Overview of Biliary Tract Cancer & Importance of Targeted Therapies

Current Treatment Landscape of Biliary Tract Cancer Hello and welcome back to the Oncology Brothers podcast. I'm Rohed Gossain and as always, I'm here with my brother and Co host Rahul Gossain. We both are practicing general community medical oncologist and just like you, we are trying to stay up to date with all that's happening in the world of cancer. More recently we've seen a lot happening in her two space, particularly this is not just target in breast cancer or gastric cancer, but we have seen bucket approvals and more and more drugs being approved in this particular space. With that in mind, we have three-part CME series where we are going to touch on the current treatment landscape of biliary tract cancer and then take a deeper dive in her two biliary tract cancer. To get us started with our first episodes, we are delighted to have Doctor Ghasan Abu Alfa, a medical oncologist focusing on Hepato Biliary space from Memorial Sloan Kettering. Hassan, thanks so much for joining us. Speaker 2 Thanks so much for having me. Thanks Rohit. Thanks Rahul. Great seeing you both. Speaker 3 Hassan, welcome. Over the next few minutes let's touch on the current treatment landscape of biliary tract cancer and then let's spend some time in appreciating the her two driven disease. So prior to the approval of immunotherapy, we had been using chemotherapy and the overall survival there was close to 10 to 11 months. Then we got the approval of dirvalumab based off Topaz 1 and pembrolizumab based off KEYNOTE 966 and the median overall survival improved to roughly 13 months. So this is still not good enough. But currently that is our standard of care, chemotherapy and immunotherapy upfront. At the time of progression, our options were limited to five FU base treatment here. But more recently, if you started to look for IDH 1 mutation, FGFR alteration and her two driven disease Ghassan, can you start us off with the treatment landscape for biliary tract cancer? And then let's take a deeper dive in the second line treatment space as well. How common are these IDH 1, FGFR and her two disease mutations? Speaker 2 Yeah. Thanks, Rahul. If anything, biliary cancers really are like the calf, like the calf, you know, unknown disease that really has been like really miss blood for long time ago. And many of us remember the days when we used to call them the unknown primaries because many of them of their own primaries turn that be collagen carcinova. And why is that? There's certain particularity regard to the cancer cells that really is hard to define. And this is where I ask all of our colleagues who are listening to us, please, please make sure that your pathologist you have a good interaction and engagement because your pathologist is going to be key in regard to pinning down that Cologne carcinoma. So you don't really get cough on different routes or really on the wrong path. With this said, the advent of the checkpoint editors came into play and of course million tumors were really more understood as being the cousin of pancreatic rather cold tumors will not necessarily respond. But that kind of enhancement of the activity of the checkpointors by throwing in with the chemotherapy, making the tumor semi hot absolutely didn't work. And that's why the Topaz one in the keynote followed with a positive outcome. Those two tests became very important because they really established that yes, checkpointors are key to carry on with berated tumors. Now here things start evolving in different directions. 1 of the questions that we also got to first line is OK, the study tells us that maybe chemotherapy plus immunotherapy, but then I stopped chemotherapy at some point like as in Topaz one. Why do we not stop chemotherapy after 6 months? And then the keynote study which was done beautifully well by Katie Kelly and colleagues. They did not stop the chemotherapy or the Gym city in specific after the six months. Why is that? I personally stand with the keynote on that part. And frankly, I apply even the same thing with the Topaz where yes, you can Max out on the platinum, but you have to keep the gym CV in because the immunotherapy by itself in that disease, as we just said to begin with, it's a relatively cold tumor, will not work. It needs to be triggered by the chemotherapy per SE. So great. We do this, people do very well. And interestingly, we don't want to promise this ever. And please, I tell, I tell my colleagues, don't ever promise this to a patient because you don't want to put a very high bar for the patient. But have we seen complete response patient totally clear for the disease? Yes, we have been. We have seen that. And it's something that we're very proud that we're able to do in that disease. Nonetheless, sadly, sometimes, yes, things will evolve not in the right direction. Here is a kind of unknown field. FOLFOX study There have been some studies in regard to chemotherapeutics. They are usually used based on some default or based on some experience. One of them is called the FOLFOX based on the ABC 06 study that even though it argued like maybe pyro platinum exposure will still benefit further on. The other one is the nifty study Liposominarity can plus 5 three years old. This study never really made the drug approved for the by the FDA in the US for the liposomatidine can for biliary cancer. But nonetheless, you can try if you have a good sponsor for your patients. And thirdly, of course, based by default, we did the study retrospectively. Full theory might be an option too. Yes, we can use all of that and probably most of the patients will end up doing one or the other of those. But interestingly, exactly as Rahul just mentioned, there are some potential genetic alterations that can occur in biliary cancers. Genetic Mutations in Biliary Cancer It's very important to all genetic testing on tumors like biliary cancers. Actually, I always jokingly say when do patients do the genetic testing on their tumors? I would say while walking to the clinic before even they see any doctor because this is going to be very critical for the patients. Yes, the numbers are not really in