Treatment Options for HER2 Positive Biliary Tract Cancers

Introduction Hello and welcome back to another episode of Oncology Brothers Podcast. I'm Rohed Ghosain that alongside with my brother and Co host Rahul Ghosain. We are both practicing community medical oncologist and our mission is to keep you, our community colleagues informed and up to date with latest in cancer, especially how fast this field continues to change. Today, we are excited to continue our discussion on her 2 positive breast biliary tract cancer. For this second episode, we are thrilled to have Doctor Shobham Puns from MD Anderson join us again. Shobham, thanks so much for joining us. Speaker 2 Thank you. It's a it's an honor and a pleasure. Speaker 3 Shobham welcome Rohit. I know you were slipping up with breast cancer because historically when it comes to her to that is what we've seen. But it's amazing how fast this fields changed. In our first episode, we set the stage by discussing the overall treatment landscape for biliary tract cancer, the role of chemo immunotherapy and then the importance of NGS and biomarker testing. Today, Shubham, we want to focus specifically on her 2 positive disease, and I hope we get to touch on who needs testing. Once we have testing what to make out of it from IHC 3 plus to fish positive versus ERBB 2 mutation on NGS and then of course the treatment options in the space. Shubham, before we talk about treatment options, can you start us off with the basics when it comes to biliary tract cancers be a intrahepatic extra hepatic colingiocarcinomas and gallbladder cancers. What is ERBB2 mutation? Who are you testing her two for and what classifieds as her 2 positive disease for? You saying all right this is when I'm going to use my treatment options here. Speaker 2 Yeah. Thank you so much for that, Rahul and Rohit. Happens all the time also because again, we are all kind of used to all the hurtus from decades back right when we were in residency hearing about, you know, prosthusumab, pertuzumab and the whole, you know, all these drugs which came out. So coming to biliary tract cancer, again that this concept is developing a little bit. So GI cancer is now the her two positivity. We are testing it in different cancers, obviously biliary tract cancer, gastric cancer, colorectal cancer. But coming to biliary tract cancer, easy answer Rahul, everybody should be tested. So when patients come to my clinic, I do test everybody for her two amplification. And I'll tell you why because let's say you know there was, we have the FG FR2 inhibitors in, in biliary tract cancer folks don't know the FGFR fusion is about 5% of intra hepatic cholangiocarstoma. So not very high coming to her two in biliary tract cancers if you have intra hepatic cholangiocarstoma it can be 5%. If you have extra hepatic cholangiocarstoma it can be 10 to 15% amplification. And if you have gallbladder cancer it can be up to 30% amplification that is high. So when you average it out, it's exactly the way I remember it and I would, you know, have your colleagues remember it is just think about like breast cancer actually Rohit think about 20%. So that's kind of, you know, on on an average that we find her to amplification in ability tract cancers. Now how do we determine who's her to amplified is is the question of the hour. How to determine HER2 amplification in biliary tract cancer So there are two ways that I normally use this is 1. You know, when patients come to me, I do try to send that next generation sequencing for them. And if you have increased her to copy number, that means you have her to amplification by that testing whatever you know, next generation sequencing testing you do, you know, I consider them as her to positive. The second one is the patients who are, you know, when you do the immunohistochemistry, if you do our old test right, you just paint, pathologist just paint on the surface of the tumor cells, you have the immunohistochemistry. If you're 3 plus, you're positive. It's a true oncogenic drive. If you're 2 plus, then you know, if you do the FISH test, which is positive, I consider them positive. But there are nuances to it and I can talk to you about the treatment, about how it differs. But overall, that's how I consider that patients are hard to amplify. But I do test them at the beginning because honestly, if you don't test, you will not find. That's the main thing. So you got to test you know and and honestly like in biliary tract cancer, it is such a target rich disease now you know that you really should be testing for approved agents and for a lot of clinical trials that our patients could be elected before. Speaker 1 Thanks for laying that foundation, Shrubham. Personalized medicine in biliary tract cancer And as you stated it is getting personalized medicine just like lung cancer and exactly is being replicated here in biliary tract cancer given the targeted therapies that we have. We just recently covered lung cancer in her two positive space there we rely on NGS