FDA Approval of Zanidatamab - HERIZON-BTC-01 Discussion with Dr. Shubham Pant

Intro Welcome back to the Oncology Brothers Podcast. I'm Rahul Ghosane here with my brother and Co host Rohit Ghosane. In the last three months, we've seen close to 10 new approvals or indications in hematology and oncology. And as a community oncologist you need to be up to date with all these recent advances. Today we're focusing on one of these FDA approvals, zanadatamab, a bispecific her two antibody, which is now indeed approved for her two amplified unresectable locally advanced or metastatic biliary tract cancer. To help us unpack this approval based off Horizon BTCO One study, we're joined by Doctor Shubham Pant, AGI, Medical Oncologist at the MD Anderson Cancer Center, who is also one of the authors in this study. Shubham, thank you so much for taking the time to be with us today. Speaker 2 Thank you for having me. Speaker 3 Shubham, welcome. Before we dive into Horizon BTCO One, it is important to lay the foundation off biliary tract cancer which mainly comprises of intra hepatic, cholangio, extra hepatic and gallbladder, which makes about 1% of solid cancers and in advanced metastatic settings. Horizon BTCO-1 study design We were utilizing gemcitabine and cisplatin until recent approvals of dirvalumab and pembrolizumab and now we are doing the triplet regimen. Looking for an actual mutation is very critical in this particular disease because it certainly opens up more doors for our treatment. This subset of patients that we are here talking about today is hard to positive. In April 2024, we saw a bucket approval of TDXT, which is mainly for all solid malignancies. Now for biliary tract cancers, we have zanadatamab based off of this particular study. Shubham, can you please with this background go go through the study design and the patient characteristics? Speaker 2 Thank you for that. You you said the right thing. What happens in biliary tract cancer is you have to do the next Gen. sequencing because if you don't look, you won't find we have her do now as a valid target, FGFRID, H1, obviously different validated targets. So it's very important to look. That's the first thing now coming to this trial. It's a very interesting drug. It's actually has something called a biparotropic drug. So it's not a classic bispecific that gives you CRS or any issues like that. It's also called a biparotropic drug. It binds to two domains on the her two ECD 2 and ECD 4 and that's similar to what rostuzumab, pertuzumab bind. But just having two drugs in one improves the response rate the compared to historical controls because it has better receptor internalization. So there's preclinical data that it has better receptor internalization and maybe the effectiveness of the little bit more, we never know the clinical, right. We can't do a randomized control trial in this rare setting. But I can tell you it's a very unique drug. So this was born out of a phase one trial that we did a basket phase one trial in at MD Anderson. We actually saw early responses in a few of our patients. It was really amazing these bili tract patients, especially gallbladder cancer, her two amplification is different amongst biliary tract cancers. It's very heterogeneous. So if you have extra hepatocalangiocorphism is different than intra hepatocalangiocorphism is different than gallbladder cancer. So gallbladder cancer can have about up to 30% her two amplification intra hepatics less 5 to 10%. So really should be testing these patients. We saw a response early in the gallbladder patient had a great response. It went pain free. And then we developed this global phase two trial, which we launched a few months before COVID hit the world. That's challenging, but we still enrolled this trial and screwed a global trial across 4 continents. And essentially this was for patients with biliary tract cancers advanced as you said, who had failed at least one line of prior therapy. They got the single agent bipartitropic bispecific, her two antibody IV every two weeks. We looked at the overall response rate as a primary objective. Interestingly, we had two cohorts, 1 cohort was was her 2 zero and one plus on IHC. All the patients were ish positive inside to hybridization positive. The second cohort we reported was her 22 plus or three plus and her 201 plus. We really didn't see a lot of responses, 7 patients known as safety signals. We did not follow through with that coord. What we reported were the 80 patients on this, her 22 plus and three plus cohort got this done in 2-2 years. Speaker 1 These are exciting times for our patients. And just a few things to reiterate what you mentioned, this is not the most common malignancies we see in our clinic today, just about 1%. But testing for her 2 is important not only for biliary tract. Here