favor, but nonetheless, I didn't think it's better than 0 is better than 0. As such, FGFR 2 fusion can definitely be of implication got to therapy. IDH 1 mutation can be a good implication for therapy. And of course, now with the add on of the her two as we just spoke, I'll pause here for a second. Just go to the layout the layout, but happy to vet a little bit more in any of those options. Speaker 3 Hassan, can you actually take a minute or two and tell how frequently are you running into FG, FR2, IDH, one, HER two, how prevalent is this? Speaker 2 So contrary to what we thought and we're a little bit excited first, but I would say probably guesswork, the FGFR 2 fusion will probably be in about like 5 to 7% of the patient. This real world data, FGR FG4, other mutation, other alterations, which is sometimes based on some data like pemigattinib, you might apply the therapy, you might probably say up to 10 to 12% of patients and that's it. The drugs are approved based on conditional approval. Hopefully it will turn into a full approval based on limited data of the phase two, but this is good phase two data. And then we jump on to the IDH 1. IDH1 IDH one, but relatively more common, about 10% give and take. And funny enough the MG42 came to us. We knew about it, we're comfortable, we pushed it, but the IDH one was rather not even of the sponsors radar screen. They were thinking more about IDH one for GBM and we actually are the one who really brought and tell them, you know, we really strongly believe that we should use this in college question and proudly we did it and very proud of the effort that we started at small catering. Now we have I was I was Adnan and it definitely shows an improvement survival actually based on certain statistical tools, you can say over a double medium survival and basically can do very well with it. Interestingly, relatively speaking, not to compare but ADH one I was Adnan is very well tolerated compared to the NTFG for 2:00 PM gather up with the battery which can have a little bit of challenges, but definitely can be doable as well. And this of course bring us to the third one as we just wrote in which is the her two now her too. Biliary tumors You know, I'm sure many of us, you argue, all of us, all our colleagues listening to the community will know it because of definitely more experienced, more talent than any of humbly us in regard to her too. In regard to breast cancer, of course, the add on gastric cancer and now woe out of nothing biliary tumors. These are relatively uncommon, but nonetheless kind of still range in the digit number, but they are very important because yes, data is coming, but very frequently where it might be valuable. Interestingly, and this we'll talk about yet, but we'll talk billiard humors, but we also use some snow or father names per SE. Bilery is ending the bile ducts. It's a big family, but in that family there are different kind of like groups in this family. If it is a bile duct inside the liver, we're not by the way, very smart. We're just like, you know, intra inside, intra hepatic inside the liver, bile duct below tuber. That's how it is called angio carcinoma. If it is outside the liver, extra hepatic, as simple as that. And then if it's in gold bladder, of course, gold bladder of the carcinoma. So now proudly, we always really kind of like saw those as being different, but we didn't know how to split it. I really, I'm very happy when I chaired the task force at the NCI for the happy Liberty humors, I helped out finally split them from each other. And after that Doctor Javali carried on with the with the effort. And we do see them separately. And why I bring this up here because interestingly, the her two mainly apply to gallbladder cancer, but on the other hand, can we see it in extra hepatic and the hepatic tumors? Of course, we can mainly interpatic humor. And that's a very important point. A certain kind of like, you know, scenario in the clinic that happened to any of us. You guys have a patient come to you and it looks like, you know what it looks like really, right. And the merge between the gallbladder and the, you know, the hilum of the liver. Not sure where it's coming from. And it's actually her 2 positive. I'm going to treat it like what? No, no, no, I'm going to treat it like because it's called blood cancer. No, but let's psychology course, you know, but don't worry much about the anatomy. Remember, we just as I said that we just call it one thing or the other. The biology is really what's driving the picture. If SER 2 treated, if you have a low blood that has IDH one treated as an IDH 1. So that's what's important. With this said, how do you test for the drug testing that we just bought? How to test for SER2 Of course the golden rule next session sequencing and as we said, we'll do with it even before the patient come to you. But on the other hand for certain and specifically for the her two, yes. Can you do the her two be the IHC which all of us know about? Yes, you can especially for the three plus and two plus we'll probably say be more comfortable with. But of course always nice to have the necessary sequencing testing all through the whole panel of whatever alteration it is because there could be other alterations. We didn't talk about them, but they could be there. Rare, but can happen, among which I'll mention at least the BRA FV600E, which is like barely 1%, but you know what with great therapies. So it's very important to really look across the board for all the gentle issues we can. Speaker 1 Thank you, Savage Kasan for that comprehensive overview. And I'll go back to your initial comment where you said working closely with pathologist. I feel like Hepato biliary cancers are the rather the poster child for a multidisciplinary approach and that does include radiation oncologist, IR surgeons and of course pathologist as well. And I'll, as you alluded to, we are tied in with a poor survival. So we cannot stress the importance of NGS testing. Kasan, with regards to IDH one or FGFR, we are relying on NGS as you stated for her two, we have the choice of IHC or NGS testing. Interpreting NGS reports And we should not forget how some of these