testing and here as you were mentioning Shrubham that you do IHC and then FISH amplification and now do you do this concurrently that will you will do IC testing followed by FISH testing in house and then also send NGS especially when we have limited tissue. Are you prioritizing one over the other at all? Speaker 2 I try to do both honestly, but I do try to get NGS, right, NGS in a way, because what happens is we, you know that in that you can find other targets also, right? So we get, you know, other, you know, other targets also. But I try to do both just to try to know how much it is driven by her. So I try to do both in a way, but the discordance rate is actually fairly low. If you've heard to three plus disease, if you're amplified, you know, again, that data is coming out in biliary tract cancer. But if you're amplified, you have a pretty good chance of being heard to three plus or, you know, the discordance in these trials came was when patients were heard to two plus, which positive sometimes they were not amplified on NGS. So you know, that can be there. But I think if they're amplified, I'm pretty confident that, you know, those patients are going to get benefit from the from the therapy. The approval is not for that. But I'm pretty, I'm pretty, you know, confident that, you know, that is that is that is the case. And we're generating more data as we go along. The thing is that we really don't see so many cholangiocarcinomas in the US. It's a relatively rare disease. So what we're doing is at MD Anderson, we're partnering with, let's say, you know, our Korean investigators, Asian investigators to bring out, you know, data in which we can kind of look at our side and then they can look at their side and we can kind of, you know, compare and contrast those data. Speaker 3 Again, in this global effort, we're hoping that these patients are living longer because of these interventions. So Shubham, now let's say that patient in front of you is indeed her 2 positive in first line. Our option is still chemo immunotherapy, correct? Just being her 2 positive disease is not changing your first line treatment in any way. Speaker 2 It is in a way that because we have these two trials now with Prostasium Abdiracitican, a phase three trial which is you know GEM, GEM Cytopen cisplatin Durvalo map of compared to trastugen of doroxitican compared to TDXD with a with a bispecific immunotherapy. So that's one trial. And then the other trial we have is called Horizon BTCO 2, which is a global trial which combines ZANI data map, which we'll talk about a little bit of new novel bispecific her two agent which is GEMS site of cisplatin Dervalo map with or without Xanadata MAP. So and those trials are available to most centers in the US and they'll probably be within like a 50 mile radius and not more that I think than 100 mile radius towards from any anybody's practice. So those trials are available also in the Horizon BTCO 2 patients can be accrued even if they've received 2 cycles of chemotherapy. So just to make it more practical, right, the patient shows up in your clinic and they're like, you know, Doctor Kussan, I want to start clinic, I will start therapy yesterday, right? Those are our patients, right? We understand that. So you can start the therapy and still send their NGS and if you have AF her to positivity, then you can still enroll on the trial. So we try to make it as patient friendly as possible, as physician friendly as possible. So there are options. But to come to your original point, Rahul, off clinical trial, yes, these agents are after first line setting. So gemcitic insist platinum with a checkpoint inhibitor, whichever 1 you choose. Speaker 3 Well, actually this is a good segue to talk about these agents. So the same patient gets chemo immunotherapy outside clinical trial, now has progressive disease in second line. Second-Line Therapy You mentioned we have trusteds, Mabdurx TCAN based off pan tumor study, recent approval of Zanadaptomab. Then we also have off label trusted mabretizumab. Shubham, can you touch on some of the data here and how are you thinking of that second line treatment decision? Speaker 2 Yes, great question. So when I look at that, so the way you have to look at it, you have to look at four kind of you know not agents but kind of you know kind of for chemotherapy or target therapies that we have seen in different trials. So first one was pertuzumab, but rostuzumab which was done by a trial called Mypathway basket trial and about 30 to 40 patients were with Colangio Karstima, her to amplified were part of that trial and the response rate in that was about 29% with that. And then the second was to cat inhibit trastuzumab and that was presented at ASCO again part of a basket trial again 30 to 40 patients which was the response rate in that was in the 40s, right. So it was about there was a 42% and then you have a 46% and then you have the 3rd and the 4th which are actually approved. So these two are in the NCCN guidelines, perduzumab, transduzumab