minority of patients do have a quote unquote actionable finding those who do have some finding that can have some matched therapy clearly do better than those who receive unmatched therapy or just have no um actionable um marketer to speak of. So when we find results and can do something about it, it is impactful and patient survival. And this was a, a nationwide effort called know your tumor. Uh To look at this question, this slide is just to indicate that it is a little bit of a needle in a haystack phenomenon because a lot of what we're trying to find in somatic testing is uh uncommonly or even exceedingly rare and just to give you a few example. So I alluded to before the, the, the subset of patients and this is probably the largest subset of is uh with patients with HR D associated pancreas cancer, specifically um BRCA or Palp. Um two mutations. The polo trial um was the a pivotal study that ultimately led to the approval of a lab in the maintenance setting for patients with germline br associated pancreatic cancers who have responded to or have sta stable disease following platinum based chemotherapy. Recalling that I said that patients with BRCA mutations should be getting Latin based chemotherapy and once their disease is stabilized after at least four months on treatment, they can then segue to receive maintenance treatment with A P inhibitor. Now, the polo trial was positive for its primary endpoint of progressive free survival. As you can see from the left hand Captain Meyer Curve. Although that did not translate into an overall survival benefit. That being said, I do think it is still meritorious to treat with a harp inhibitor. You can see other outcome measures like the you do see a a substantially higher proportion of patients still alive at two years who received maintenance, elaborate versus placebo and the time free from cytotoxic therapy by, by being on a maintenance strategy also uh clearly favored um the elaborate versus the placebo group. And I do want to give a shout out to another important Cooper group study that is looking at the potential synergy between part inhibition and immunotherapy that is taking the same criteria of patients in the maintenance setting and seeing whether the addition of pembroke to elaborate is superior as a maintenance strategy compared to ela as monotherapy. This is an ongoing study that a again um if you have patients who sort of fit this bill and are and are interested, it's not open at U CS F. But there are other um uh regional sites that um it's possible for patients who might be interested in this. I'll give, I'll briefly touch on a couple of other uh examples briefly. One is obviously we know that KRS mutations are exceedingly common in pancreas cancer. Uh Some series show up upwards of 90% the vast majority are these G 12 D gene type um with a smaller proportion having um mutations such as G 12 C. That is obviously relevant because we know that G 12 C inhibitors which have a lot of traction in in non small cell lung cancer and others actually are effective in pancreatic cancer as well. So we have data, for example, from a phase 12 trial of soda acid um where you see a response rate of 21% for patients with G 12 C mutated pancreas cancer. But a really impressive disease control rate and really minor responses in in quite a significant proportion of patients. Now granted the the median progression free survival is only four months. So patients do invariably develop resistance to the strategy. But between this and other studies, including of a, a grassy and in fact, other G 12 C uh inhibitors, um you do see that there is at least some activity. So, and we do have these studies ongoing at U CS F through our early phase program. So for patients you have may have who have G 12 C mutated pancreas cancer, recognizing that it is still only two or 3%. This is a very viable strategy. Um again, either off label or preferably in the context of clinical trials. But what's perhaps even more exciting is that the larger swath of patients who have other mutations in KRS like the G 12 D or G 12 V um where these pan ras inhibitors. Uh one example being this uh uh R MC 6236, which is this so called Rass multi on inhibitor. And this works across multiple different gene types of, of Kras mutations. And you can see actually for a pretty sizable cohort of pancreas cancer patients who are heavily pretreated, an objective response rate of 20% sense and, and even a much higher disease control rate. So there is clearly some activity here in these Pras inhibitors. Um there is some promise even with some very specific G 12 D inhibitors. So this brings up a lot of excitement for trials again, not quite ready for prime time yet. But um uh just a, a lot of promise for a strategy in terms of rest targeting that in the past had been just really a holy grail. But uh now perhaps being able to confront a previously insurmountable problem. Example, three, I'll give just briefly is immune checkpoint inhibition for uh a defective MS metroair or M SI F high. Again, pointing out that for pancreas cancer, this is only about 1%. I showed these data from the keynote 158 study of Pembroke for sort of different solid tumors that are uh M si high to show number one that yes, there is some activity in pancreas cancer but highlighting the immunologically cold nature of pancreas cancer. The fact that the response rates for pancreas cancer. Even that our MS A high is the lowest of basically just any other um solid tumor. Uh suggesting that we really need to think of additional strategies to prime the immune system. Beyond just um immune checkpoint inhibition, there are other NCCN approved alternatives as well including IVO and dost Starlab, um uh sort of um more disease agnostic approvals and then in the interests of time, I'm not gonna talk about just these other very rare um findings. But if you happen to have a patient with an ran fusion or a BRV 600 D mutation, these patients actually can respond to the corresponding Trek inhibitors or a raf me inhibition strategy. I'll close by just briefly mentioning word on a few novel or investigational approaches in in treating pancreas cancer. Highlight that the tumor micro environment is this obviously this dense stromal compartment but also an immunologically and immunosuppressive milieu where you don't have a lot of this sort of a rich infiltrate of of, of CD eight T cells, you really just have these um more immune suppressive type of uh cells, uh tr uh tumor, so, macrophages, et cetera. And so all of this conspires to make these tumors both not receptive to effective drug penetration and just being um sort of not responsive to uh immunotherapy approaches. So as we try to move beyond conventional chemotherapy for pancreas cancer, I, you show this Venn diagram that really are overlapping, but I mentioned a few mole target agents. But we also have these newer strategies for um for trying to prime prime the immune system as well as agents targeting the tumor micro environment and trying to modify the Perumal stroma. And I just summarize a number of the strategies both for immunotherapies as shown here, uh ranging from next generation immune checkpoint inhibitors to um c 40 agonist all the way to uh even some strategies of, of the cellular therapies and and car T cells even though that is very much in its infancy and very early in clinical development. And then vaccine based strategies which obviously have been around for quite a long time. We quite interested in some of these. Although these perhaps more useful in the adjuvant setting to try to prevent relapse for patients who have already undergone resection. To this point. I perhaps I won't dwell on this too much. But this is just one. Ultimately what turned out to be a case report of an effective um um T cell receptor um strategy directed against uh Kra um for a patient with lung metastasis. Um And I do want to highlight this because it is a study that we will be opening at U CS F shortly that is using a RN A based vaccine based on identification of neo epitomes in patients undergoing surgery. Where in addition to their A Fox, they receive um this personalized um uh