NGS reports are interpreted where they're mentioning ERBB 2, it is still her two disease. How do you define particularly this? Her 2 positive status where these drugs are approved especially for zanidatamab and TDXT may lead her to IHC 3 plus setting and all. Speaker 2 No, thanks so much, Rohit. So two points. Please remember that nature sequencing is critical for any patient. And in other words, what you just implied in regard to there to testing by AFC, we're doing it as a default until the nature sequencing testing is out because we know very well that this can happen a bit faster. And that's why so we don't delay therapy. Why don't delay therapy by the way, it's very important to mind patients as well. It's not like, Oh my God, things are going to happen overnight. There's not the patient you're going to treat anyway. But if anything, sometimes patient anxiety want to be on a plan. People love to have a plan and that's really what all what we're trying to do. But please reassure the patient, if things are going to take a week, two weeks, it's not the end of the world. It's probably more likely than they would benefit from therapy. With this said, in regard to now the staining, we've been kind of defaulting more toward the 2 + 3 plus, same as the many studies have done and reported. We're able to always depend on the NGS, but yes we do depend on the HC for the her two with 2 + 3 plus. Speaker 3 And the other thing is IT ends up being in house testing. So even though now the NGS is coming back quicker and quicker, I see if it's in house is a lot faster. Kassam just to build a foundation for next two episodes where we're going to take a deeper dive in our treatment options for her two and some of the side effects that we have to worry about when it comes to her two disease. Treatment Options for Herceptin-Receptor-Independent Cancers Is this acting any different? Do we have to worry about more aggressive disease? Do we have to worry about how these patients can have a different metastatic spread? And then I know we touched on the front line treatment in breast cancer, gastric cancer from the gecko. We're talking about anti her two therapy. Any patient outside clinical trial where you're using this AFANT? Speaker 2 Yeah, another good point. So yes, we are. And if anything, as we know, the approval are evolving because of the studies, etc. But at the same time, we don't have them all yet. And if anything, yes, what I'm seeing her too, especially if it is the 2 + 3 plus as we just mentioned, can I be tempted to make sure that I treat? Of course I am. And I have to give credit, a lot of the insurance companies have been really understanding that component and they definitely will support us on that. So by all means for the Zenith lab or for the fam, trust this lab. We're definitely are dependent on there too until we get the results. But are we doing it out of the trial if we have to? Yes, even though we do our best if the patient's eligible for control to make sure that you want to come trial. So can help hopefully better information and better understanding of the disease. Speaker 1 Fortunately we have these options available to us. But again with regards to sequencing, it is going to be very difficult especially when you have trastuzumab based approach with to catnip or pertuzumab and now TDXD as well as zanidatumab Gasan. With regards to testing, are you testing this upfront or on progression? Testing Thanks so much, Rohit. So most of the patients and if anything or patients who come to us from the start, we do it right at the start. Now understandably, sadly, sometimes patients might not have been tested before and we have to do it up on the portion because they come for second opinion for second blind therapy. So we do it at that point in time. But I please urge all our colleagues, please don't try to wait. I don't need it now. I have gemsis, dervalumab, I'm OK, I'll do it when I need it. Guess what, time is much longer when you need it. So just do it in the beginning so you have it, keep it on the shelf, do it or use it whenever you have to rather than wait. Now you bring another important point though is would it matter if I you have to test it at both times being at the start as well as a progression. Does it matter if you test it at both times? That's a fascinating component in regard to the stressors of the therapy onto the tumors. Interestingly, the gender cult rations of the tumors and we tested that at slow catering and about 76% will never change. On the other hand though, in regard to the FG42 and the IDH, interestingly the stressor of the therapy, specifically anti FG42 or anti IDH can actually cause a stressor to the tumors and IEA tumor. Can it change from being a certain genetic specific alteration for the FGFR 2 to another? Yes, it can. Actually there's a beautiful paper that was reported beforehand that showed how those tumors might be stressed out enough that the genetic can occur. This was done again by Lipica Goyal and colleague at MGH. One she was at MGH and another one in regard to H1H2, we probably did it from Strong Kettering and we have seen that the tumor can change from the IDH one to the IDH 2. So yes, at the moment we're doing it at baseline, at start of therapy, but by all means, futuristically we might see ourselves testing more than one occasion. Speaker 3 We would have to come from the same bandwagon. These are not resistant mutations. Yes, you can see these stress limitations evolve and the disease has evolved some, but testing upfront, BFRIDH, her two and FGFRI think it's very important. Speaker 1 Right, again, such a heterogeneous humor and glad to have multiple therapies available, especially when we are tying in with a poor overall survival. Son, thank you so much for taking the time to go over the current treatment landscape and rapidly evolving space for her two positive biliary tract cancer. Make sure to check out our next podcast in the series where we take a deeper dive into the data for our available options in the Her two space and also discuss how to manage some of the common side effects that we see with these therapies. Thanks for joining us. We are the oncology brothers.