to catanib, NCCN guidelines part of basket trials. Third basket trial was the DESTINY trials that you were talking about which was a basket trial for trostuzumab diroxitican, the patients who had her 2/3 plus disease. Again, it was about, you know, the, the cohort was like 30 to 40 patients. Again, patients who are her 2/3 plus disease had a 56% response rate. Again, these are refractory patients. That's that's, that's amazing considering if you feed the full Fox, that's a 5% response rate in the phase three trial. So 56% response rate. And then the newest get on the blog Zani data map, which is a very interesting agent. It's a bispecific her two agent, which binds to something called ECD two and four, so extracellular domain two and four of of the her pathway and it leads to better binding by doing that and it better receptor internalization, better target engagement with that. And that trial was a unique trial because it's it's the only biliary tract cancer focused trial. So it was a global trial. It was in 32 sites across 4 continents. 80 patients were enrolled who are her two amplified. That means they're either her 2/3 plus or two plus ish positive, which was inside the hybridization positive and that the response rate for the whole cohort was about 42%. But when you look at the her 2/3 plus it was 52%. The interesting thing about that study which I which I found was and you know, I was involved in the study for disclosure is that patients had this duration of response. That means once you started getting a response, those patients the duration of response was 14.9 months. And for refractory disease that is like the median overall survival for patients with her 2/3 plus disease on that study was 18.1 months. It is like you know, and honestly the way I look at her two disease and biliary tract cancer, I look at it like breast cancer, it seems to be a little bit more aggressive disease because gallbladder cancer is actually a lot more aggressive than intra hypedicular angio and extrapedicular angio. They're very different diseases. So gallbladder cancer, you want to hit them hard, hit them fast because it's a very those cells rapidly divide. Intra hypedicular angiocarism is a little different. So I think some of it this is also hard to hard to driven that if you have hard to possibly you can have a worse prognosis just like we had in breast cancer, but we don't have that big data of breast cancer. Speaker 1 Well, thanks so much for covering that. And we know that there are multiple options as you stated trip them. So patient shared decision making is the key one. We have to keep side effects in mind and patient comorbidities in mind. Something to address. With regards to zanadetamab, even though this is a BI specific, it is certainly not engaging our T cells or B cells. The Role of T Cells in Cancer Therapy As a result, it does not 'cause cytokine release syndrome that we've seen with some of the bispecific hematological agents or even with tarlatumab in small cell lung cancer, though we could see infusion reactions, but often not severe. Speaker 2 You're, you're 100% right, Rohit, and sorry to interrupt you. So which people don't understand, it's called a bi specific. It's actually something called a biparatropic. I won't go into that, but it's actually should be called a biparatropic, but I think it's too like wonky for people to understand that. So, but it's, it is, you're right. It's not tied to like a CD3 agent that's going to cause CRS. Main side effects that we saw was Zanadata map were actually diarrhea. So actually I started a patient yesterday on zanadata map. So we just educated them, gave them Imodium to take home. Hey, if you get diarrhea, you get fluids, let us know you know how things, let us know how things go. So that's the main thing. Infusion reactions very rare, but you have to premedicate the patients with Benadryl and steroids and I also give them Pepcid. And then that infusion reaction I think does greatly was like 1%. It was, it was, it was, it was fairly, fairly low. So yeah, they differ according to the side effect profile. So it's, that's a really important point. Thank you for bringing it up. Speaker 1 There's certainly favorable side effect profile, but with regards to TDXD, at least as a community and call it just because of these bucket approvals, we have a bit more experience, though 1 still has to keep in mind nausea, vomiting, fatigue, cytopenia is at the end of the day, it still has some chemotherapeutic side effects. Something very important is the ILD, which is associated with mortality. We will dive into more into the side effect profile with Doctor Rashna Shraf into our next episode. What's more important here, Shubham, is sequencing. Sequencing How are you planning with regards to that, using zanadatamab first and then keeping TDXD or TDXD first and then zanadatamab and another one? Are you doing her 2 testing when the patient progresses? Speaker 2 Great question. Keep the best for the last. So so the way we