vaccine and this is gonna be uh again uh the, the basis of a study that is opening at U CS F amongst a number of other major centers across the country. Finally, I will just note a number of stromal depleting or modifying agents without going into too much detail here. Um I just use it as a segway and this is my last slide to show that one of our new studies right now is a combination of chemotherapy together with a drug called defective, which is a fac inhibitor, focal adhesion Kinase inhibitor uh that may ideally uh uh reduce external density in combination with the so-called rath me clamp. So uh basically inhibiting Mac ka signaling, this study is now open to enrollment at U CS F for so, for any providers who are um uh who are seeing patients with me pancreas cancer, newly diagnosed, we would welcome um uh referrals um to our Gerontology program. With that. I think I'm gonna stop there. I know that was a little bit of a whirlwind tour, but I wanted to give uh the audience just a little bit of flavor of both chemotherapy, but also what we have coming down the uh uh pipe, which hopefully you can see um shows a lot of promise um um for additional investigational approaches in the future. Thanks very much for your time. Thanks uh Andrew, love that picture of the bridge too. It's a, a new newish one for me. To see. So that's great. Um This was fascinating, really. It's unbelievable how much uh there is going on in pancreatic cancer um For to the audience, if you have any questions, comments, thoughts, please put them in the Q and A section. You can see the little Q and A button on the bottom. Uh We'd love to hear from you. Uh So let me just start with a question about uh some of the things you talked about. Of course, one of the things that comes up with pancreatic cancer is that the survival is so short uh in these studies, you know, you're, it's being improved, but it's still pretty short. Um What's is there a way to try and uh diagnose these earlier who gets screened? I mean, we know if you have a BRCA mutation, people are being screened maybe, but what's the next step for that? Yeah. So, you know, I think what you're asking is what ultimately might be the most impactful, which is trying to catch pancreas cancer either at a very early stage or ideally in sort of the pre malignant uh stages because at this point, we don't have a population wide way of screening. They're obviously big in sort of pan cancer initiatives. Um looking for CT DNA and things like that, that might point you in the direction of doing that for a sort of general risk patient population for your higher risk patients who have a known um germline germ line, um uh hereditary susceptibility to it or who have a strong family history. There are programs going on at various places around the country. Hopkins, University of Washington everywhere where they will do a screening where they will undergo annual screening which might consist of MRI S alternating with endoscopic ultrasounds to try to pick up um either very early stage or, or high the equivalent of high grade dysplasia in the pancreas. Um and those, those are successful screening efforts but are not yet Generali just to be the broader patient population, right? Because of course, breast cancer is so common. Um And although we, I think we recently heard news that the incidence of pancreatic cancer is increasing um in the US and worldwide, but still the rate is low enough that there isn't really a screening strategy for the population, correct. Uh That is correct. I mean, it is continuing to increase uh over time. Um Even at, you know, we we obviously hear a lot about the epidemic of early onset uh colorectal cancer. It's probably not quite as striking in pancreas cancer, although we are seeing it also at a um we are also seeing it at a younger age. Um But I do want to highlight that even though perhaps it's not as uh common as a number of other diseases that, you know, we the the projection is sort of it's gonna be the number, the second leading cause of, of cancer mortality after lung cancer, probably by 2030. So, because it's obviously a disease, as you pointed out that has such a poor mortality where the mortality rate almost approximates the, the incidence rate. That's why it's, um, you know, it's sort of a, a very top leading cause of cancer death, unfortunately. Yeah, it's interesting. And of course, there's been a lot of interest in the other forms of pancreatic malignancy. You were talking about adenocarcinomas, right? Um But like, you know, Steve Jobs case brought up a lot of interest in these are even rarer, right? The other. Yeah. And thanks for clarifying that, that my, my focus was on adenocarcinoma of the pancreas, which is about 85% of pancreas tumors, a smaller subset have cancers that arise from the endocrine component of the pancreas. So, Isle cellar neuroendocrine tumors, we actually have a fantastic program uh led by uh one of our world class, uh clinicians and researchers, Emily Bros. And um uh and that is a completely different biology with many other therapeutic uh options. Um uh And that's its own, that's w that's worthy of its own separate talk because there is a lot of exciting stuff specific for neuroendocrine tumors. That's great. And the, the work you're doing now, the first line treatment generally is a chemotherapy combination, the kinds of things you were talking about. Um And then, but there are some studies still in the first line as well as second line. Right. The answer is yes. You know, patients will often ask. Oh, well, is there a way I can do something without chemotherapy? And, and I tell them at this point in 2024 for your first line treatments, chemotherapy really still needs to remain the the bedrock, the sort of the backbone of treatment we can be adding investigational agents onto it. But we are nowhere at a point yet where that supplants or replaces um chemotherapy. Even some of the data I showed you with like immune checkpoint inhibitors for patients who should be more responsive to that is not as good as chemotherapy. So we're not yet at a point where immunotherapy or ras inhibitors or any of those data, I show you are yet ready to be moved into the front line setting in place of chemo. Um maybe that day will come. But right now, um our studies um do still include chemotherapy um as the backbone. Yeah, it's interesting about the perp inhibitors. You know, you wonder because of the data and breast cancer also showed no improvement in survival in the metastatic setting. But a hint that maybe in the first line setting with no prior platinum, there might have been an improvement in survival, but it was post hoc and then in the adjuvant setting, there was clearly survival benefit. So it does I is there work in, I guess the adjuvant area in pancreatic cancer is small but that, so there is actually a very good study. It's another cooper who study looking at a laid in the adjuvant setting for uh BRC and P two associated pancreas cancer after they finished their adjuvant or neoadjuvant chemotherapy of receiving a Laib. Uh Again, we do not have that study open at U CS F. The closest site for that is in Vacaville. Um So I've actually sent a handful of my patients who me who meet those criteria um to, to participate in the study. And that's a very important national initiative. Looking at that very ad that very adjuvant question. Well, that's great. I so appreciate your talk. It was fabulous and, uh, I appreciate everybody who's listening in, uh, and excited about your studies that you're doing in the upcoming Cooper Group study, et cetera. That's a vaccine. Uh Really exciting work. Thanks again. Thank you. And again, if for any of you who have patients who you'd love to, who you would like to refer either first or second line or we have a great maintenance, a different maintenance trial going on, please feel free to send them to um, our G I Oncology program. We have a great group. Um And we'd love to see your patients. Thank you. You do indeed. Thanks again, Andrew. So now we're gonna move on to, uh, talk about if you uh stop sharing, Andrew the, um, we're gonna move on to doctor, uh, Adam who's gonna talk