we're seeing that 30% of gallbladder patients have her 2 positive disease, but just now with these bucket approval that is so critical. So boom, can you share the key findings from the study? Key Findings from the Global Phase II Trial Yes. Speaker 2 The key findings word, you know, so this again, you know first was overall response rate. So to give your listeners a historical kind of unselected concept, if you have unselected patients, the trial tested full Fox worst is best supportive care. And the response rate was about 5% of the unselected population in this population, you know, I was expecting, hey, it'll be better than that. But when we saw the results, it was about 41 percent, 41.3% to be exact. And that's one part of it, Rahul. But the important thing is, you know, so let's say in our practice, a patient has a great response, more than 30% decrease in recessed lesions and then you do the scan next time, right? So two months you do a scan looks great, you high 5 the patient, this is great. The patient comes in next time and they've already grown, right? So it's not about getting that response, but maintaining that response, right? That's important. The important thing in this was when we first reported this in ASCO last year, the duration of response was 12.9 months. This year when we reported the results, the duration of a response actually came up, it was 14.9 months. So you know, so response rates, we are seeing high response rates with her two targeted agents in BTC, but this is one of the unique ones that we can't across trial comparisons, the small numbers, this is unique because the duration of response was that once that patient got that response, they kept on going on this response at Anderson, we still have one patient who actually went two years, right. So it says trial is 2 years still getting a response. It's about that ongoing response which was exciting. And again, an important thing is the approval is in her 2/3 plus. So we did her 22 plus and her 2/3 plus the response and her 2/3 plus were even higher. They were close to 52%. Her two plus were 5%. You've got the response, but I think the duration response. I think as a clinician, that's what really excites me. Speaker 3 Oh Shavam, congratulations on this word because this is an additional therapy that is added to our back pocket now. How to sequence HR2 positive cells It is exciting to see lot of this hard to space getting crowded with. The question is going to be how to sequence them. But before we dive into that, it is important to understand how we even define her 2 positive space. As you stated the response do differ. In breast cancer, we tend to be relying on IHC 3 plus or two plus fish amplified. For lung cancer, we've seen most activity with her two mutation and TDXT bucket approval and Zenadatamab approval is on IHC 3 plus. Though I wouldn't be surprised if at least in community or outside of FDA approvals or FDA labels, we are still utilizing these drugs because these patients are associated with poor prognosis. Speaker 2 One thing I forgot to mention was this was only trial with her two amplified BTC specifically for that indication. The rest more basket trials, all of the results are great. So I think it's more options for our patients whether it's ADC antibody like like Xani, any other trials. So I think that's the exciting part as you're showing here, the median overall survival for IC3 plus was 18.1 months. That's that's, that's pretty cool. But you're right. I think the main thing is, I mean, breast cancers went from IC3 plus to IC0 or do low, low, low, Yeah, for ability drag cancers when you look at it, it's mostly seems to be driven by her to three plus. So testing the IHC is important. Now the important question is like a lot of the times folks don't do IC right. You do the NGS and it shows amplified. Now what do you do about the approval is not for that, but I'm guessing if you're her to amplified with one of the clear certified tests chassis your her 2/3 plus you know that concordance could be there though we have to know we're looking at. Speaker 3 Our. Speaker 2 Data set in this trial to really look at the biomarker and see how that matches up. So I think that's another important fact when we do it, it's a rare disease, right? We don't have so much tissue in this, unlike breast cancer. We have sometimes a little bit of FNA. It's a little bit harder in this, but I think if you're hard to amplify it on an NGS test, right, I think you should definitely do the IHC. There could be a good concordance between the two, but you should do the IHC and all your patients because of all this, because of you know prosthesma barracks began because of zanadatumab approval. So I think you know you should do that because it seems to be driven on that IHC 3 plus side the benefit lot of