don't know that honestly, that's the honest answer after frontline therapy, you can use either. I think both are great agents. Any data map or transfers? Remember oxytocin? I'll tell you how I made that choice in this patient of mine that he got gems is Derva. And then you know, because the trouble was he didn't have tissue and you know, we kept on sending tissue. We didn't. So I re biopsied him. I start him on FOLFOX, re biopsied him and then I got my heart to amplification. OK. And like literally 2 months, he's gall bladder cancer two months and then he progressed on FOLFOX. But the issue is he's having like the side effects of chemo. He's having fatigue, tiredness and things. So for him, I chose Xanadata map. There's you know that, you know, I've had a lot of decent experience with it and it's just kind of, you know, patients don't get like the chemotherapy side effect because it's just kind of, you know, it's just binds to these two ECD two and four. So it's fairly well tolerated because I just you know, trusters or directed can. I haven't given it because I do mostly I have given it to number of people, but in the ability track concept, because I don't treat other, you know, other than GI cancers. I just feel like the patients do get the side effects, like I've had, you know, nausea and you know, so they feel like they're on, they're on chemo essentially. So just keeping the ID aside, they still feel it. So fatigue, nausea, things like that. So I, I chose that for him. But if a patient like breathes through chemotherapy is doing great, I could, I could just transfer them to Rexitican for them. I think it's a, it's a appropriate choice. Now, if they progress this patient progress on ZANI data map, then I'm definitely going to biopsy, rebiopsy or send the CTD in it to see if that amplification is still there to before I treat with the next agent, which probably is going to be transferred drugs again, if the patient is you know, but there is no data for that in biliary tract cancer. But I'm extrapolating that from gastric cancer where you know, once they've had transfusumab before you give them her to target agent second line, you want to retest them essentially. So I'm going to do that. Not a lot of data for that, not enough patients, but that's how I choose. I really look at the patient and if they're getting those chemo toxicities that try to give them a kind of a little bit of a break. Because honestly, you know, it's, it's just nine data map is just, you know, doesn't does not have those side effects, but you know, either 1 is fine. I think so. Speaker 3 If I'm coming back to your clinical trials that you brought up, once these agents are available in first line, this sequence is going to be more and more important because we want to make sure these patients are exposed to these active agents before we close. You had also said that her 2 ends up being more aggressive disease. Surveillance brain MRI in HER2 positive cancer When we're talking about her 2 positive cancer, we often worry about intracranial disease. We've seen this in breast cancer, colorectal cancer, lung cancer. What about biliary tract cancer? Any role of surveillance brain MRI in these patients? Is the incidence high even in biliary tract cancer? Speaker 2 The the the tragedy has been that patients don't live long enough, you know, so you need to live long enough for let's ability of pancreatic cancer to really great get the brain metastases, which is true for breast cancer and for lung cancer and for other cancers. So we want to change biliary tract cancer into a more like in a way, chronic disease, as we call it with breast cancer and such be there. They've been anecdotal reports of patients showing with brain metastases, but honestly, it's not very common, but I hope to. I mean, I don't have to see brain, but I see more. But what I'm saying is our patients live long enough and we we can know if that develops or not. They have been anecdotal reports of brain metastasis showing up. But honestly, in my practice and I see quite a few biliary tract cancers. I can't remember the, you know, last patient who got a brain metastasis. It's just, it's just rare still. It's rare just because of median survival again, 12 months. But I know we are pushing the envelope. So you know, here's hoping, you know, for for that patients do stay on these drugs for longer and have longer progression free survival and run longer overall survival. Speaker 3 You know, we've covered a lot here. The biliary tract cancers we're looking for these actionable mutations and biomarkers that's driving our treatment decision is very important. Shubham, thanks for covering the data for Destiny Pantumor for TDXD, Horizon, BTCO, One for zanidatamab and our other available options for her two positive biliary tract cancer. To our listeners, thank you for joining us. Make sure to check out our next episode where we touch on side effects and management of these available options in her two positive space. We are the oncology brothers.