to us about uh cyto reductive surgery and high pack. A really cool new thing. At least to me new, don't forget to unmute that. That always happens. Uh Thank you so much, uh Doctor Ruger and Doctor Crucio for the opportunity to connect with our attendees today and thank you for staying uh this late um over the next 20 minutes. I'm hoping to go over some terminology, explain why the perineum should be considered as a separate organ or a unique organ. Uh I'll talk about psycho reductive surgery and hype, talking about the principle and um the rationale for it. Uh And then we'll talk about its indication, focusing mainly on appendix and neoplasm and colorectal cancer review some data, special consideration and some cases embedded throughout that presentation. Uh I would like to start with uh this patient. Uh KB was one of the first patient that I've seen at U CS F. Um when I started in 2020 she's 73. She was a 7073 year old woman with mucinous append a neoplasm, what we call low grade pseudomyxoma puni diagnosed initially in 2016 and underwent debulking surgery at that time. And then not surprisingly, two years after she progressed, she continued to progress in 2020. And then in September of 2020 she started becoming obstructed and you could see that the small bowel is being pushed and getting a little bit dilated and larger. And this is when I saw her in December of 2020. At that point, she was unreceptable and she had obstruction and, uh, she went into hospice care and, uh, passed away. Unfortunately. So this sort of bring the question was debulking surgery at the time. The right answer for her. How about when she occurred two years, two years ago, how about 2019 and early 2020? Did we miss an opportunity? But I think indeed access is a big problem in the past patient used to travel from San Francisco to San Diego and this is predate. Um uh our program and um people could travel but it's very hard. It's not for everybody, especially people with limited resources. And since then, we've started our U CS F high tech program and this is a picture from our first case on 6, 14 of 2020. Uh So what is uh pernial magnes? And I think the correct terminology is pernia surface malignancies because they either originate in the surface or on the surface and or they come from somewhere else, what we call secondary pernial malignancies. So, if they come from the perineal membrane, they are either malignant perineal methio or dismal plastic round the cell tumor. These are sarcomatous tumor or if they are secondary, they should be either considered carcinomatosis, meaning that they are coming from adeno an adenocarcinoma primary or from the appendix as pseudomyxoma 328. But not adenocarcinoma of the appendix for the carcinomatosis. This could be coming from a giag or an extra abdominal metastasis. But if you look collectively at the uh this field of peroneal surface malignancy, it represent a good chunk of patients is not only a limited area and sometimes we see it that way. We know that pernial carcinomatosis is really bad. And this natural history study from France, they, it's an observational trial where they observe patients um over with carcinomatosis until they passed away. And when they looked at colorectal uh cancer patients with carcinomatosis, the median survival ranged from 4 to 5. But how about uh you know, if you were to use systemic modern systemic chemotherapy, is that different than before? And it's a little bit better, but it's just suboptimal. And this is specifically talking about pernial carcinomatosis. This is a um uh secondary analysis of the arcade database of multiple clinical trial pa uh multiple clinical trial um and included thousands of patients. And you could see that the survival of patients with pernia metastasis worse than lung or liver metastasis. And to better understand this and get a little bit of insight as why perineal metastasis worse than liver lung metastasis. We can go back to the embryology and we see that they, the perineum and the ovary, they share where they came from, from the mesoderm as opposed to the liver and the lung. And that might mean something because in colorectal cancer, pernia, metastasis, we often see cumber tumors and I think they as a similar mechanism between the two. Also, another consideration is that the massive area, uh surface area of the per um you know, it covers the whole surface, the inner lining of the abdomen, as well as the line, the vis in the middle. So it's about 2 m in size. But if you compare that to the longer the liver, it's a little bit. Um the the comparison, it's um um they are not comparable. Also, if you look at the pattern of spread, if you have per metastasis, the pattern is spread through seeding cell detachment, but it exfoliate and then you have this exponential growth of and and dissemination of tumor as opposed to liver metastasis where you have one nodule that's growing and spreading and confined to the pinch comma of the liver or the lung. And that's the danger of corneal metastasis. It can get out of control very soon. Also, if you think about the blood supply and how much of the cardiac output that goes to the peroneal cavity, it's very limited, almost like less than 5%. But if you compare it to the liver, compare it to the lung, you're getting more blood. And that has implications in terms of the efficacy of systemic treatment. With that cyto reductive surgeon Hae was pioneered by uh Doctor Sugar Baker and he wasn't the first one. There is nothing new under the sun. It has been used randomly here and there. But he's the one who pioneered it at the NIH. And the idea is that you remove all of the tumors. So you address macroscopic disease with psycho reductive surgery. And then for the microscopic disease, then you add in the heated chemotherapy because systemic chemo does not reach there. Well. So you start the procedure with removing and cy to reducing and hear the term cyto reduction instead of debulking the tumor to tumor limiters. So that you um you know allow adequate chemo penetration of the residual tumor that is not removed. Also a big thing is visual preservation. So you try to preserve the visual as much as possible to uh enhance quality of life. And then after that, the chemo comes to control microscopic residual disease. And um that another advantage of that if you remember that the blood flow to the, the perineum is limited. But histologically also, if you look at it, there is a perineal plasma barrier, it's kind of like the blood, you know, brain barrier similar to that that does not allow high concentration of intraperineal chemotherapy to cross over and cause toxicity which could be exploited by using high concentration of heated intraperineal chemotherapy. The hyperthermia is to enhance chemo penetration and add to the synergistic cytotoxic effect of uh chemotherapy. These are the indication. But today we're gonna focus on appendicis, neoplasm and colorectal cancer. So, if we look at appendiceal neoplasm. They have been the poster child of cyto reductive surgery and hyping. And they are unique because they are mucinous theyre limit aside to the liver to uh the lymph nodes. And, and that's why mechanical cy reduction with chemotherapy works really well and you can achieve good survival with that. Then how does it happen? And it's very interesting. This is a disease that killed people but it is not biologically active. It doesn't metastasize to the bloodstream. It's not that smart. And all of it is kind of mechanical uh seeding detachment and mechanical compression of the bowel. And people die because patients die because of bowel obstruction. It's not like this in the appendix, what we call mule where you have an adenoma in the appendix that produces mucin and the muse production increases until this, uh you know, the appendix. I'm not sure if you could see the hole here in the appendix, it ruptures, then you have spillage and then you have a spillage of m in the perineal cavity. And then it looks like this. This is from another patient just to show you how it um the disease progress and this become absorbed and becomes solid. And then you have your uh uh tumor implant and