the benefit. Speaker 1 Absolutely when the community we're so used to NGS. But at the end of the day her 2 is available in house IHC. I don't have to wait for that NGS. The quick turn around is also something we have to keep in mind for these in house testing, right? I know you briefly touched on this, but let's talk a little more of sequencing, especially when it comes to her 2 positive disease in community as breast cancer or when I'm treating that. We sequence her two agents from the get go, right? And we've seen the similar paradigm in upper GI. That was not the case. But now her two agents are used up front. Then at the time of progression, we're still pushing for more her two agents for biliary tract cancer. Shubham, would you use anadatamab and then still consider TDXT or vice versa for these her 2 positive patients? Anadatamb vs TDXT for biliary tract cancer Great question. First of all, I don't know how you guys do it, man. I don't know how you guys see a lymphoma, then a breast cancer, then a pancreatic, then a colorectal. It's a good thing, right? But it is tough. So I'm glad there are folks like you who are providing all this information. This is so, so very commendable. So I'll tell you they're two different things. I'm going to take the two common ones, right, Trans Tuma, Drugstican and Zanadata map. Obviously, you know my conflict of interest. I've shown the slides and everything. I was one of the main global Co chairs of this trial. And so I've used this drug. Zanadata map has not been approved for anything else. So folks haven't used it, right? But I can tell you in use, diarrhea is the main side effect, but it's controlled by Imodium. I have to keep a check on that. But it's not like arena tic and diarrhea. It's actually easier to control. There was infusion reaction, but everybody gets pre medications now. After that we really didn't see a lot of infusion reactions, did not see pneumonitis. One patient had a kind of toxicity which was a pulmonary toxicity, but not a high rate of pneumonitis. So it's actually for these patients, you know, who really get going. It's a very well tolerated. You just keep on giving it like, you know, when I had this patient on this trial and everything, it read a number of them in the phase one setting, right in the basket setting in which we did have breasts and others in this trial. It's it's it's for me, you know, it was a honestly remarkably easy drug to get because it just really did not have any serious side effect. There were some patients where the EF lower, but even that if you followed, it was not any more than, let's say trostuzumab that I had to really worry about. I didn't have anybody in my small cohort that really I had that issue. But I think it's a it's an incredibly well tolerated drug overall for my ADCUSI can tell you I don't treat breast cancer and I used to treat in my previous life. But you know, for me, the ones I have used edxd and it's a really good drug. It does have side effects associated with that. When I tell patients, I say it's most like starting chemo, they've just come of gemsis, durvalumab. So they're a little beat up. That's my consideration. If you've used it a lot, it could be muscle memories. You guys are probably better at it than me. For me personally, I would maybe give them zanadatamab because I think it would give them a chemo break. And then if I feel that I still feel like I have that punch with ADCI think that patients can stay on biliary tract cancer is not like pancreatic cancer. These patients can stay on to get multiple lines of therapy, especially if her two directed therapy. So I think, you know, my thought for me, would we give ZANI then if the progress give trusted or directed to can. But if you do it the other way, that should be fine. Also, that's my thought about sequences, giving them a break from chemo, seeing this agent. I still have something in my back pocket to give, but depends on how you've used it, who's used it. I think once folks start using Zani, it's not a top drug to use. It's a bispecific. There's no CRS or anything. So it's not like ACD 3 linked compound. So I think that's kind of my heart over of doing sequencing. But I encourage everybody to do what they feel comfortable with, right, because both the drugs great options for our patients. Speaker 3 Certainly, TDXD has great responsiveness. We are certainly used to it because of utilizing in breast cancer space and other bucket approval. However, we cannot undermine the mortality that is associated with ILD with TDXD. Certainly we will get used to zetidatamab Now touching importantly for the side effect profile as you stated, infusion related reaction diarrhea. Infusion-related reactions In terms of those reductions or dose interruptions, how do you manage some of the important clinical pearls, at least from community oncology standpoint that we need to be aware of? Speaker 2 I really didn't have to interrupt anybody, most of my patients came off after some time for progression of disease. But as you can see you won't do it for infusion related reactions. And look at the great trees. 