then if not treated in a timely fashion, then you have the disease kind of seeded and, and dissected through the small bowel and then you have a small bowel disease and then it will be too late to operate. So this is a study from the mayo clinic looking at the natural history and treatment of um uh this mucinous tumor or pseudomyxoma. Yeah. And what they showed is that the recurrence rate is 2.5 if you do debulking and this is that was the old paradigm is to debulk when it reached a point where it's causing symptoms. And when you debunk that then the progression happens 2.5 years. And if you remember KB, that patient exactly happening over two years, period. But then the immediate survival of the debulking surgery was 5.9 years or six years, which is not ideal for um such a biologically active disease. This is we don't have clinical trial that's showing cyto reductive surgery versus cyto reduction versus new surgery. But this is um this study that was published in JCU obviously from the pog data set registry, over 2000 patients that were treated with psycho reductive surgery and hype. And you could see the in the blue curve here, you could see their survival and survival was about, the meeting was 16 years, which is really good. And the recurrence rate was about, you know, uh about eight years and over 60% of them survived past 10 years, which is really remarkable. Um So just to show that this prolonged or excellent survival, it's real. This is a U CS, a patient that I helped treat she's a 64 CD, a 64 year old woman had, had a history of massive cyto reduction ma massive pseudomyxoma in 2003, about 21 years ago. And um her PC I, which is a, it sort of showed the tumor burden was really high, the max at 39. So she was reaching that point. So one of doctor uh Doctor Escobar, one of Doctor Sugar Baker's partner operated on her in 2003. And then 20 years later, she recurred in the abdominal wall and this is her recurrence and this is her CT scan. Then we did, took her back to the operating room 20 years later to manage this recurrence IC reductive surgeon high. And this is 2.5 month uh post up. This is her CT scan. So she's back to normal and uh gain, regaining her uh quality of life and her baseline activity. Uh the problem with appendix neoplasm. And there is a lot of confusing nola it's a rare disease. It is um often confused with uh adenocarcinoma of the appendix. And that's why patients are mismanaged to give you an example that this is a 40 year old diagnosed at the outside, out at, at an outside institution with metastatic appendiceal cancer. And she was told to go to hospice and you could see the tumor all around her abdomen thinking that this is adenocarcinoma. She, we reviewed her path and it showed low grade pseudomyxoma 320 I and then I did cyto reductive surgery and hype. And this all of the procedure that we've done this is, you see that paragraph is not a presentation. All of these are procedure about 50 specimens and this is her post op uh in six month follow up and she's doing well then moving on to colorectal cancer, uh pernial metas and the setting of colorectal cancer is very uh it's a big problem. And uh however, CRS hype is very controversial in this setting because we don't have a lot of data. These are the criteria that we use to select patient for CRS hy pick. Obviously, the minority of minority of patients are candidate, but you would have to have reasonable tumor burden. Meaning that complete psycho reducibility is achievable that we are able to remove all of the tumor. It's also that we also wanna leave adequate a small bowels. So the patient would be able to eat and not be TB independent. Also absence of extra peroneal disease is a must, obviously acceptable performance status and comorbidity uh status. Also, it's one of the surgical uh criteria. So, is there any data to support CRS hy uh in um colorectal cancer? And the answer is yes, this is an all trial from 2003. It's a what we call the Dutch trial that compare patients to standard treatment or systemic therapy versus psycho reductive surgery and hype And um you could see that the survival is better with um hype almost double. But then more importantly, this is the median survival on the left side. But on the right side here, among patients who underwent complete cy reduction, meaning that all of the tumor has been removed and they underwent high tech. The immediate survival was for a month but then also over half of them approximately survived past five years, which is truly remarkable. These are the criticism uh of the this trial. But the main thing is that at that time, modern systemic chemotherapy did not exist because the treatment happened in the 19 nineties. So now the question is that modern chemotherapy, um how about high pick in the setting of modern systemic chemotherapy? And this graph that I showed you earlier um that we know that even with that the median survival is 16 months and uh almost none of these patients survived past uh five years. There is a one seminal trial. This is the pro seven trial that um was done in France uh trying to emulate what the Dutch has done. And here in this trial that everybody underwent CRS, everybody had went underwent surgery, but there's no systemic only arm. But the question was that does the addition of chemo perfusion to CRS help and this is the two arms, everybody underwent surgery, high tech and no high tech meaning that just a profusion and they showed that they are ident. The survival is really identical, 41 month, 41 month or 42 months or the high peak. But there is no statistically significant difference between the two. Then what does it tell us? Uh This trial? It tells us that at least Ciara is an acceptable uh treatment for some patients with uh Pernal uh carcinomatosis. Um But then the role of hype may need to be examined and that the problem with this trial, I think there's a lot of people who are picking and a lot of surgeons are complaining about this trial and some of the concerns about it. But I think the main concern is that the profusion aspect of um of their high pick was only for half an hour and the standard is 90 to 100 minutes. So basically a third of what the perfusion time and if you are in the operating room and you do these cases, you often pre heat the patient with Saline for half an hour to get him to that level of hyperthermia. So I'm not sure if they accounted for that or not. So this is a big, big limitation. I think the takeaway is that this just like when we say that this systemic chemotherapy regimen doesn't work and you know that the 30 minutes um the 30 minute uh regimen does not work for patients with colorectal cancer. I think this is how I would look at it ad hoc analysis of patients with PC I of 11 to 15. This is how we quantified uh uh carcinomatosis. There was a survival difference but this is not the main analysis. There are certain things that we need to be mindful of when we treat these patients with corneal metastasis. Number one is that imaging are notoriously inaccurate. It does underestimate extent of disease in almost all patients. And just here is an example, this is AC T scan of a patients with uh pseudomyxoma. And you could see the diaphragm just here on top of the liver. And here this is the intraoperative picture of the same patient. You see implant, they are not visible on the CT scan. But then when we resect the specimen, then we are getting more disease posteriorly. So this is the same uh patient um uh Escobar ato showed that CT scan versus intra op almost double tumor Burton was seen. So it's notoriously inaccurate and that's why almost all patients when appropriate or when they uh when it's possible, we do diagnostic laparoscopy because we wanna assess resect. We wanna say that if the small bowel excuse me is involved or not, and w would there be enough small bowel? We wanna quantify extent of surgery. So that also patients are interested to know whether they will have stool bag or not or sto or ileostomy or a colostomy. And that often could be predicted. Another thing is that the PC I which is a carcinomatosis index and it's an outdated back of the envelope kind of scoring system that sugar baker came from, but it looks at divide the abdomen in nine areas. And then you look at the small bowel and the max score is from uh you know, 39 from the 39. And you could see the subjectivity in that um especially if you are not experienced surgeon. We here at U CS F and this is my lab working on um using A I and computer vision to automate this process. And here this is some pre lien data that we've generated. We were able to classify patients with high and low PC I and hopefully, that would help democratize the process, morbidity and mortality of CRS. He big it's a big concern. So it's 40 to 50 maybe sometimes 70% morbidity or significant morbidity among patients. Uh You could look also at the mortality. Uh You remember that the strike of the mortality was 8% there. So that's why the techniques matter and making sure that your post op care is really optimal and making sure that you the patients are operated on by experienced Pernal surgeons, not by any surgeons. Uh Here also at U CS F. This is uh you know, heart of the press, we just presented this at the advanced Cancer therapies meeting. This is an externally validated uh machine learning decision tool where you can plug in the numbers and it gives you the the probability of having severe complications. So it helped with the discussion and if the indications are soft, then it potentially could be um use. This is just a demo of it and then it would give you that 25% chance uh This patient had of achieving or sustaining uh severe complication. Any, any guidelines. The answer is for, especially for appendiceal. But isn't we have some consensus guidelines? I'm part of this group. I'm also uh we are also working on the appendiceal cancer guidelines and uh this is uh will be updated for next year. And I'm, I'm very grateful for the opportunity to cole um uh that, that section uh at U CS F. Our program is started in 2021. We've done almost 80 cases um so far and our severe complication rate is 20% which is lower so far, zero death. Um And, and this is a testament of the multidisciplinary collaboration and, and um and care that offer here at U CS F as I started with the patient, I would like to conclude it with the patient. This is um and that patient died because of bowel destruction. This patient also because of access was gonna die because of bowel destruction. And uh you know, this is a 53 year old from a, a very disadvantaged background, came in with a massive pseudomyxoma to see her ct gone. All of this is tumor this is I she gave permission to publish all of these pictures and show it. Um This is the abdomen looked like this when you go in. This is not normal anatomy and it's very difficult to do these cases. And this is more of that. And this is if you heard about a mental king, this is what it looks like. And uh we've removed about 30 specimen. These are some of them 15 L of mucinous asciis. We finish by 1 a.m. in the morning, but the abdomen looks like this after cleaning everything up. This is her post op ct scan and you could compare the two of them and this is her picture. Uh you know, uh about two months in two month follow up. So in somebody appendiceal neoplasm or surgical diseases, systemic chemotherapy does not work in appendiceal neoplasm, cyto reductive surgery and hype does not change the biology but works well on like patients. Cyto surgeon hype is a morbid operation but it can improve survival with a proper patient selection. Seattle's hy does not replace chemo. It works in conjunction with chemo in colorectal uh cancer and appendiceal adenocarcinoma. Uh and all of this can need to happen in a multidisciplinary uh fashion. Um Medical oncology is front and center as well as pathology as well as uh surgery and, and thank you so much for the opportunity uh to uh connect with you today. Thanks so much. That was such a great talk and such an interesting area. Certainly that I don't think about very much. And we've been interested in hyperthermia for chest wall disease. We were interested for a long time, but it was hard to get it actually to move forward because people didn't have access to it. And I think insurance coverage and in some ways what you showed, you know, showing that it's better than not doing it. Um And so for these kinds of cancers, it's a great opportunity. A couple of questions. I actually, I have a bunch of questions, but we won't have time for much. So, um the first question is when there are complications that people die from, is that from perforation or infection? Is that what happens? Yeah, it, it can happen from any of those. So as you could tell that the, you know, uh you know, sustaining toomy or, you know, judgment sometimes, you know, removing something that is, would not, would not need to be removed or being inexperienced and trying to do more than what it needed. For example, if I see an implant on the colon, I'm just gonna shave that off and, and, and use different techniques as opposed to how colorectal surgeons deal with things where they need to remove any, everything in blocks. So uh when the, the bile duct is involved, then, you know, I I'm a HPV surgeon as well. I'm very careful with that. So it's very important to um you know, you know, surgical experience, surgeon experience is really important in this setting. Uh And then the institution also comes in because some of these patients go to the IC, you need an institution that have, you know, has good IC U care and you need somebody, you need an institution where you have great medical oncologists that are collaborative with the surgeon. So it it all sort of kind of like, you know, it takes a village to take care of these patients. But I think, you know, the surgical expertise is front and center. Yeah, it's fascinating. Unfortunately, we're gonna have to move on. Although I have lots more questions and I'm really interested in whether or not one could do chemo with hyperthermia, just high tech without all the surgery for some of our breast cancer patients where that's a huge area, but they obviously have other disease. So lots of interesting things and look forward to hearing more from you in the future. Um But because of time, I think we're gonna move on and uh start with the next section. Uh Katie Kelly's discussion on updates in advanced biliary tract cancers where we've really seen uh big improvements and we're really excited to have Katie here to talk about her work as well as what's going on in the field. Thanks so much. Hope I'm gonna share my slides here and I'll try to stay on time. All right. Can you see this yes, looks great. Just converting to presentation mode, which always takes a moment. There we go. Let's see. Is that, are you seeing the right screen right now? Now we are perfect. Great. Um So a lot has changed in biliary tract cancers over the past few years and I'm gonna try to summarize the key uh advances um in first line, as well as later line advanced disease. And right now, these advances are really focused on advanced disease data. But as I'll conclude at the end, we're hoping some of them will translate into earlier stage as well. But just for background, what I'm presenting today is predominantly in advanced or metastatic disease. Um Here are my disclosures largely related to clinical trials and clinical research. So here's an outline, what of what I'll review first a little bit of background, then discuss systemic therapy in the first line with chemo IO thera. Now um in play as well as uh subsequent lines of therapy with a specific role for targeted therapy and subsets. So beginning with background, um biliary tract cancers are a cancer of a lot of acronyms. Um These are uncommon tumors with rising incidence worldwide about 2.7 per 100,000 globally. Um But certain areas such as Japan have much higher incidences. And overall, though we see rising rates of particularly of introed cholangiocarcinoma, perhaps related to the epidemic of fatty liver and underlying liver disease, we see rising rates of intra cholangiocarcinoma globally. So, seeing more and more of these patients, unfortunately. Um so as I mentioned the acronyms that the anatomy of biliary tract cancer is highly