1% essentially if you pre Med them, they're really not going to have that for the confirmed cardiac can be stopped and everything, but it would be a rare phenomenon. One more thing about the ADC is the toxicity profile could be different in different malignancies. So coming back to the first question, the tox profile could be a little different in biliary because I've seen a lot more fatigue than I've heard happens with breast cancer. So again, coming back to that original point of like maybe works differently in different malignancy. Speaker 1 And again, one thing to mention that about TDXD, yes, a lot of the discussion around that ends up being ILD, but nausea, fatigue, alopecia are big things that we have to worry about. Shaboom. What should be on our radar for this drug in community settings in the near future? Before we close, this was an accelerated approval I take. There are larger studies on its way. What should be on our radar for this drug in the community settings in the near future? Any combination trials? Speaker 2 Yes, and that's the main thing, right? There's the axle approval single arm study. So we have already launched another global trial in America specifically in the frontline setting. So again, that tells you about the combination of this drug, right? We're combining it with GEM, SIS and Derva, Pembro with or without this drug. So I'm telling you that's why on single agent think about combining other agents like GEM, SIS, Derva or pembroids. That's a little challenge. But similarly as you do in the upper GI, you do the combi combination and everything with the checkpoint and with Pembro with Falfox and then you have constitutumab, kind of the similar concept. So that global trial as much as the frontline setting. But we did recognize that patients show up and then you want to get started, right? You don't want to wait for things. What I would recommend is especially for all the community and colleges, if you have a patient with biliary or tract cancer, just do an IT on them. The trial is run globally, multiple centers, there'll be a center near you. If you don't have it, you can actually give up to two cycles of chemotherapy with immunotherapy before add the drug on basically. So it's a unique design, but we did it because it's a rare patient population. We really didn't want to miss any patients. We think moving it early will really improve those outcomes for these patients similarly as it's done in upper GI. But if you don't test, we won't find. I would really encourage your colleagues and folks in the community, especially Gallbladdis can be up to 30%. You know, do test that. Just do a quick ISC. As you were saying, if you're not running the trial, there's probably the center very near you. In the US, we tried not to have more than 100 mile radius, you know, to not to have a center probably be a center near you. You know who is, who has the trial going and they can even join after the first two cycles. So it gives a six week kind of window to enroll that patient onto that trials. Speaker 3 Both certainly exciting times and the key takeaways as you mentioned that should be is that IHC positivity is the key and one should be testing for it and other is that biliary tract cancer as we've stated that it is not common. So utilizing the need for tertiary care center multidisciplinary approach and getting them on the right clinical trial is extremely important. Doctor Pon, thank you so much for sharing your expertise and thoughts on this recent approvals and study led by you and your colleagues. Zenidatamab is now approved for her 2 positive biliary tract cancer based on Horizon BTCO One study for listeners. Let us go or a quick recap. Speaker 1 In our discussion today with Doctor Shubham Punk from MD Anderson Cancer Center, we had a chance to discuss the recent accelerated FDA approval of zenidatamab in her two amplified locally advanced or metastatic biliary tract cancer, the Horizon BTCO. One study that led to disapproval showed an overall response of 41% and a median duration of response of 14.9 months. Speaker 3 With bucket approval for TDXD and now Zenadatamab, HER 2 testing should be considered for all advanced biliary tract cancer patients with Zenadatamab. It is important to keep diarrhea and fusion related reactions in mind. Thanks for joining us. Make sure to check out our other discussions around conference highlights, treatment algorithms, recent FDA approvals and talks. Check for these approvals. We look forward to seeing you at GI ASCO 2025 in person.