heterogeneous. Um And just for purposes of this talk, as well as when you think about biliary tract cancers, we're talking about gallbladder, cancers or G BC tumors that arise in the gallbladder, more common in South America and in certain parts of Asia than in the US. And then Cholangio uh or CC A which are tumors that arise from the bile ducts, either intrahepatic um within the liver IC C or um down uh distal to the bifurcation, extrahepatic. And that includes Peri Hyler, also known as the old Eponym cla skin tumor and then distal to the cy cy cystic duct takeoff is called distal CCL cars down to the um head of the pancreas. So, anatomically, this is a very complex and challenging part of the body, obviously for surgeons. But in addition to the heterogeneous anatomy, um biliary tract cancers also have extremely heterogeneous etiology and biology. Um etiology can include any underlying liver disease caused by viral hepatitis. Um certain types of flu infection, particularly in Thailand and other parts of Asia. Also, the, as I mentioned, the scourge on the horizon is fatty liver um causing an increase in in cio carcinoma. A subset not trivial um or hereditary, probably upwards of 5 to 10%. Um and then autoimmunity like primary closing cholangitis, but um those, those risk factors count for a lot, but still many are or most are even i idiopathic and these heterogeneous risk factors and heterogeneous anatomy lead to highly heterogeneous biology which I'll talk about particularly in the second line setting. So, talking about systemic therapy options. Um historically, our option since 2010 has been the combination of gem cyto plus CISplatin and that was it. And that was based on a trial that compared gemcitabine plus CISplatin to gemcitabine alone. There was never a randomized trial of gem cytopan. We just extrapolated from pancreas cancer and adding the platinum um did improve survival as well as response rates and it was very consistently beneficial across subgroups. So the combination of gem sis has been our historical standard of care, but again, not an aspirational standard of care with media and overall survival. Less than 12 months in the advanced setting and objective response rate only about 25 26% here. So, again, better than gem but really difficult for most patients still. Um a recent phase three trial in the Cooper groups. Um based on really provocative phase two data was the triplet combination of gems I plus nab paclitaxel. Unfortunately, this turned out to be a negative trial just presented at GIO last year showing no significant improvement in survival, a little bit higher response rate, but um overall not a significant benefit and much higher rates of grade three adverse events. So this regimen isn't moving forward in the advanced setting at this time. So just to summarize um median overall survivor around 12 months and response rate around 25% from Genesis alone. Um And the median duration of these benefits um of, of response is pretty limited only around six months. So, uh what about immunotherapy? Um We obviously are having a renaissance in the immunotherapy realm across solid tumor types. Um Unfortunately, biliary tract cancers are not highly responsive to immune checkpoint inhibition. The best study of this was keynote 158, which showed out of 100 patients with mismatch repair proficient. So these were not deficient patients um treated with pembrolizumab. The central review objective response rate was only 5.8%. So a tiny minority got benefit and the median progression free survival was 2.0 months. This was pretty similar to the response rates for other immune checkpoint inhibitors, but they were well tolerated. We didn't see any more rates of immune hepatitis than other tumor types. So this begs the question, you know, th though these this efficacy leaves a lot to be desired, the safety was good. Um Could we combine chemotherapy with immunotherapy immune checkpoint inhibitors and specific to improve upon our chances of immune response? Um This, what's the rationale for that? While combining immune checkpoint inhibitors with chemotherapy, we know can improve outcomes in a variety of other tumor types. There's a lot of different mechanisms why um by which this could occur including pro inflammatory cytokines with the combination of cytotoxic. Um certain chemotherapies including CISplatin can trigger immune cell infiltration. Um such as F aosis um process, um you can inhibit the regulatory T cells and increased tumor and immunogenicity particularly to cytopan. So again, there's a good rationale for trying this um leading to a couple of phase three trials that have now changed our standard of care. So the first of these was the Topaz trial which took standard um gem cis and placebo and compared it to Derval plus GSIS for six months, which is the the typical GSIS regimen. And then after that six months, the Derval was continued alone as maintenance and these were patients with first line locally advanced or metastatic biliary tract cancers. Um And the primary endpoint of overall survival showed a significant improvement here in the purple line for Genesis, the median of 12.8 months for the combination with your value A versus sorry GSIS per your value A versus GSIS alone. Um And again, while the curves aren't separating as much as we would like to see in the median isn't, is improved as much as we'd like to see. We can see the tail separating with longer follow up and the duration of response is much longer when the devali A was on board. Um So this is hinting at the possibility of achieving an immune response and durability in a subset of these patients and was statistically significant. Um Fortunately, the toxicity was actually better in the triplet arm with Valium or, you know, quite similar without any signals for significant safety and trended towards actually a little better across these parameters and steroid rate was quite low. Um And if we look at this is a busy slide, but the point of this is in these forest plots is that pretty much every relevant subgroup in biliary tract cancer trended towards benefit with the addition of Derval A for overall survival as well as progression free survival. And this includes some of the key um points of both uh region as well as etiology, hepatitis or no hepatitis Asian or non Asian. So we saw benefit across all those groups. So then uh the second such study that was done um I had the of being part of which was keynote 966, basically almost identical study looking at gem cyst um backbone with, with or without pembrolizumab. And so here's the schema. One key difference though is I and for those of you who do see a lot of cio biliary tract cancer patients, you know that the gem cyst regimen after six months, it's really invest at the investigator discretion whether to continue the gemcitabine or not. And uh most of us based it on patient factors like how, what's their tumor burden? How much, how's the tolerability of the regimen? So the Topaz trial that I showed you earlier with Deval A mandated that everyone stopped Gemcitabine at six months so that the data would be clean and either Deval or placebo is continued after six months. That doesn't really reflect practice patterns in a lot of parts of the world where we like to continue the gym Cytopan longer. So the keynote trial allowed continuation of gem cy amine after that key six months, there's no maximum. So the difference between these two trials is after six months, keynote allowed it to be pem bro plus gem versus um gem alone. So, slightly different maintenance strategy um and baseline characteristics were balanced. Um Here's the survival data where we again see a separation of the curves favoring the green curve which is the addition of pembroke to GSIS. Um and a a separation with prolonged time and median was significantly improved 12.7 months for the Pember edition versus 10.9 for uh placebo plus GSIS with a significant hazard ratio, 0.83. We don't see quite as much um delta over time perhaps due to the fact that Gemcitabine was continued, it was an active uh treatment arm for the con um the um control arm. So we continued the Gem cytopan which contributes to a little bit better outcomes in that arm than the Topaz trial. Um And overall, while the response rates weren't significantly different, we didn't convert more responders um to more patients to responses. We can see the duration of responses again much longer for the pembroke arm in the green curves here. Um both at 6, 12 and 24 months. So again, suggesting a subset of patients are being converted to these long immune responders by adding the checkpoint inhibitor. Again, toxicity was actually quite similar between the two arms. So pembroke did not add significant toxicity. The rate of steroid use for toxicity was less than 10% in both arms and only 4% more in the Pembroke arm than placebo. So this, this regimen was FDA approved on Halloween in 2023 and is now another treatment option. So, just to summarize where we stand on first line, based on these two trials, the addition of either do Valium or pembrolizumab to standard GSIS chemo improved survival and first line therapy for advanced biliary tract cancers and really pretty symmetrically across our key subgroups. Um Overall, I'll be the first to say that these improvements are modest, not, not as strong as we want them to be. But what really matters in the clinic is that we do see a subset of patients having much more prolonged responses and survival um consistent with an immune mechanism. And this works whether we continue gem after six months or whether we decide to go to maintenance. And I again, make the decision based on how much tumor burden does the patient have? How's their tolerability? Um And um the safety is quite acceptable without significant signal of no higher rates of immune related hepatotoxic say for example, than we expect for a checkpoint inhibitors monotherapy and both of these regimens are FDA approved. And I think they are really interchangeable. One can make a clinical decision for either DBA or Pemba based on your pharmacy preference or, or insurance company preference. So turning to a very dynamic next part of the talk, um sub subsequent treatment options um and the role of targeted therapy and subsets. This is where we've seen a lot of movement in FDA approvals in biliary tract cancer as well. Um So just to remind people, um there really is no FDA approved or has been no historical standard second line therapy after GSIS, the ABC 06 trial in 2019 compared Fox to active supportive care, which means basically nothing and full Fox barely outperformed nothing um with a median survival of 6.2 versus 5.3 months and a PFS of four months and a response rate of 5%. So this is a very low bar and a very dismal place to be as a patient obviously. Um And so we use historically, have used Fox full theory gem nab Paclitaxel based on phase two data, none of these have FDA approvals and they're all really disappointing um but better than nothing, you know, a little bit better than nothing, I guess. Um And so this is where that it has become so much more positive as a oncology provider to have new options based on molecular targets. I mentioned at the beginning that biliary tract cancers are molecularly heterogeneous. This picture shows that heterogeneity with therapeutic actionable targets here. And um these targets are somewhat anatomically um predisposed. Um For example, in intra paic cholangiocarcinoma, we see a much higher rate of FJFR two fusion in about 10% or it's almost 0% in gallbladder or extra Paic. Likewise, I DH one or two mutations in about 15%. Um And then uh conversely, extra paddock has a bit higher rate of her two or B two amplification or over expression. Um And we do see a little bit higher rates of Kr in the distal or extra Paic and gallbladder. Um M si hired or MS Metro para deficient are pretty rare. 1 to 3% across sites. B raf mutations are rare about 1 to 5% across all these sites. Um And then they're a tiny proportion of patients will have something else tractable like tracker rat fusion. So worth looking for but very rare. Um So starting with one of the most prevalent and one of the most exciting are FGFR two fusions. These are present in about 10% of inic cholangiocarcinoma as I mentioned, but rare elsewhere, this is where you have the kinase domain, the functional domain of FGFR two fused to a different partner that allows it to escape its no normal type controls and cause all of its oncogenic activity without the normal checks and balances with a constituent constituently active FGFR two kinase. There are a variety of ways of inhibiting active FGFR two F KASE. Fortunately, there are a TP competitive inhibitors, non A TP competitive PFGFR inhibitors and now a very selective FJFR two specific covalent inhibitor Roy 4008. Um So in the, looking at the A TP competitive inhibitors which hit the market first, um several phase two trials looked at um drugs called Infra Gratin and Pemigatinib, which are inhibitors predominantly of FGFR 12 and three less so of four. And they both showed that most patients have some shrinkage. Um at least a range of 20 to 35% have actual confirmed responses and these responses are pretty durable with a PFS in the 6 to 7 months um range. Um and not that these, this is a small population of a rare tumor type. Um These phase two data led to FDA approvals for Infra Gratin and pa Megat based on the duration of response and the high response rate. Again, bearing in mind what the comparator of full fox does, which is a 5% response rate in a four month PFS. Now F two R two inhibitors do require do have a bit of a learning curve for us as, as treating providers, they cause hyperphosphatemia stomatitis, hand foot syndrome or Palma planar Orris aesthesia and eye toxicity among other things. So they do take a lot of supportive care, but generally people feel better than on chemo now. Um kind of following in the model of what we see in lung cancer. Um The challenge is acquired resistance and what's interesting about these FJR two fusions is that um resistance happens when the kinase domain which is normally intact, even though it's fused to something else, the kinase domain will get a resistance mutation that allows it to escape the tart the small molecule inhibitor by changing the um the confirmation of the molecular break or the di hydrophobic folding. Um And this leads to to acquired resistance over time. Um but just like lung cancer, there are now next generation agents such as the covalent inhibitors, like really like 408 F food bat and actually a couple others in clinical trials that show activity against specific resistance mutations. Um And so here's one of them uh Foodie battened. Now FDA approved has a response rate of about 40% and quite durable responses as well. You can see most patients have some sort of regression and it actually works against some of the resistance mutations as well. It's now FDA approved as of um 2023. Um And yeah, Pff again, definitely better than full Fox in the second line. Um Both FDF proved in 2022 sorry. And then another um highly selective FDFR two inhibitor alone doesn't inhibit FDFR one or three is relay 4008, which um also is, is in getting ready for hopefully FDA submission someday soon. Um It shows an even higher response rate um over 60% in a small phase two cohort. So we're really excited to have and it inhibits some of the resistance mutations too. Um So here's one example just to show a real world case that was a, a life altering ex ex experience really for me as a physician or as the kind of patient we really want to help the most. This was a, a young woman who happened to have a one year old and a four year old came in with this scan. She had really terrible shortness of breath, uh obviously with lung meds, ton of ascites and tumor burden, their liver bone, um met a lot of different places and she had an FGFR two fusion. She progressed right away on first line therapy. And then we started her on the relay 4008 clinical trial that I showed on the um prior slide. And after just four cycles, all that fluid went away, her lung meds nearly disappeared and her hypercalcemia normalized, she felt better. She went back to work, she took care of her little babies for another um two years of life. Um Unfortunately, she progressed after about a year and got these uh multiple kinase domain resistance mutations. So it worked magically for about a year and then she got the resistance mutation and passed away. Um But this just shows we're on the right track and there's potential with this target. Um A couple others real quickly. I DH one mutations are present in about 13 to 15% of intrahepatic cholangiocarcinoma. Um They cause a block in different uh onco metabolite called two HG caused by the mutant I DH one protein causes a block of differentiation and accumulation of really poorly differentiated cells. Um A drug called IVAY is now FDA approved to um block selectively mutant I DH one. And um while it has a pretty low response rate, only around um 2% it actually does prolong progression free survival, which is the primary endpoint of this um phase three trial called clarity shown here. The trial allowed crossover. So the placebo arm had um most patients ended up taking the drug when um mathematical modeling was performed to anticipate how patients would have done if they hadn't crossed over. This light blue line shows that the PFS improvement probably would have been more dramatic without crossover as we'd expect. So, based on um this phase retrial of with PFS as a primary endpoint, um I Vidin um was approved by the FDA in 2021 as an option for I DH ONE mutant cholangiocarcinoma. So a different subgroup than the FGFR group. Um B raft mutations are also present across an atomic sites in the biliary tract about 3 to 5% and inhibition with the um combination of Debra nib and trametinib. In the rare trial showed again pretty dramatic benefit in these patients and it lasts for a while about um media duration of uh response. Nine months, about half of patients get a great response. And this regimen does have a Agnos, tumor agnostic, accelerated approval from the FDA. So you can give this to your patients as well and it does work for a while. Um I mentioned um mismatch repair that most biliary tract cancers are proficient mismatch repair or M si low. But um M MS SM mismatch repair is stable. Um A subset around 1 to 3% do have M SI high and those patients do really well and some have complete responses in like in the gray bar here. Um In basket trials of mismatch prepared um deficient, treat solid tumors treated with checkpoint inhibitors. So if you have a patient with um M si high cholangio or biliary tract cancers, you can use PD one inhibitors as monotherapy with a very high response rate and quite durable response. And a subset of complete responses. I have several patients that are cured. It's been six years. Um So summary of targeted therapies. This is like my second or third to last. I have a couple more slides, but I hope you can cut me off if we're out of time. Um So we have I DH one inhibitors for I DH one mutant FGFR inhibitors for FTFR two fusion and then a selection of tumor diagnostic approvals for these other rare subsets. I want to highlight what's on the horizon that we have a fair number. 5 to 10% of biliary tract cancers do have overexpression or amplification of her too. And so that's sort of the next frontier I think on the horizon, we do know that um her two mono targeted monoclonal antibodies. Um The Pertus Trust two combination of my pathway had a response rate in 23%. Um TV XD in the herb trial showed a response rate of 36% in the three plus patients in the her two high by IHC. Um And then patients with her B two mutations um showed a small response in um the summit trial with the Neurotin. So again, there are, if you have patients with these um mutations that usually can be approved off label based on these phase two trials. And um what's on the horizon? No pun intended is um there is a phase three trial anticipated of the drug zany zany daum A from Jazz pharmaceuticals based on data presented at as 0 2023 showing a response rate in the second line of 41% which was quite durable in the um either um IHC three plus or amplified IH two. Um I see two and then another trial called um of two cat nib plus trust tab also showed really encouraging results um at oo 2023 as well um with a, a pretty high response rate and a long duration of response. So last slide here, um our standard first line therapy options have now included immune checkpoint inhibitor, either gems cys plus the value or gems C plus pembroke. Um in patients who are have don't have contraindications to immune checkpoint inhibitor based on survival improvement in both keynote +966 and Topaz one trials. Um in the second and later line, please make sure to do molecular profiling of all your patients. Um and include her two IHC because a lot of the clinical trials are based on IHC not amplification at this point. Um Folfox is our standard chemo but has modest activity at best and we do have FDA approved drugs now for FDFR two, rearranged IH one BRM si high or B two and then others with smaller frequencies. Um And then again, stay tuned for more on her two in biliary tract cancers down the road. And we do hope in the long run that these active options, particularly the ones with the greatest response rate like FDFR two and maybe the her two therapies will be warranted to test in earlier stages of disease. So with that, I will conclude and say, thank you so much. Thanks so much Katie. That is just incredible progress. It's really impressive and um it's great to see your research team too. Um That's great. And uh I'm uh I'm so impressed with the work that's gone on and also kind of balancing the toxicities, et cetera. The story about the patient with the FGFR Two me amplify is very cool because we're searching in breast cancer for a way to target FGFR and have just been fraught with toxicities that have really limited uh any exploration. So that's a really interesting direction. I'm excited to hear that it might get approved based on that data. So really good. And I guess the main thing is that now we would, you know, for patients who have this disease, it does seem as though uh considering clinical trials with some of these new agents is really worthwhile. Uh And uh talking to the specialist team at U CS F might be very helpful in determining next steps. Yeah, we we definitely are more than happy to field a phone call or an email or see a patient when there are questions and we do have access to some drugs that are not yet available such as the um some of the newer FTFR two inhibitors for resistance mutations, I should say pan FGFR for resistance mutations, we have one of the new drugs that's designed specifically for those kinase domain um mutations. So if you have a patient progress on FGFR inhibitor, there might be a second line option with the next generation um kind of the main inhibitor. Um And likewise, we're hoping to have a her two trial opening up um in the near future. Um And hopefully down the road, maybe some of the Krs trials and Basket and the Kendra Karma Foundation is I would, I'll give, I'd like to promote, looking at their website and directing your patients or yourself to their website because they have a lot of information there. Um including some patient directed materials that you can um have them send to your patient, including things like the FDFR kit for C creams and nail care for some of the unusual toxicities. Yeah, I think that that's great. And I love the, again, the foundation and the uh Billy project, et cetera. You've done great work in this. It's great to hear about it. Um And to the audience, thank you for participating. Uh There is ac Meq uh link that I showed earlier. But if you go into the chat, if you're um asking for CME, uh there's a survey which of course we appreciate anyway. And then the link will be sent doubt and feel free to share this link broadly because uh we can actually um share it around including on uh now X Twitter and uh and share the amazing discussions we've had here in advances more broadly. So, thank you very much Katie and uh thanks to the uh organizers, our uh joy and of course, a Laura whose idea this web series, what is and uh we look forward to seeing you at our next uh cancer center lives uh radiation oncology, updates in April. Thanks so much.
